research article on immunotherapy

• Open access
• Published: 19 June 2019

Advances in cancer immunotherapy 2019 – latest trends

• Stephan Kruger 1 , 3   na1 ,
• Matthias Ilmer 2 , 6   na1 ,
• Sebastian Kobold 3 ,
• Bruno L. Cadilha 3 ,
• Stefan Endres 3 ,
• Steffen Ormanns 4 ,
• Gesa Schuebbe 1 ,
• Bernhard W. Renz 2 , 6 ,
• Jan G. D’Haese 2 ,
• Hans Schloesser 5 ,
• Volker Heinemann 1 , 6 ,
• Marion Subklewe 1 , 6 , 8 ,
• Stefan Boeck 1 , 6 ,
• Jens Werner 2 &
• Michael von Bergwelt-Baildon 1 , 6 , 7 , 8  

Journal of Experimental & Clinical Cancer Research volume  38 , Article number:  268 ( 2019 ) Cite this article

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Immunotherapy has become an established pillar of cancer treatment improving the prognosis of many patients with a broad variety of hematological and solid malignancies. The two main drivers behind this success are checkpoint inhibitors (CPIs) and chimeric antigen receptor (CAR) T cells. This review summarizes seminal findings from clinical and translational studies recently presented or published at important meetings or in top-tier journals, respectively. For checkpoint blockade, current studies focus on combinational approaches, perioperative use, new tumor entities, response prediction, toxicity management and use in special patient populations. Regarding cellular immunotherapy, recent studies confirmed safety and efficacy of CAR T cells in larger cohorts of patients with acute lymphoblastic leukemia or diffuse large B cell lymphoma. Different strategies to translate the striking success of CAR T cells in B cell malignancies to other hematological and solid cancer types are currently under clinical investigation. Regarding the regional distribution of registered clinical immunotherapy trials a shift from PD-1 / PD-L1 trials (mainly performed in the US and Europe) to CAR T cell trials (majority of trials performed in the US and China) can be noted.

The importance of immunotherapy has been acknowledged by the Nobel prize for physiology or medicine 2018 awarded for the discovery of cytotoxic T-lymphocyte-associated protein (CTLA-4) to James P. Allison and programmed cell death protein 1 / programmed cell death protein ligand 1 (PD-1 / PD-L1) to Tasuku Honjo [ 1 ]. Malignant tumors take advantage of the inhibitory PD-1 / PD-L1 or CTLA-4 pathways to evade the immune system [ 2 ]. Disruption of this axis by blocking monoclonal antibodies can induce durable remissions in different cancer types and has led to numerous FDA and EMA approvals, among others, for the treatment of melanoma, lung cancer, urothelial cancer, head and neck squamous cell carcinoma (HNSCC), renal cell cancer (RCC) and Hodgkin’s disease [ 3 ]. Up-to-date reviews providing a comprehensive overview of approved indications for different CPIs have been published previously [ 3 , 4 ].

This review focuses on clinical and pre-clinical findings that might guide future clinical application of CPIs in general. We identified potentially trendsetting studies on CPIs for combinational approaches, perioperative use, new tumor entities, response prediction, toxicity management and use in special patient populations. Further, we identified studies focusing on efficacy and toxicity of anti- CD19 CAR T cells in larger patient cohorts as well as seminal findings on adoptive T cell therapy in other hematological and solid malignancies.

Checkpoint inhibitors

Combinational therapy

Combination with chemotherapy.

Traditionally, chemotherapy and radiotherapy were believed to mediate their anti-cancer effect by direct killing of cancer cells. This concept was challenged over a decade ago by Zitvogel and co-workers who discovered that the antineoplastic effect of chemotherapy, in part, depends on the immunogenic cell death of cancer cells. This leads to immune stimulatory signals via activation of the innate immune system through pattern recognition receptors such as toll-like receptor 4 (TLR4) [ 5 ]. Different studies confirmed the immunological effects of chemotherapeutic drugs, in particular, platinum-based agents, and paved the way for the development of combinational regimens using PD-1 / PD-L1-blockade together with established chemotherapeutic drugs [ 6 , 7 , 8 , 9 , 10 , 11 ]. Last year saw the completion of several practice-changing phase III trials showing the efficacy of combining PD-1 / PD-L1-blockade with chemotherapy in small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), HNSCC and breast cancer [ 12 , 13 , 14 , 15 ]. Currently, more than 170 studies are investigating the promising combination of PD-1/PD-L1 blockade plus chemotherapy in different cancer entities [ 4 ].

Combination with radiotherapy

Anecdotal reports on systemic anti-tumor response after irradiation of a single tumor lesion date back more than one century [ 16 ]. Regression of non-irradiated lesions after localized radiotherapy of a single lesion was first termed ‘abscopal effect’ in 1958 [ 17 ]. The underlying mechanism remained unexplained for a long period and it took almost another 50 years, before Demaria et al. concluded that “ Ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune mediated” [ 18 ] . Nowadays, the causative link between local radiation, immunogenic cell death and systemic tumor response is well-established [ 19 ]. While the abscopal effect remains a sporadic event, numerous strategies are now under investigation to harness the immunogenic effect of radiotherapy [ 19 ].

Given the clinical success of checkpoint blockade, combining radiotherapy with PD-1 / PD-L1 blockade is of special interest. Pre-clinical evidence highlights the synergistic potential of this combination [ 20 ]. Translational results from an ongoing phase I/II trial (NCT01976585) investigating local radiotherapy in combination with local application of immunostimulatory agents in patients with indolent lymphoma further support the combination of radiotherapy and PD-1 / PD-L1 blockade [ 21 ]. In this trial, patients received 2 Gy of local radiotherapy as part of a so-called “in situ vaccination” (ISV: radiotherapy plus intratumoral application of Fms -related tyrosine kinase 3 ligand [Flt3L] and a Toll-like receptor 3 [TLR3] ligand). ISV was able to induce systemic (“abscopal”) tumor regression in three out of eleven treated patients. Importantly, in non-responding patients, the induction of tumor infiltrating PD-1 + CD8 + T cells was observed, prompting a follow-up trial, which is now recruiting patients for ISV in combination with PD-1 blockade (NCT03789097).

Despite these encouraging findings, negative results for the combination of radiotherapy and checkpoint-blockade have also been recently reported. In a phase II trial in metastatic HNSCC, the addition of local radiotherapy to systemic PD-1 blockade was not able to boost the effect of PD-1-blockade. Here, patients were randomized to receive either nivolumab monotherapy or nivolumab plus stereotactic body radiation therapy (SBRT) of a single tumor lesion. The primary study endpoint - response rate in none-irradiated tumor lesions – was not met. Response rate in patients receiving nivolumab plus SBRT was 22.2% (95% confidence interval [CI]: 10.6–40.8%) versus 26.9% (95% CI: 13.7–46.1%) for single agent nivolumab [ 22 ].

The placebo-controlled, randomized phase III PACIFIC trial investigated the addition of durvalumab (anti-PD-L1) to platinum-based chemoradiotherapy in locally advanced (stage III) NSCLC. The addition of durvalumab resulted in an impressive increase in progression-free (PFS) and overall survival (OS) (17.2 versus 5.2 (PFS) and 28.7 months versus “not reached” (OS), respectively) [ 23 , 24 ]. In this context, the timely administration of PD-1 blockade appeared to be important: patients receiving durvalumab within 14 days after completion of chemoradiotherapy had a better overall survival than patients starting durvalumab-treatment at a later time point [ 25 ].

While recent results encourage further in-depth investigation of checkpoint blockade plus radiotherapy, successful concepts might depend on additional combination partners like the above-mentioned in situ-vaccination or chemotherapy. Additional well-designed clinical trials are necessary to identify optimal strategies for combinations and treatment sequences.

Combination with immunomodulatory drugs

The first CPI approved for clinical use was ipilimumab, targeting CTLA-4. Given the success of ipilimumab and the even greater success of PD-1-blockade, it is not surprising, that - with more than 250 clinical trials - the combination of PD-1 and CTLA-4 blockade is the most vigorously investigated combinational approach of two immunomodulatory drugs [ 4 ].

Due to the large number of clinically approved immunomodulatory agents (currently more than 25) and many more in pre-clinical and clinical development, there is an almost infinite number of combinatorial regimens for further clinical evaluation. In this regard, it is important to note, that the combination of two immunomodulatory drugs can also have antagonistic instead of synergistic effects [ 26 ]. Wise selection strategies based on pre-clinical data to select combinatorial approaches for clinical testing are important [ 26 ]. In light of this, Tauriello et al. provided an example for an elaborate pre-clinical model system. By using a quadruple mutant colorectal mouse model, they were able to recapitulate important immunological hallmarks of microsatellite stable colorectal cancer (MSS CRC) [ 27 ]. While PD-1 / PD-L1 blockade showed only marginal efficacy in this setting paralleling results of clinical trials with PD-1/PD-L1 blockade in MSS CRC, impressive effects were achieved when PD-1/PD-L1 blockade was combined with inhibition of transforming growth factor beta (TGF-β) [ 27 ].

Building on pre-clinical and early clinical data for simultaneous targeting of CD40 and PD-1 / PD-L1 in pancreatic cancer (a disease for which all immunotherapeutic efforts have failed so far), a phase I trial investigating the combination of CD40, durvalumab and chemotherapy was initiated. The promising results were recently presented at the annual meeting of the AACR (2019), making this combinational strategy one to keep track of in the years to come [ 28 , 29 , 30 ].

Peri-operative use

Up to now, the clinical use of CPIs has been mainly restricted to advanced tumor stages. Yet, efficacy of checkpoint blockade has been reported to be dependent on baseline tumor burden (with better efficacy observed in patients with low tumor burden), making peri-operative usage of checkpoint blockade an attractive treatment option from a theoretical point of view [ 31 , 32 ].

Although ipilimumab was approved for the adjuvant treatment of melanoma patients by the FDA (but not by the EMA) based on a placebo-controlled phase III trial reporting superior recurrence-free and overall rates, its use was internationally disputed given the relatively high frequency of serious immune-related adverse events in patients receiving treatment with ipilimumab [ 33 , 34 , 35 ]. In Europe, nivolumab was the first checkpoint inhibitor approved for adjuvant treatment of melanoma patients, based on results of the CheckMate 238 study reported in 2017 [ 36 ]. In this study, nivolumab was compared to ipilimumab as adjuvant therapy for patients after resection of stage III-IV melanoma. Recurrence-free survival was reported to be superior while severe adverse events were significantly lower in patients treated with nivolumab (12-month recurrence-free survival: 70.5% vs 60.5%; grade 3 or 4 adverse events: 14.4% versus 45.9% for patients receiving nivolumab or ipilimumab, respectively).

A logical next step to consider would be neoadjuvant use of CPIs. Theoretically, neoadjuvant immunotherapy might be able to prime systemic immunity for tumor surveillance after complete resection – at a time point when tumor antigens are still abundantly present [ 37 ]. This concept is supported by recent translational findings from an early clinical study in patients with resectable melanoma: in a randomized phase Ib study, neoadjuvant treatment with nivolumab and ipilimumab induced a higher number of tumor specific T cell clones than adjuvant treatment [ 38 ]. Early clinical findings reported from patients with NSCLC, HNSCC and microsatellite unstable (MSI) CRC further emphasize the high potential of neoadjuvant treatment [ 39 , 40 , 41 ]. In the latter study, seven out of seven patients with MSI CRC (100%) responded to neoadjuvant treatment with complete remissions observed in 4/7 (57%) patients [ 41 ].

A large number of clinical trials is currently investigating neoadjuvant immunotherapy for different disease entities (for example, we identified nine clinical trials for neoadjuvant anti- PD-1 / PD-L1 treatment in NSCLC: NCT03197467, NCT02938624, NCT02259621, NCT03694236, NCT03732664, NCT02994576, NCT03030131, NCT02716038, NCT02818920). Given the considerable side effects of checkpoint blockade – particularly, if administered as combinational therapy - wise selection of patients that might benefit from neoadjuvant or adjuvant treatment is mandatory. One possibility for adjuvant treatment stratification might be detection of minimal residual disease (MRD) by circulating tumor DNA (ctDNA), a strategy, that is currently investigated by a clinical trial in triple-negative breast cancer (TNBC) (NCT03145961) [ 42 ].

New tumor entities

Current studies show the efficacy of CPIs in patients with malignant melanoma (MM), NSCLC or neoplasms with mutational defects in DNA mismatch repair proteins (micro satellite instability or MSI) independent of the actual tumor entity. Intriguingly, all of these tumors share a relatively high mutational load when their genetic characteristics are comparatively analyzed [ 43 ]. This common characteristic leads to increased expression of neo antigens in the tumor, stimulating an increased infiltration of the tumor by immune cells, which in turn can be “ activated ” by CPI administration. This fact can also be used to explain why CPI studies in certain tumor entities (among others pancreatic ductal adenocarcinoma (PDAC) or colorectal carcinoma (CRC) without DNA mismatch repair protein defects) haven’t been successful as of yet.

On average, breast cancer and AML are also characterized by a low mutational load [ 43 ]. With that background, two remarkable studies from 2018 should be mentioned here in more detail. On the one hand, the phase III trial IMpassion130 tested the combination of atezolizumab (anti-PD-L1) plus nab-paclitaxel versus nab-paclitaxel monotherapy in treatment-naïve patients with metastatic, triple-negative breast cancer (TNBC). The addition of atezolizumab not only improved the patients’ PFS (PFS), but also their overall survival (OS) [ 14 ]. For patients with TNBC, this was the first phase III study that showed a strong benefit of targeted (immune) therapy. A total of 144 studies on PD-1 / PD-L1 blockade in TNBC are currently registered on clinicaltrials.gov (Fig.  1 a).

Included tumor types ( a , b ) and regional distribution ( c ) of clinical PD-1 / PD-L1 and CAR T cell trials in 2019. ClinicalTrials.gov was searched for “pd-l1” OR “pd-1” OR “programmed death ligand” OR “car t cell” OR “chimeric antigen receptor”. All registered trials were sorted for tumor type and country/region. Search was performed on 2019-05-06. Most frequent tumor types ( a , b ) and regions ( c ) are shown as indicated. Several clinical trials included multiple tumor types or were performed in more than one country/region. Abbreviations: GI: gastrointestinal, HN: head and neck

On the other hand, for AML, data on nivolumab maintenance therapy in high-risk AML patients was presented at the annual meeting of the American Society of Clinical Oncology (ASCO) in 2018. This study investigated whether the administration of nivolumab might prolong the time of complete remission (CR) in patients that do not qualify for an allogenic stem cell transplantation. In 14 patients that were followed-up for a median of 19.3 months, the median duration of CR averaged 8.3 months, whereas the median OS had not been reached at the time of presentation of the data. Despite the very limited number of patients, this study shows an exciting treatment concept for this specific treatment group [ 44 ].

In conclusion, both studies exemplify that successful CPI concepts might also be feasible for tumor entities with a low mutational load. Numerous clinical trials are currently investigating the use of CPIs in different cancer entities (Fig. 1 a). It will be interesting to see whether further positive results for tumor entities with low mutational burden will follow in the future.

Biomarkers for response prediction of checkpoint blockade

Determination of PD-L1 expression by immunohistochemistry is an FDA-approved diagnostic test and a prerequisite for treatment with anti-PD-1 / PD-L1 therapy in various indications (e.g. monotherapy treatment of urothelial cancer with atezolizumab or pembrolizumab). However, determining PD-L1 expression does not identify all patients that profit from anti-PD-1 / PD-L1 therapy, highlighting the need for additional and better biomarkers [ 45 ].

Tissue biomarkers

Microsatellite instability and tumor mutational burden.

Another approved biomarker test (for pembrolizumab) is the determination of microsatellite instability (MSI) or deficient mismatch repair (dMMR). Pembrolizumab was the first drug that was FDA-approved with a “tumor-agnostic” indication based on findings from five different clinical trials including 15 tumor entities with MSI/dMMR tumors (KEYNOTE -012, − 016, − 028, − 158 and − 164). MSI/dMMR results in increased tumor mutational burden (TMB) with subsequent increase in neoantigens and immune cell infiltration, rendering tumors susceptible to PD-1 /PD-L1 blockade [ 46 ]. In different studies, the direct determination of TMB was also established as predictive biomarker for immunotherapy [ 47 , 48 , 49 ]. However, recently presented data suggests that not all patients with MSI/dMMR tumors also have a high TMB [ 50 ]. Furthermore, TMB high is also observed in the absence of MSI/dMMR [ 46 ]. More studies are therefore necessary to inform strategies on selection of MSI/dMMR or TMB as biomarker for response to checkpoint blockade.

Tumor mutational burden and PD-L1 expression

It was previously described that TMB does not correlate to PD-L1 expression [ 51 ]. This finding was confirmed and put into therapeutic context by the ChekMate227 trial [ 52 ]. In this trial, NSCLC patients were stratified according to tumoral PD-L1 expression (≥ 1% vs < 1%). Patients were then randomized (1:1:1) between either chemotherapy, nivolumab (nivolumab plus chemotherapy for patients with < 1% PD-L1 expression, respectively) or nivolumab plus ipilimumab. One predefined endpoint was response rate in patients with a TMB high (defined as > 10 mutations per megabase). Independent of PD-L1 expression, nivolumab plus ipilimumab was superior to chemotherapy in patients with high TMB [ 52 ].

Inflammatory gene signatures

Apart from the biomarkers mentioned above, different inflammatory TMB-signatures determined in tumor tissues can serve as biomarkers for checkpoint blockade. These signatures indicate infiltration by a specific immune cell subset (e.g. effector T cells) or activation of a specific signaling pathway (e.g. interferon-γ signaling). Recently published data from the IMmotion150 trial suggests that these signatures could even be superior to TMB in patients with metastatic renal cell carcinoma: patients were randomized between the combination of atezolizumab (anti-PD-L1) +/− bevacizumab versus sunitinib. T-effector, interferon-γ and myeloid inflammatory gene expression signatures were superior to TMB in predicting response to atezolizumab [ 53 ]. It should be noted, that these analyses were exploratory.

Further research is necessary to integrate the aforementioned tissue biomarkers into one clinical applicable diagnostic algorithm. Well-designed translational studies might also be able to identify completely new tissue biomarkers to predict clinical response to CPI treatment. One example are gene fusions producing immunogenic neoantigens. Such gene fusions were recently shown to predict response to checkpoint blockade in HNSCC patients with low TMB and minimal immune cell infiltrate [ 54 ].

Soluble biomarkers

Identifying soluble biomarkers for response prediction in peripheral blood would have several advantages over tissue biomarkers. For instance, they are easily and noninvasively accessible and can be sampled repetitively for continuous response prediction. The soluble forms of PD-1 and PD-L1 (sPD1 and sPD-L1) are also present in the peripheral blood [ 55 , 56 ]. Only few studies have investigated sPD-1 and sPDL-1 as biomarkers for response to checkpoint blockade. One small study in NSCLC patients suggested that high sPD-L1 levels predict poor response to nivolumab [ 57 ], a finding that is somewhat contrary to tissue PD-L1, because high PD-L1 tissue expression indicates higher likelihood of response to checkpoint blockade. Findings from patients with pancreatic cancer suggest that sPD-1 and sPD-L1 are rather indicators of systemic inflammation and independent from tumoral PD-L1 expression [ 56 ]. Together these findings question the aptitude of sPD-1 and sPD-L1 as biomarkers for checkpoint blockade.

An emerging soluble biomarker for checkpoint blockade is ctDNA in peripheral blood. It can be used for different applications. First, ctDNA can be used to determine tumor mutational burden (TMB) [ 58 ]. TMB measured in peripheral blood has been shown to predict response to checkpoint blockade in NSCLC patients [ 58 , 59 ]. In patients receiving conventional chemotherapy, repeated ctDNA measurement can be used for early response prediction [ 60 ]. Recently published studies suggest that changes in ctDNA levels can also be early predictors for response to immunotherapy [ 61 , 62 ]. Importantly, it might also aid to distinguish pseudo-progression from truly progressive disease in patients treated with immunotherapy [ 63 ].

Immune related adverse events as biomarker for tumor response

Different studies suggested that immune related adverse events (IrAEs) indicate response to checkpoint blockade [ 64 , 65 ]. These studies, however, were not controlled for lead time bias [ 66 ] and it is therefore not clear, whether IrAEs are truly independent predictors for response or merely reflect a longer time under treatment. Recent studies controlled for lead-time bias reported conflicting data: a large monocentric study including different cancer types presented at ESMO 2018 did not find a correlation between IrAEs and response to checkpoint blockade after controlling for lead-time bias [ 67 ]. Yet, another recent study in renal cell carcinoma reported better efficacy of nivolumab in patients with IrAEs after controlling for lead-time bias [ 68 ].

Toxicity management

Use of steroids.

The occurrence of immune-mediated side effects (e.g. colitis, autoimmune hepatitis, endocrine or neurological side effects) requires treatment with glucocorticoids (e.g. prednisolone) as early as possible depending on the severity [ 69 ]. Whether the use of glucocorticoids has a negative effect on the success of CPI treatment remains controversial. A study presented at the annual meeting of the ASCO in 2018 retrospectively investigated NSCLC patients who received glucocorticoids at the beginning of CPI therapy. The reasons for glucocorticoid administration included the treatment of symptoms caused by brain metastases as well as respiratory distress or fatigue. In a multivariate analysis which included performance status and presence of brain metastases, patients who received glucocorticoids at the start of treatment responded significantly worse to CPI administration [ 67 ]. On the other hand, as mentioned in the biomarker section, it is often postulated that patients who develop immune-mediated side effects (and receive glucocorticoids) benefit from CPI therapy over a longer period of time (or at least not shorter) than patients without immune-mediated side effects.

As a practice-based approach, immune-mediated side effects (depending on the severity and type of side effects) should be treated early with glucocorticoids to prevent permanent damage [ 69 ]. On the other hand, the need for symptomatic and sustained administration of steroids for other reasons (e.g. brain metastases or respiratory distress) during CPI therapy should be critically scrutinized in everyday clinical practice.

Special populations: patients with pre-existing autoimmune disease or HIV

Most clinical trials on CPI therapy have excluded patients with pre-existing autoimmune diseases or human immunodeficiency virus infection (HIV). In this regard, it remained unclear whether a CPI therapy is also conceivable in these patients.

The safety and efficacy of CPIs in patients with pre-existing autoimmune diseases has been recently studied in a French registry study including different tumor entities [ 70 ]. Patients with and without pre-existing autoimmune diseases were included (patients with pre-existing autoimmune disease: n  = 45, patients without pre-existing autoimmune disease: n  = 352). Although the incidence of immune-mediated side effects was significantly increased in the group of patients with pre-existing autoimmune diseases (44% versus 23%), there was no difference in overall survival between the two groups.

For the use of CPIs in patients with HIV, data from a small HIV-positive cohort of patients ( n  = 20) with NSCLC or multiple myeloma was presented at the annual meeting of the European Society of Medical Oncology (ESMO) in 2018. Overall, the therapy with CPIs was well tolerated in patients with HIV and no immune-mediated side effects were observed. An increase in HIV viral load was observed only in one patient who had paused his antiretroviral therapy. A response to therapy (PR or CR) was observed in 24% of patients [ 71 ].

Overall, both studies suggest that CPI therapy might be feasible and effective in patients with pre-existing autoimmune disease or HIV. Due to limited data on these special patient groups, a careful assessment of potential benefit versus potential harm is mandatory before starting CPI therapy in these patients.

Cellular immunotherapy

Chimeric antigen receptor T cells

Tisagenlecleucel and axicabtagen-ciloleucel were the first two cellular cancer immunotherapies receiving FDA and EMA approval in 2017 and 2018, respectively. They are approved to treat patients with acute lymphoblastic leukemia (ALL, tisagenlecleucel ) and diffuse-large B cell lymphoma (DLBCL, tisagenlecleucel and axicabtagen-ciloleucel ). Approval was based on impressive response rates observed in the ELIANA trial (relapsed or refractory [r/r] ALL in pediatric patients or young adults treated with tisagenlecleucel ), JULIETH trial (r/r DLBCL, tisagenlecleucel ) and ZUMA-1 trial (r/r DLBCL, axicabtagen-ciloleucel) [ 72 , 73 , 74 ].

Tisagenlecleucel and axicabtagen-ciloleucel are autologous T cell products. After leukapheresis, T cells are genetically engineered to express an anti-CD19 chimeric antigen receptor (anti-CD19 CAR T cells). Re-infusion of CAR T cells is preceded by a lympho-depleting chemotherapy to allow for subsequent in vivo expansion of CAR T cells (Fig.  2 ).

Different strategies for adoptive T cell therapy. Abbreviations: CAR: chimeric antigen receptor, TCR: T cell receptor, TIL: tumor infiltrating lymphocytes

Numerous clinical trials (as of May 2019 more than 550, Fig. 1 b) are investigating CAR T cell therapies for different hematological and solid cancer types [ 75 ]. Of interest and in harsh contrast to trials on PD-1 / PD-L1 blockade is the regional distribution of clinical trials on CAR T cell therapy (Fig. 1 c). The USA and China by far outcompete the EU in terms of registered CAR T cell trials. This regional imbalance has been described and discussed previously and should be addressed by researches and health care policy makers in the European Union [ 76 ].

Recently reported studies on cellular therapy mainly addressed two important questions: (I) Long term and “real world” experience regarding toxicity and efficacy of CAR T cells (II) Can the striking success of CAR T cells in ALL and DLBCL be translated to other hematological and – more importantly - solid malignancies?

Updated results from CD19 CAR T cells clinical trials

Follow-up results for efficacy and toxicity from the ELIANA, JULIETH and ZUMA-1 trial were recently presented at the annual meetings of the European Hematology Association (EHA) and the American Society of Hematology (ASH).

As of 2018, 97 patients aged ≤21 years with r/r ALL were enrolled in the ELIANA trial, 79 patients were infused with CD19 CAR T cells and a complete remission was achieved in 65 patients. After a median follow-up of 24 months, response was ongoing in 29 patients (45%), with a maximum (ongoing) duration of response of 29 months [ 77 ]. For r/r DLBCL patients treated with tisagenlecleucel, the updated analysis presented at EHA 2018 included 111 infused patients. Overall response rate (ORR) was 52% (40% CR, 12% PR) [ 78 ]. After a median follow-up time of 14 months, median duration of response was not reached. Median overall survival for all infused patients was 11.7 months [ 79 ]. For axicabtagen-ciloleucel, the 2-year follow-up data was presented at ASH 2018. A total of 108 r/r DLBCL patients had at least one year of follow-up. ORR in this cohort was 82% (58% CR). An ongoing response was observed in 42% of all patients after a median follow-up of 15.4 months, no updated overall survival data was reported [ 80 ].

For axicabtagen-ciloleucel, “real world” efficacy was confirmed by data from seventeen US academic centers who evaluated axicabtagen-ciloleucel outside of clinical trials, independent of the manufacturer after commercialization. The authors reported an ORR of 79% (50% CR), confirming the results reported in the clinical trials mentioned above [ 81 ].

While these results support the high therapeutic potential of CAR T cell therapy, a cohort of patients does not respond to – or relapses after – CAR T cell therapy. Considering the latter group (relapse after an initial complete response), it is important to explore further treatment options for these patients. One possibility might be allogeneic stem cell transplantation, which has recently been reported to improve prognosis after anti-CD19 CAR T cell therapy for ALL patients who had not received a previous stem cell transplantation [ 82 ].

The updated data for ELIANA, JULIETH and ZUMA-1 confirm the previously described safety profile with cytokine release syndrome (CRS, incidence of CRS grade ≥ 3: 7 to 48%) and neurologic events (NE, incidence of NE grade ≥ 3: 11 to 31%) as most significant adverse events [ 78 , 79 , 80 , 81 ].

In the pivotal trials for anti-CD19 CAR T cells, treatment-related deaths have been reported [ 77 ]. No treatment-related deaths were observed in a US multi-center cohort of 165 patients who received axicabtagen-ciloleucel for r/r DLBCL after commercialization outside of clinical trials [ 81 ]. Recently, safety of axicabtagen-ciloleucel w as also confirmed in patients ≥65 years [ 83 ]. Further it has been reported that neurotoxicity is fully reversible in most patients [ 84 ].

While the mentioned results are reassuring regarding saftey of CAR T cell therapy, different strategies are currently under investigation to further improve the safety profile of CAR T cells. These strategies include: (I) modification of the chimeric antigen receptor cell itself [ 85 , 86 ]; (II) identification of predictive biomarkers for CAR T cell toxicity [ 84 ]; (III) “safety switches” such as inducible suicide genes [ 87 ]; and (IV) novel drugs to mitigate CRS and NE [ 88 ].

Adoptive T cell therapy in other hematological and solid malignancies

Chimeric antigen receptor t cells for hematological and solid malignancies.

The success of CAR T cells in ALL and B cell lymphoma led to the initiation of numerous follow-up trials in these disease entities (Fig. 1 b). Regarding other cancer types, chronic lymphocytic leukemia, multiple myeloma and gastrointestinal cancers are the ones with most clinical CAR T cell trials underway (Fig. 1 b).

Additionally, a large variety of strategies to improve efficacy of CAR T cells in solid malignancies are under pre-clinical investigation [ 89 , 90 , 91 , 92 , 93 , 94 ]. Yet, the direct translation of the CAR T cell approach to solid malignancies is often impeded by the lack of a suitable cancer specific antigen resulting in either disappointing efficacy or substantial off target toxicity in early clinical trials [ 95 ]. Another important consideration is the tumor environment which is substantially different to the one seen in the above referenced hematological cancers and impedes CAR T cell efficacy [ 96 ].

Alternative approaches are genetic modification of the T cell receptor (TCR) itself or the adoptive transfer of “naturally” occurring tumor reactive T cells (also termed tumor infiltrating lymphocytes or TILs) isolated from autologous tumor tissue or tumor draining lymph nodes (Fig. 2 ). The manufacturing of TCR-modified T cells is complex, dependent on a specific human leukocyte antigen (HLA)-haplotype and can lead to unexpected off-target toxicity [ 97 , 98 ]. On the other hand, the use of tumor reactive (TCR-native) T cells has been investigated in numerous clinical studies (mainly in melanoma patients) with promising results [ 99 , 100 ]. Recent studies suggest that this approach could also be successfully translated to other solid malignancies.

Ex vivo expansion and reinfusion of autologous tumor reactive T cells

In contrast to CAR T cells, tumor reactive T cells recognize tumor cells via their native (unmodified) T cell receptor (Fig. 2 ). Tumor reactive T cells can be isolated from tumor tissue or tumor draining lymph nodes [ 101 , 102 , 103 , 104 , 105 , 106 ]. After a potential selection step followed by ex vivo expansion, tumor reactive T cells are re-infused after lymphodepleting chemotherapy – typically with parallel intravenous administration of interleukin 2 [ 101 ]. The high potential of this approach was recently confirmed in melanoma patients after failure of PD-1 / PD-L1 blockade [ 107 ] and is currently investigated in a phase III trial as first-line treatment for advanced melanoma patients (NCT02278887). In other solid tumor entities an ongoing early clinical trial (NCT01174121) is currently investigating immunotherapy with tumor reactive T cells in patients with metastatic gastrointestinal, urothelial, breast, ovarian or endometrial cancer. Case reports from three individual patients described striking responses for this treatment approach for cholangiocarcinoma, colorectal cancer and breast cancer, respectively [ 104 , 105 , 106 ]. Further studies are necessary to evaluate the expansion of this promising treatment approach to larger patient populations.

Immunotherapy of cancer is a rapidly evolving field. Results of currently ongoing studies on checkpoint blockade will most likely expand the use of CPIs to additional patient populations (e.g. new tumor entities, perioperative use, use in special patient populations) and might identify new combination partners for CPI.

The major challenge for adoptive T cell therapy in years to come is the translation of this treatment modality to solid malignancies. A successful strategy has yet to be defined and might include more advanced genetic engineering of CAR T cells as well as the development of more advanced protocols for the use of tumor reactive (TCR-native) T cells.

Regarding the regional distribution of clinical trials on immunotherapy a shift from the European region (for PD-1 / PD-L1-trials) towards China (leading in terms of number of available CAR T cell trials) is evident and should be met by intensified research efforts on cellular immunotherapy in Europe.

Availability of data and materials

The datasets generated and analysed for Fig. 1 are available in the U.S. National Library of Medicine repository, https://clinicaltrials.gov/

Abbreviations

Acute lymphoblastic leukemia

American Society of Clinical Oncology

Complete remission

Colorectal cancer

Cytokine release syndrome

Circulating tumor DNA

Cytotoxic T-lymphocyte-associated protein-4

Diffuse-large B cell lymphoma

Deficient mismatch repair

European Hematology Association

European medicines agency

European Society of Medical Oncology

U. S. food and drug administration

Good manufacturing practice

Human immunodeficiency virus

Head and neck squamous cell carcinoma

Immune related adverse events

Microsatellite unstable

Microsatellite stable

Neurologic events

Non-small cell lung cancer

Overall response rate

Overall survival

Programmed cell death protein 1

Pancreatic ductal adenocarcinoma

Programmed cell death protein ligand 1

Progression free survival

Partial remission

Relapsed or refractory

Renal cell cancer

Ribonucleic acid

Stereotactic body radiation therapy

Small cell lung cancer

Soluble form of PD-1

Soluble form of PD-L1

T cell receptor

Toll-like receptor 4

Tumor mutational burden

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Stephan Kruger is supported by the “Else Kröner-Forschungskolleg: Cancer Immunotherapy”.

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Stephan Kruger and Matthias Ilmer contributed equally to this work.

Authors and Affiliations

Department of Medicine III, University Hospital Munich, LMU Munich, Marchioninistr. 15, D-81377, Munich, Germany

Stephan Kruger, Gesa Schuebbe, Volker Heinemann, Marion Subklewe, Stefan Boeck & Michael von Bergwelt-Baildon

Department of General, Visceral, and Transplantation Surgery, University Hospital, LMU Munich, Munich, Germany

Matthias Ilmer, Bernhard W. Renz, Jan G. D’Haese & Jens Werner

Center of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Department of Medicine IV, University Hospital, LMU Munich, Munich, Germany

Stephan Kruger, Sebastian Kobold, Bruno L. Cadilha & Stefan Endres

Institute of Pathology, LMU Munich, Munich, Germany

Steffen Ormanns

University Hospital of Cologne, Cologne, Germany

Hans Schloesser

German Cancer Consortium (DKTK), Partner Site Munich; and German Cancer Research Center (DKFZ), Heidelberg, Germany

Matthias Ilmer, Bernhard W. Renz, Volker Heinemann, Marion Subklewe, Stefan Boeck & Michael von Bergwelt-Baildon

Center for Molecular Medicine Cologne (CMMC), Cologne, Germany

Michael von Bergwelt-Baildon

Gene Center LMU, Munich, Germany

Marion Subklewe & Michael von Bergwelt-Baildon

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Writing of the manuscript: SK and MI. Conception of the review: SK, MI, SebK, SB and MvB. Figure  1 : SK. Figure  2 : BC. Identification of potential studies to include and careful revision of the final manuscript: SK, MI, SebK, BC, SE, SO, GS, BWR, JGD, HS, VH, MS, SB, JW, MvB. All authors read and approved the final manuscript.

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Kruger, S., Ilmer, M., Kobold, S. et al. Advances in cancer immunotherapy 2019 – latest trends. J Exp Clin Cancer Res 38 , 268 (2019). https://doi.org/10.1186/s13046-019-1266-0

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Published : 19 June 2019

DOI : https://doi.org/10.1186/s13046-019-1266-0

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New cancer treatment may reawaken the immune system

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Immunotherapy is a promising strategy to treat cancer by stimulating the body’s own immune system to destroy tumor cells, but it only works for a handful of cancers. MIT researchers have now discovered a new way to jump-start the immune system to attack tumors, which they hope could allow immunotherapy to be used against more types of cancer.

Their novel approach involves removing tumor cells from the body, treating them with chemotherapy drugs, and then placing them back in the tumor. When delivered along with drugs that activate T cells, these injured cancer cells appear to act as a distress signal that spurs the T cells into action.

“When you create cells that have DNA damage but are not killed, under certain conditions those live, injured cells can send a signal that awakens the immune system,” says Michael Yaffe, who is a David H. Koch Professor of Science, the director of the MIT Center for Precision Cancer Medicine, and a member of MIT’s Koch Institute for Integrative Cancer Research.

In mouse studies, the researchers found that this treatment could completely eliminate tumors in nearly half of the mice.

Yaffe and Darrell Irvine, who is the Underwood-Prescott Professor with appointments in MIT’s departments of Biological Engineering and Materials Science and Engineering, and an associate director of the Koch Institute, are the senior authors of the study, which appears today in Science Signaling . MIT postdoc Ganapathy Sriram and Lauren Milling PhD ’21 are the lead authors of the paper.

T cell activation

One class of drugs currently used for cancer immunotherapy is checkpoint blockade inhibitors, which take the brakes off of T cells that have become “exhausted” and unable to attack tumors. These drugs have shown success in treating a few types of cancer but do not work against many others.

Yaffe and his colleagues set out to try to improve the performance of these drugs by combining them with cytotoxic chemotherapy drugs, in hopes that the chemotherapy could help stimulate the immune system to kill tumor cells. This approach is based on a phenomenon known as immunogenic cell death, in which dead or dying tumor cells send signals that attract the immune system’s attention.

Several clinical trials combining chemotherapy and immunotherapy drugs are underway, but little is known so far about the best way to combine these two types of treatment.

The MIT team began by treating cancer cells with several different chemotherapy drugs, at different doses. Twenty-four hours after the treatment, the researchers added dendritic cells to each dish, followed 24 hours later by T cells. Then, they measured how well the T cells were able to kill the cancer cells. To their surprise, they found that most of the chemotherapy drugs didn’t help very much. And those that did help appeared to work best at low doses that didn’t kill many cells.

The researchers later realized why this was so: It wasn’t dead tumor cells that were stimulating the immune system; instead, the critical factor was cells that were injured by chemotherapy but still alive.

“This describes a new concept of immunogenic cell injury rather than immunogenic cell death for cancer treatment,” Yaffe says. “We showed that if you treated tumor cells in a dish, when you injected them back directly into the tumor and gave checkpoint blockade inhibitors, the live, injured cells were the ones that reawaken the immune system.”

The drugs that appear to work best with this approach are drugs that cause DNA damage. The researchers found that when DNA damage occurs in tumor cells, it activates cellular pathways that respond to stress. These pathways send out distress signals that provoke T cells to leap into action and destroy not only those injured cells but any tumor cells nearby.

“Our findings fit perfectly with the concept that ‘danger signals’ within cells can talk to the immune system, a theory pioneered by Polly Matzinger at NIH in the 1990s, though still not universally accepted,” Yaffe says.  

Tumor elimination

In studies of mice with melanoma and breast tumors, the researchers showed that this treatment eliminated tumors completely in 40 percent of the mice. Furthermore, when the researchers injected cancer cells into these same mice several months later, their T cells recognized them and destroyed them before they could form new tumors.

The researchers also tried injecting DNA-damaging drugs directly into the tumors, instead of treating cells outside the body, but they found this was not effective because the chemotherapy drugs also harmed T cells and other immune cells near the tumor. Also, injecting the injured cells without checkpoint blockade inhibitors had little effect.

“You have to present something that can act as an immunostimulant, but then you also have to release the preexisting block on the immune cells,” Yaffe says.

Yaffe hopes to test this approach in patients whose tumors have not responded to immunotherapy, but more study is needed first to determine which drugs, and at which doses, would be most beneficial for different types of tumors. The researchers are also further investigating the details of exactly how the injured tumor cells stimulate such a strong T cell response.

The research was funded, in part, by the National Institutes of Health, the Mazumdar-Shaw International Oncology Fellowship, the MIT Center for Precision Cancer Medicine, and the Charles and Marjorie Holloway Foundation.

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Explore  CRI’s 2023 Cancer Research Impact

Immunotherapy at a glance

The Solution to Cancer: Personalized, Powerful, Predictable

Research indicates that immunotherapy may offer a long-term solution to ending certain forms of cancer.

Immunotherapy The Answer to Cancer

Immunotherapy capitalizes on the innate power of the immune system to eliminate cancer, giving patients hope for a cure. By taking advantage of our immune system’s ability to remember cancer cells, there is the potential to offer patients permanent protection against cancer recurrence.

Solving a Global Health Crisis

Approximately 40% or 3 billion people alive today will be diagnosed with cancer at some point in their lifetime .

2018 expenditures for cancer care in the U.S. was $150.8 billion .

By 2040, the number of global cancer-related deaths is expected to rise by 73% to 16.4 million .

By 2030, the number of cancer survivors is projected to increase to 22.2 million in the U.S. alone .

Impacting Every Day While Transforming Tomorrow

Immunotherapy is here and is leading to highly effective cancer treatments for patients around the world. To that end, CRI offers valuable tools, support, and insights to hasten the advancement of immunotherapy research, propelling it forward to reach its greatest potential.

Our immune system is the greatest weapon we have in the fight against cancer

The immune system can adapt continuously and dynamically to keep pace with cancer’s rate of mutation and growth.

Specifically, it targets constantly mutating cancer cells while sparing healthy cells. Immunotherapy is a “living drug” that remains active thanks to the immune system’s “memory,” enabling it to keep up and even outpace cancer.

Immunotherapy research is vital to understanding key resistance levers in patient responses and overcoming treatment failures. With breakthroughs happening at a rapid pace, it is our hope and collective goal to see that immunotherapy becomes readily available to the patients that need it.

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New biomarker predicts success of immunotherapy in kidney cancer

by University of Innsbruck

Immunotherapy increases survival rates in kidney cancer, but does not work for everyone. A Leuven research team has developed a new method to predict which patients will benefit from it. The team of Francesca Finotello (Computational Biomedicine Group) from the University of Innsbruck also contributed.

Their study , published in the journal Nature Medicine , also opens new avenues to even more effective treatments.

Every year, roughly 1,300 people in Austria are diagnosed with kidney cancer . Thanks to immunotherapy, survival rates for metastatic kidney cancer have increased dramatically in recent years: more than half are still alive five years after diagnosis, compared to only 10% in the past. Unfortunately, the innovative treatment does not work for all patients.

To investigate why there is such variation in the efficacy of immunotherapy, and in the hope of better predicting in which patients the treatment will succeed, a Leuven research team set up a large retrospective study. They analyzed many samples from kidney cancer patients treated with immunotherapy at UZ Leuven over the past decade.

Molecular signature

Doctoral researcher and oncologist in training Dr. Lisa Kinget and postdoc Stefan Naulaerts explain, "We examined both tumor biopsies and blood samples with advanced laboratory techniques. Via machine learning , we combined gene expression in the tumor with hereditary characteristics of the patients' immune system, more specifically the HLA genes, which come in hundreds of variations depending on the individual.

"This approach allowed us to find a 'molecular signature' that showed a clear association with clinical response and survival rates. We further confirmed this association on independent samples from more than 1,000 kidney cancer patients from other international studies."

The lab analyses further showed that a successful response to immunotherapy was tied to a good interaction between two types of immune cells, namely CD8 + T cells and macrophages.

Dr. Francesca Finotello from the University of Innsbruck's Department of Molecular Biology and the Digital Science Center (DiSC) adds, "We integrated and analyzed large-scale multi-omics data from The Cancer Genome Atlas (TCGA) to associate this novel, molecular signature with the mutational landscape of the tumors, demonstrating that it brings orthogonal information with respect to the sole genetic background of cancer cells, capturing efficiently their interaction with the immune system ."

Prof Abhishek D. Garg, KU Leuven says, "Previously, researchers mainly looked at immune cells at the level of individual cell types, which led to oversimplified biomarkers. As a result, we thought macrophages were 'bad' for immunotherapy. With this study, we show that the interaction between different types of immune cells in a specific spatial context is more important in fighting kidney cancer."

Prof Dr. Benoit Beuselinck, medical oncologist at UZ Leuven, says, "In the future, we hope to be able to use our method as a biomarker to predict in which patients immunotherapy will be effective. The new insight that the interaction between certain T cells and macrophages is important for the success of immunotherapy opens up interesting avenues for future treatments.

"We are currently busy setting up new clinical trials of combination therapies to stimulate both cell types and make them work better together, which may be more effective than current treatments."

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Unlocking the body’s defences: understanding immunotherapy

Professor of Biomedical Sciences, Anglia Ruskin University

Disclosure statement

Justin Stebbing does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.

Anglia Ruskin University (ARU) provides funding as a member of The Conversation UK.

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In the battle against diseases, the human body boasts an intricate defence network capable of identifying and neutralising threats – the immune system . It serves as a guardian, constantly patrolling the body to keep it safe from invaders like bacteria, viruses, and even cancer cells.

Scientists are harnessing the power of the body’s natural defence mechanism to develop immunotherapy, revolutionising the landscape of medical treatment. It enhances, redirects, or restores the body’s immune response to recognise and eliminate abnormal cells, such as cancer cells or those responsible for autoimmune diseases like multiple sclerosis, rheumatoid arthritis and type 1 diabetes.

Immunotherapy, however, is expensive. So, chemotherapy and radiation therapy are still the primary cancer treatments for most patients. But these conventional methods can damage healthy tissues as well as abnormal cells. They also tend to have debilitating side effects , such as nausea, vomiting, tiredness and hair loss.

Immunotherapy uses the body’s immune system to combat diseases with precision and minimal harm by blocking molecules – called checkpoint inhibitors – like PD-L1 or CTLA-4 that cancer cells use to turn off the immune systems.

Checkpoint inhibitors are a Nobel prize -winning discovery and they’re now one of the most widely used forms of immunotherapy. They work by blocking surface proteins that prevent immune cells from attacking cancer cells. By lifting the brakes on the immune response, these inhibitors unleash the body’s natural defence mechanism against cancer.

Hot and cold tumours

Tumours are often categorised as “hot” or “cold” based on their interaction with the immune system.

Hot tumours are characterised by a robust immune response, with infiltrating immune cells actively engaging with cancer cells. In contrast, cold tumours exhibit minimal immune activity, often evading detection by the immune system.

Immunotherapy has worked in hot tumours such as melanoma, kidney cancer and lung cancers. However, many tumours – such as most types of colon cancer – respond poorly to immunotherapy because they’re able to evade immune surveillance.

However, immunotherapies are emerging that could expand the benefits to more cancer patients , including those with cold tumours. These approaches include combination therapies using more effective immune checkpoint inhibitors with other agents, including chemotherapy and drugs in trials, to prime the immune system and enhance tumour recognition.

There are other approaches too.

CAR-T cell therapy

CAR-T cell therapy involves extracting a patient’s immune cells and genetically engineering them to produce chimeric antigen receptors – proteins on the surface of the immune cells that recognise cancer – before reintroducing them into the bloodstream. Once inside the body, the modified immune cells target and destroy cancer cells. This treatment has been used in tumour conditions like lymphomas or leukaemias but now these are moving into other cancer types .

Invariant natural killer cells

A 2024 trial used “invariant natural killer cells”, which help coordinate the body’s immune response, as immunotherapy during very severe infections, when people affected by a viral attack on their lungs could no longer breathe. The trial found that most patients recovered despite being critically unwell.

Unlike traditional vaccines that prevent infectious diseases, cancer vaccines stimulate the immune system to recognise and attack cancer cells. Cancer vaccines may contain tumour-specific markers called antigens or genetic material to train the immune system to target cancerous cells.

This means that immunotherapy can offer truly personalised medicine. There’s data, for example, on cancer vaccines from clinical trials based on the changes or mutations of a specific patient’s tumour.

Benefits beyond cancer treatment

While immunotherapy has gained widespread recognition for its efficacy in cancer treatment, its applications could extend far beyond oncology . By harnessing the immune system’s ability to distinguish self from non-self, immunotherapy offers promising avenues for combating a diverse range of ailments.

For example, researchers are exploring its potential in treating autoimmune diseases, allergic disorders, infectious diseases, and even neurological conditions like Alzheimer’s disease.

The treatment can be highly effective but it’s not everyone. For reasons we don’t yet fully understand, some people are resistant to treatment. Immunotherapy isn’t free of side effects either. Autoimmune complications can include colon and lung tissue inflammation. The current high cost of immunotherapy can prove prohibitive for many potential patients. Additionally, uptake of the treatment is limited by patient selection – choosing who would most benefit from this treatment and developing personalised treatment regimens remain critical for maximising results.

Ongoing research into immunotherapy could herald an era of targeted and tailored treatments. These include oncolytic viruses that can attack cancer directly, and microbiome modulation , which uses bacteria to enhance the activity of checkpoint inhibitors.

As our understanding of immunology continues to deepen and technology advances, immunotherapy could offer precision medicine and personalised treatments for a host of previously incurable conditions – the challenge is to make it available and accessible to more patients.

• Immunotherapy
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Immunotherapy to Treat Cancer

Immunotherapy is a type of cancer treatment that helps your immune system fight cancer. The immune system helps your body fight infections and other diseases. It is made up of white blood cells and organs and tissues of the lymph system .

Immunotherapy is a type of biological therapy . Biological therapy is a type of treatment that uses substances made from living organisms to treat cancer.

How does immunotherapy work against cancer?

As part of its normal function, the immune system detects and destroys abnormal cells and most likely prevents or curbs the growth of many cancers. For instance, immune cells are sometimes found in and around tumors. These cells, called tumor-infiltrating lymphocytes or TILs, are a sign that the immune system is responding to the tumor. People whose tumors contain TILs often do better than people whose tumors don’t contain them.

Even though the immune system can prevent or slow cancer growth, cancer cells have ways to avoid destruction by the immune system. For example, cancer cells may:

• Have genetic changes that make them less visible to the immune system.
• Have proteins on their surface that turn off immune cells.
• Change the normal cells around the tumor so they interfere with how the immune system responds to the cancer cells.

Immunotherapy helps the immune system to better act against cancer.

What are the types of immunotherapy?

Get Answers >

Wondering if immunotherapy is an option for you? Connect with a Cancer Information Specialist.

Several types of immunotherapy are used to treat cancer. These include:

Learn more about immune checkpoint inhibitors .

T-cell transfer therapy may also be called adoptive cell therapy, adoptive immunotherapy, or immune cell therapy.

Learn more about T-cell transfer therapy .

Monoclonal antibodies may also be called therapeutic antibodies.

Learn more about monoclonal antibodies .

Learn more about cancer treatment vaccines .

Learn more about immune system modulators .

Which cancers are treated with immunotherapy?

Immunotherapy drugs have been approved to treat many types of cancer. However, immunotherapy is not yet as widely used as surgery , chemotherapy , or radiation therapy . To learn about whether immunotherapy may be used to treat your cancer, see the  PDQ ® adult cancer treatment summaries and childhood cancer treatment summaries .

What are the side effects of immunotherapy?

Immunotherapy can cause side effects , many of which happen when the immune system that has been revved-up to act against the cancer also acts against healthy cells and tissues in your body.

Learn more about immunotherapy side effects .

How is immunotherapy given?

Different forms of immunotherapy may be given in different ways. These include:

• intravenous (IV) The immunotherapy goes directly into a vein .
• oral The immunotherapy comes in pills or capsules that you swallow.
• topical The immunotherapy comes in a cream that you rub onto your skin. This type of immunotherapy can be used for very early skin cancer.
• intravesical The immunotherapy goes directly into the bladder.

Where do you go for immunotherapy?

You may receive immunotherapy in a doctor’s office, clinic, or outpatient unit in a hospital. Outpatient means you do not spend the night in the hospital.

How often do you receive immunotherapy?

How often and how long you receive immunotherapy depends on:

• your type of cancer and how advanced it is
• the type of immunotherapy you get
• how your body reacts to treatment

You may have treatment every day, week, or month. Some types of immunotherapy given in cycles. A cycle is a period of treatment followed by a period of rest. The rest period gives your body a chance to recover, respond to immunotherapy, and build new healthy cells.

How can you tell if immunotherapy is working?

You will see your doctor often. He or she will give you physical exams and ask you how you feel. You will have medical tests, such as blood tests and different types of scans . These tests will measure the size of your tumor and look for changes in your blood work.

What is the current research in immunotherapy?

Researchers are focusing on several major areas to improve immunotherapy, including:

• Finding solutions for resistance. Researchers are testing combinations of immune checkpoint inhibitors and other types of immunotherapy, targeted therapy, and radiation therapy to overcome resistance to immunotherapy.
• Finding ways to predict responses to immunotherapy. Only a small portion of people who receive immunotherapy will respond to the treatment. Finding ways to predict which people will respond to treatment is a major area of research.
• Learning more about how cancer cells evade or suppress immune responses against them. A better understanding of how cancer cells get around the immune system could lead to the development of new drugs that block those processes.
• How to reduce the side effects of treatment with immunotherapy.

How do you find clinical trials that are testing immunotherapy?

To find clinical research studies that involve immunotherapy visit Find NCI-Supported Clinical Trials or call the Cancer Information Service, NCI’s contact center, at 1-800-4-CANCER (1-800-422-6237).

NCI’s list of cancer clinical trials includes all NCI-supported clinical trials that are taking place across the United States and Canada, including the NIH Clinical Center in Bethesda, MD.

• Letter to the Editor
• Open access
• Published: 26 May 2024

Revisiting the role of pregnancy zone protein (PZP) as a cancer biomarker in the immunotherapy era

• Jie Huang 1 ,
• Ying Xu 2 ,
• Yidan Chen 3 ,
• Juan Shen 1 ,
• Yao Qiu 1 ,
• Xueqin Chen 1 , 4 &
• Shenglin Ma 1  

Journal of Translational Medicine volume  22 , Article number:  500 ( 2024 ) Cite this article

Metrics details

To the Editor,

Immunotherapy with PDL1/PD1 or CTLA4 based immune checkpoint inhibitors has greatly improved survival in various cancers, however, the efficacy is limited and cancer as an aggressive disease still faces many unmet needs. Pregnancy related proteins have been associated with carcinogenesis, in which alpha fetoprotein (AFP) and carcinoembryonic antigen (CEA) have been widely used as tumor markers in cancer diagnosis, prognosis and therapy response evaluation. Pregnancy zone protein (PZP), as another pregnancy related protein, is abundantly secreted in the plasma by placenta during pregnancy [ 1 ]. was initially evaluated as a potential tumor marker but have been demonstrated to be unsuitable due to no apparent associations between PZP plasma levels and either tumor burden or treatment response [ 2 , 3 ]. However, we also noticed that recent publications demonstrated a clear role of PZP for screening lung adenocarcinoma in type 2 diabetes mellitus patients [ 4 ], which hints the possible usage of PZP as a biomarker in specific circumstances. And notably it is worth emphasizing that a comprehensive evaluation of PZP in various cancers especially associated tumor immune microenvironment and immunotherapy response are still needed in the current tumor immunotherapy era since PZP, classically recognized as a pan-protease inhibitor, mediates immune tolerance during pregnancy [ 5 ], implicating its possible role in regulation of tumor immune microenvironment. Hence, we performed a pan-cancer analysis of PZP to reveal its expression levels and prognosis indications in various cancer types and its links with cancer hallmarks especially the associations with tumor immune microenvironment and immunotherapy responses.

The distinct expression and prognosis indications of PZP in various cancers

Through comparing the expression levels of PZP among cancers and their peritumor normal tissues in The Cancer Genome Atlas (TCGA), we found that PZP expression in most cancer tissues including BLCA, BRCA, CESC, CHOL, COAD, KICH, KIRP, LIHC, LUAD, LUSC, READ, and UCEC were significantly lower than their peritumor normal tissues, while only GBM, KIRC, and STAD cancer types had higher PZP expression levels than their normal tissues (P < 0.05) ( Fig.  1 A ) ( full names and abbreviations of cancer types in TCGA were listed Supplementary Table S1). Comparisons between paired tumor-normal tissues also confirmed decreased PZP expressions in BLCA, BRCA, CHOL, COAD, KICH, KIRP, LIHC, LUAD, LUSC, READ cancer types but increased expressions in KIRC and STAD (P < 0.05) ( Fig.  1 B ) . Then, we wondered whether PZP might be a risk factor in specific cancer types and the univariate COX regression analyses in different cancers in TCGA revealed that PZP indicated a good progression-free survival (PFS) in BRCA and a good overall survival (OS) in LIHC, KIRC, SKCM, and SARC, but a poor PFS in STAD, STES and a poor OS in STAD, THYM, and STES (P < 0.05) ( Fig.  1 C, D ) (Supplementary Figs. S1, S2). Notably, PZP was further validated as a risk factor of OS by another two independent STAD datasets including GSE51105 ( Fig.  1 E ) and GSE62254 ( Fig.  1 F ) . Additionally, higher PZP expressions also indicated worse PFS ( Fig.  1 G ) and post-progression survival (PPS) ( Fig.  1 H ) , as demonstrated by STAD dataset GSE62254.

PZP expression and its prognostic relevance across different cancer types in pan-cancer analysis. A , B Expression variations of PZP between cancer and peritumoral tissues (Wilcoxon rank sum test) ( A ) and paired cancer and peritumoral tissues (Wilcoxon signed rank test) ( B ) in various cancer cohorts from the TCGA database. Symbols “*”, “**”, and “***” denote statistical significance with p < 0.05, p < 0.01, and p < 0.001, respectively. C , D Forest plot of univariate Cox regression analysis illustrating the HRs of PZP in pan-cancer for PFS (C) and OS (D) . E–H Survival plots of Kaplan–Meier log-rank analysis of OS between PZP low and PZP high expression stomach adenocarcinoma patients grouped by best cut-off values of PZP in STAD dataset GSE51105 (E) and OS (F) , PFS (G) and PPS (H) in STAD dataset GSE62254

PZP linked with tumor immune microenvironment and immunotherapy response

Regarding the role of PZP in mediating tumor immune evasion, we checked the correlation of PZP expressions with immune regulator genes. Remarkably, the results demonstrated positive correlations of PZP expressions with most immune checkpoint genes including well-known CD274, CTLA4, TIGIT, LAG3, etc., chemokines, receptors, MHC, and other immune regulators in most cancers including STAD ( Fig.  2 A ) . When we delve into the detailed immune cell subtypes infiltrated into the tumor microenvironment, we noted that PZP expression was positively correlated with M2 macrophages and Tregs in most cancers ( Fig.  2 B ) . Notably, when exploring the impact of PZP expression on immunotherapy response using immunotherapy datasets in Kaplan–Meier Plotter, we unexpectedly found that responders to anti-PD1 or anti-CTLA4 immunotherapy had significantly higher PZP expression than non-responders ( Fig.  2 C, G ) and PZP could predict the response to anti-PD1 and anti-CTLA4 immunotherapy with AUC of 0.646 and 0.693, respectively ( Fig.  2 D, H ) , and a insignificant trend in anti-PDL1 immunotherapy datasets ( Fig.  2 E, F ) . Patients with higher PZP expression had obviously better PFS and OS compared to lower ones when treated with either PD1 inhibitors ( F i g.  2 I, J ) , PDL1 inhibitors ( Fig.  2 K, L ) , or CTLA4 inhibitors ( Fig.  2 M, N ) .

Correlations between PZP expression and immune-related genes, immune microenvironment and immunotherapy response. A Heat maps of associations between PZP expression and immune regulator genes including chemokines and chemokine receptors, MHC, immunoinhibitory or immunostimulatory genes in pan-cancer. Symbols “*”, “**”, and “***” denote statistical significance with p < 0.05, p < 0.01, and p < 0.001, respectively (Pearson correlation). B Heat maps of associations between PZP expression and infiltrated immune cells analyzed by QUANTISEQ algorithm in pan cancer. Symbols “*”, “**”, and “***” denote statistical significance with p < 0.05, p < 0.01, and p < 0.001, respectively (Pearson correlation). C , E , G Box plots showing the PZP expression levels between responders and non-responders to anti-PD1 (C) , anti-PDL1 (E) , and anti-CTLA4 (G) immunotherapy datasets. D , F , H ROC curves showing the AUC values of PZP to predict response to anti-PD1 (D) , anti-PDL1 (F) , and anti-CTLA4 (H) immunotherapy. I – N Survival plots of Kaplan–Meier log-rank analysis of PFS and OS between PZP low and PZP high expression patients grouped by best cut-off values in cancer patients receiving PD1 inhibitors (I , J) , PDL1 inhibitors (K , L) , CTLA4 inhibitors (M , N) as analyzed by Kaplan Meier Plotter

Conclusions

In summary, we performed a comprehensive evaluation of PZP in various cancers, which revealed its underlying role as a prognostic indicator several cancer types including STAD and its links with immune microenvironment. PZP widely regulates immune regulators including immune checkpoint genes, facilitates the immune-tolerant tumor microenvironment, and predicts the immunotherapy response. Thus, PZP may become a new biomarker guiding PD1 or CTLA4 based immunotherapy in cancers.

Availability of data and materials

The dataset supporting the conclusions of this article is included within the article. The data supporting the findings of this study are deposited in the TCGA and GEO (GSE51105, GSE62254 for STAD prognosis validation), and Kaplan–Meier Plotter for immunotherapy response evaluation ( https://kmplot.com/analysis/index.php?p=service&cancer=immunotherapy ).

Abbreviations

Pregnancy zone protein

Programed-cell death protein 1

Programed-cell death-ligand 1

Cytotoxic T-lymphocyte associated protein 4

Alpha fetoprotein

Carcinoembryonic antigen

The Cancer Genome Atlas

Progression-free survival

Overall survival

Post-progression survival

Cluster of differentiation 274

T-cell immunoreceptor with Ig and ITIM domains

Lymphocyte-activation gene 3

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Acknowledgements

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This study is funded by Hangzhou Health Science and Technology Plan project (A20220840) and Zhejiang Provincial Medical Health Science and Technology Plan (2023557997).

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Department of Oncology, Hangzhou Cancer Hospital, No.34 Yanguan Lane, Shangcheng District, Hangzhou, 310002, China

Jie Huang, Juan Shen, Yao Qiu, Xin Li, Xueqin Chen & Shenglin Ma

The Forth Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, 310006, China

Cancer Research Institution, Hangzhou Cancer Hospital, Hangzhou, 310002, China

Affiliated Hangzhou First People’s Hospital, School of Medicine, Westlake University, Hangzhou, 310006, China

Xueqin Chen

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J.H, X.C, and S.M made substantial contributions to conception and design; J.H, Y.X, J.S, Y.Q, and X.L contributed to acquisition of data, or analysis and interpretation of data; J.H, Y.C, and X.C wrote the manuscript draft and J.H, and S.M revised the manuscript accordingly. All the authors read and agreed to the final version.

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This study comprised a bioinformatics analysis and did not involve any experimental work on human or animal subjects. The research was conducted using publicly available datasets and computational methods, which do not necessitate ethical approval or informed consent. We confirm that all data used in this study are fully anonymized and that there are no concerns related to participant confidentiality.

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Supplementary Information

12967_2024_5321_moesm1_esm.pdf.

Supplementary Material 1. Figure S1. Kaplan-Meier survival curves for PFS in cancers stratified by expression of PZP. A-E. Kaplan-Meier survival curves for PFS in STES (A), UCS (B), LIHC (C), STAD (D), BRCA (E) stratified by expression of PZP.

12967_2024_5321_MOESM2_ESM.pdf

Supplementary Material 2. Figure S2. Kaplan-Meier survival curves for OS in cancers stratified by expression of PZP. A-G. Kaplan-Meier survival curves for OS in THYM (A), STES (B), STAD (C), SKCM (D), SARC (E), LIHC (F) and KIRC (G) stratified by expression of PZP.

12967_2024_5321_MOESM3_ESM.docx

Supplementary Material 3. Supplementary Table S1. Full names and abbreviations of enrolled cohorts in the TCGA database.

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Huang, J., Xu, Y., Chen, Y. et al. Revisiting the role of pregnancy zone protein (PZP) as a cancer biomarker in the immunotherapy era. J Transl Med 22 , 500 (2024). https://doi.org/10.1186/s12967-024-05321-5

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PD-1 blockade immunotherapy as a successful rescue treatment for disseminated adenovirus infection after allogeneic hematopoietic stem cell transplantation

• Fei Zhou 1 ,
• Feng Du 2 ,
• Ziyan Wang 2 ,
• Mengxing Xue 1 ,
• Depei Wu 1 ,
• Suning Chen 1 &
• Xuefeng He 1  

Journal of Hematology & Oncology volume  17 , Article number:  34 ( 2024 ) Cite this article

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Disseminated adenovirus infection is a complication with a relatively high mortality rate among patients undergoing hematopoietic stem cell transplantation. The low efficacy and poor availability of current treatment options are of major concern. Programmed cell death 1 (PD-1) blockade has been used to treat several chronic viral infections. Herein, we report a case of disseminated adenovirus infection in the early posttransplant period. The patient was diagnosed with diffuse large B-cell lymphoma at first and underwent 8 cycles of chemotherapy, including rituximab. She was subsequently diagnosed with acute myeloid leukemia and received haploidentical transplantation. She was diagnosed with Epstein‒Barr virus (EBV)-positive posttransplant lymphoproliferative disorder (PTLD) 2 months after the transplant, and 3 doses of rituximab were administered. The patient was diagnosed with disseminated adenovirus infection with upper respiratory tract, gastrointestinal tract and blood involved at 3 months after transplantation. She was first treated with a reduction in immunosuppression, cidofovir and ribavirin. Then, the patient received salvage treatment with the PD-1 inhibitor sintilimab (200 mg) after achieving no response to conventional therapy. The adenovirus was cleared 3 weeks later, and concomitant EBV was also cleared. Although the patient developed graft-versus-host disease of the liver after the administration of the PD-1 inhibitor, she was cured with steroid-free therapy. Therefore, PD-1 blockade immunotherapy can be considered a promising treatment option for patients with disseminated adenovirus infection after transplantation, with fully weighing the hazards of infection and the side effects of this therapy.

To the Editor,

The reported prevalence rate of Human adenovirus (HAdV) infection after hematopoietic stem cell transplantation (HSCT) ranges from 5–21% [ 1 ]. Approximately 10–20% of patients with HAdV infection may develop disseminated adenovirus disease (dAdV), with mortality rates ranging from 20 to 80% [ 2 ]. DAdV infection is characterized by systemic symptoms with adenoviruses detected in two or more organs, or adenoviruses detected in one organ accompanied by high viral copy numbers in blood (> 10E4 per milliliter) [ 3 ]. Reducing immunosuppression and using antiviral drugs, including cidofovir, are still the main treatment methods. The prognosis of patients with dAdV remains poor even if they are treated with combined therapy [ 3 , 4 , 5 ]. Herein, we report a patient with dAdV who was successfully treated with a PD-1 inhibitor rapidly and effectively. This is the first report of PD-1 inhibitors being applied to treat dAdV patients after transplantation.

Case presentation

The patient was a 54-year-old female who was diagnosed with diffuse large B-cell lymphoma in March 2020. She underwent 8 cycles of chemotherapy, including rituximab, and reached complete remission. The patient was subsequently diagnosed with MLL-ELL-positive acute myeloid leukemia, presumed to be treatment-related, in October 2022 and underwent 3 cycles of chemotherapy. She reached morphological remission and received haploidentical transplantation from her son on June 14, 2023. Unfortunately, she was diagnosed with EBV-positive PTLD at 2 months posttransplant. Immunosuppressive agents were rapidly tapered, and 3 doses of rituximab (375 mg/m 2 ) were administered. The number of EBV copies in the blood decreased from 4.1*10E5 to 4.5*10E3 per milliliter after treatment. Moreover, the patient got intermittent fever, nausea, vomiting, diarrhea, and cough, and HAdV was detected positive in blood, throat swabs and stool specimens, at 3.7*10E4 copies/ml (cp/ml) in blood and 4.0*10E8 cp/ml in stool at 3 months posttransplant. She was diagnosed with dAdV disease, with upper respiratory tract, gastrointestinal tract and peripheral blood involved. After administration of 2 doses of cidofovir (5 mg/kg per week), the patient’s clinical symptoms and inflammatory indicators worsened, and her HAdV copy number continued to increase to 1.7*10E6 cp/ml in blood. Since PD-1 inhibitors have been successfully used to treat several chronic viral infections [ 6 , 7 , 8 ], it is speculated that PD-1 inhibitors might be effective for HAdV clearance. Therefore, 200 mg of sintilimab (a recombinant human IgG4 monoclonal antibody against PD-1) was administered as a salvage treatment with the prior informed consent of the patient. The viral copy numbers in blood and stool both decreased gradually and finally became negative 3 weeks later (Fig.  1 ). The patient developed acute graft-versus-host disease (GVHD) grade III in the liver. She was treated with cyclosporine and 3 doses of basiliximab (20 mg, twice a week) and showed a complete response. Surprisingly, the patient also became negative for peripheral EBV soon after receiving sintilimab. Routine bone marrow exams at 4 months posttransplant showed molecular relapse of leukemia, with MLL-ELL being positive, so the patient was treated with 100 mg of sintilimab again. MLL-ELL turned negative 1 month later and no recurrence of GHVD occurred. At 9 months posttransplant, the patient was in good condition with no recurrence of leukemia, HAdV infection or GVHD.

Treatment process and development trends of viral copy numbers in the patient

Discussion and conclusions

We treated the dAdV patient with sintilimab as a salvage therapy successfully and rapidly, though the additional efficacy of cidofovir cannot be completely ruled out. Concomitant EBV infection also seemed to respond to PD-1 blockade. Chen et al. reported that inhibitors targeting the PD-1 pathway could rescue T cells from an exhausted state and revive the immune response against EBV [ 9 ]. You et al. reported a successful case of sintilimab in the treatment of chronic active EBV infection after allogeneic HSCT [ 10 ], which, together with our case, suggests that PD-1 blockade has a curative effect on viral infections in HSCT setting.

The administration of PD-1 inhibitors in patients posttransplant has the risk of inducing GVHD, with one study showing that the incidence of GVHD can reach 55% [ 11 ]; hence the use of PD-1 inhibitors in the treatment of transplant recipients needs to be carefully managed. However, considering the relatively high mortality rate of dAdV infection, treatment with PD-1 inhibitors is still worth trying in patients with dAdV infection after HSCT.

Data availability

No datasets were generated or analysed during the current study.

Abbreviations

Programmed cell death 1

Epstein-Barr virus

Posttransplant lymphoproliferative disorders

Human adenovirus

• Hematopoietic stem cell transplantation
• Disseminated adenovirus disease

Copies per milliliter

Graft-versus-host disease

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Haverkos BM, Abbott D, Hamadani M, et al. PD-1 blockade for relapsed lymphoma post-allogeneic hematopoietic cell transplant: high response rate but frequent GVHD. Blood. 2017;130(2):221–8.

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Acknowledgements

We thank the patient, and her relatives, for their participation in this study, and the staff at The First Affiliated Hospital of Soochow University and Soochow Hopes Hematonosis Hospital who offered help to finish this report.

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In the author list, FZ, XH, SC wrote the main text, FD, ZW, and MX provide clinical materials of the patients, DW gave suggestions for polish and revise, XH and SC were responsible for staff management and workflow for the project. XH and SC initiated and was responsible for the whole work. All authors read and approved the final manuscript.

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Zhou, F., Du, F., Wang, Z. et al. PD-1 blockade immunotherapy as a successful rescue treatment for disseminated adenovirus infection after allogeneic hematopoietic stem cell transplantation. J Hematol Oncol 17 , 34 (2024). https://doi.org/10.1186/s13045-024-01557-2

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Correction to: Monozygotic Twins with MAGT1 Deficiency and Epstein-Barr virus-positive Classic Hodgkin Lymphoma Receiving anti-CD30 CAR T-cell Immunotherapy: A case Report

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Recent Advances in Cancer Immunotherapy

The strategy to use the immune system to fight cancer is not a novel concept; in 1891, Coley reported the treatment of three cases of sarcoma by inoculation with erysipelas [ 1 ]. However, less than 10 years have passed since cancer immunotherapy began attracting a great deal of attention from clinicians, oncologists, and cancer researchers.

In 2011, ipilimumab, an immune checkpoint inhibitor (ICI) that blocks CTLA-4, was the first ICI approved by the US FDA and used to treat patients with late-stage melanoma. This was rapidly followed by the development of monoclonal antibodies targeting another immune checkpoint molecule, PD-1, and its ligand PD-L1 [ 2 ]. These anti-PD-1 (nivolumab and pembrolizumab) and anti-PD-L1 agents (atezolizumab, durvalumab, and avelumab) have shown dramatic and durable response in clinical trials and have now become some of the most widely prescribed anticancer drugs for a wide range of malignancies including non-small cell lung cancer, melanoma, cutaneous squamous cell carcinoma, urothelial carcinoma, cervical cancer, Hodgkin’s lymphoma, head and neck squamous cell carcinoma, Merkel cell carcinoma, renal cell carcinoma, MSI-H or dMMR colorectal cancer, and hepatocellular carcinoma [ 3 ]. Furthermore, chimeric antigen receptor (CAR) T cell therapies have recently joined the list of approved cancer immunotherapies as treatments for mantle cell lymphoma or certain types of large B-cell lymphoma.

The dramatic development and evolution in cancer immunotherapies has accelerated basic, translational, and clinical research in this field. The purposes of these research studies include, but are not limited to, the following areas: (i) evaluating the immunological status of cancer/the tumor microenvironment, (ii) finding biomarkers to predict the efficacies of current immunotherapies, (iii) exploring inherent and/or acquired resistance mechanisms, and (iv) developing novel immunotherapies. Because cancer immunotherapies are active against a wide range of malignancies, the findings obtained in the analysis of one type of cancer may be applicable to other malignancies. Therefore, in this Special Issue, I set the scope to provide a broad (i.e., pan-cancer) and updated overview on the recent progress of all types of cancer immunotherapy research. The collection includes two original research papers and four well-summarized review articles.

Among these six papers, three are classified into topic (i) evaluating the immunological status of cancer/the tumor microenvironment. The first study is from our group, which reported that PD-L1 expression is significantly lower in lung adenocarcinomas with ground-glass opacity (GGO) compared with those without GGO (pure-solid tumors) [ 4 ]. This study reveals the immunological differences between these two types of lung adenocarcinomas. Additionally, the results of this report provided an important speculation regarding the prognostic impact of PD-L1 expression in lung adenocarcinomas, which had been controversial in previous studies [ 5 ]; the ratio of tumors with GGO, which are associated with favorable prognosis, will determine the apparent prognostic implication of PD-L1 expression in a cohort [ 4 ]. The second paper on this topic is a review article written by Fujimura et al. [ 6 ]. The authors comprehensively reviewed the roles of immunosuppressive cells, such as tumor-associated macrophages, myeloid-derived suppressor cells, regulatory T cells, and tumor-associated neutrophils in the development and maintenance of melanoma and non-melanoma skin cancers. The third study is a review paper written by Baleydier et al., which summarized a difficult but interesting issue: cancer immunotherapies for children with cancer with primary immunodeficiencies [ 7 ]. First, the authors summarized the list of primary immunodeficiencies prone to cancer (lymphoma or other hematological malignancies in most of the cases) and their corresponding gene defects (see Table 1 in their review) [ 7 ]. The authors then described the molecular mechanisms of immune deficiencies in each syndrome and the oncogenic mechanisms involved in tumorigenesis in children with primary immunodeficiencies. The authors finally summarized the possibilities of cancer immunotherapies, which were classified into humanized monoclonal antibodies, cell therapies including CAR T cells, and immunomodulators, for this specific cohort.

The second topic, (ii) biomarkers to predict the efficacies of current immunotherapies, is one of the hottest issues in the field of cancer immunotherapy research. PD-L1 expression, which is the only approved companion/complimentary diagnostic for the efficacy of anti-PD-1/PD-L1 agents, and other potential biomarkers, such as tumor mutation burden or infiltration of CD8 positive T cells, are all imperfect in predicting the efficacies of cancer immunotherapies. The paper by Fujimura et al. further highlights this point, stating that immunosuppressive cells are also the target of current immunotherapies and that tumor-associated macrophage-related biomarkers, such as soluble CD163 or CXCL5, will be useful to predict the efficacy of anti-PD-1 agents in melanoma [ 6 ].

(iii) Exploration for the inherent and acquired resistance mechanisms to cancer immunotherapies is also an important topic. In this Special Issue, two groups independently summarized the resistance mechanisms to checkpoint inhibitors in solid tumors [ 3 , 8 ]. Koustas et al. summarized the pan-cancer data for the resistance mechanisms to ICIs that include roles of the tumor microenvironment and autophagy, as well as genetic and epigenetic alterations (such as PTEN loss, JAK1/2 mutations, or microphthalmia-associated transcription factor suppression). The authors also summarized the clinical trials for many types of malignancies that are evaluating the combined immunotherapies to overcome ICI resistance (see Table 1 in their study) [ 8 ]. The second paper, written by Perrier et al., focused on the epigenetic changes (modifications of histones, DNA methylation, and miRNAs) that are related to ICI resistance. The authors also provide a useful summary of miRNAs that regulate PD-L1 expression in many types of cancer cells (see Table 2 in their study) [ 3 ].

Regarding topic (iv) developing novel immunotherapies, there is only one research article on this area in the Special Issue. In this study, Moz et al. reported that treatment with the vitamin D analogue calcipotriol prevented apoptosis signaling of peripheral blood mononuclear cells that is induced by pancreatic ductal adenocarcinoma cells [ 9 ].

The roles and impacts of cancer immunotherapies will expand dramatically, including through the development of immunotherapies for special populations, immunotherapy combinations, or immunotherapies in neoadjuvant or adjuvant settings. I expect that thematic issues for pan-cancer immunotherapies, as exemplified by this Special Issue, will accelerate the understanding of the immunological status of cancer/the tumor microenvironment, the exploration of novel predictive biomarkers for immunotherapies, the development of strategies to overcome inherent/acquired resistance to immunotherapies, and the clinical application of novel immunotherapies in the near future.

Conflicts of Interest

The author declares no conflict of interest related to this Special Issue.

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• Review Article
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• Published: 13 February 2023

Immunotherapy in breast cancer: an overview of current strategies and perspectives

• Véronique Debien 1 ,
• Alex De Caluwé   ORCID: orcid.org/0000-0001-5989-7017 2 ,
• Xiaoxiao Wang 3 ,
• Martine Piccart-Gebhart   ORCID: orcid.org/0000-0001-9068-8504 4 ,
• Vincent K. Tuohy 5 ,
• Emanuela Romano   ORCID: orcid.org/0000-0002-1574-5545 6 &
• Laurence Buisseret   ORCID: orcid.org/0000-0002-3751-0819 3 , 7  

npj Breast Cancer volume  9 , Article number:  7 ( 2023 ) Cite this article

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• Breast cancer

Recent progress in immunobiology has led the way to successful host immunity enhancement against breast cancer. In triple-negative breast cancer, the combination of cancer immunotherapy based on PD-1/PD-L1 immune checkpoint inhibitors with chemotherapy was effective both in advanced and early setting phase 3 clinical trials. These encouraging results lead to the first approvals of immune checkpoint inhibitors in triple-negative breast cancer and thus offer new therapeutic possibilities in aggressive tumors and hard-to-treat populations. Furthermore, several ongoing trials are investigating combining immunotherapies involving immune checkpoint inhibitors with conventional therapies and as well as with other immunotherapeutic strategies such as cancer vaccines, CAR-T cells, bispecific antibodies, and oncolytic viruses in all breast cancer subtypes. This review provides an overview of immunotherapies currently under clinical development and updated key results from clinical trials. Finally, we discuss the challenges to the successful implementation of immune treatment in managing breast cancer and their implications for the design of future clinical trials.

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Introduction.

Cancer immunotherapy represents one of the most significant advances in oncology in recent years. It has demonstrated impressive anti-tumor activity and a durable clinical benefit in diverse malignancies with recent success in triple-negative breast cancer (TNBC). Historically considered poorly immunogenic, breast cancer (BC) was initially not extensively investigated for its susceptibility to immunotherapy. However, recent breakthroughs with immune checkpoint inhibitors (ICI) in other cancers coupled with increasing evidence of the influence of the immune system in cancer behavior, have led to the development of clinical trials evaluating different types of immune therapeutic strategies for BC patients. The presence of tumor-infiltrating lymphocytes (TILs) in the tumor microenvironment (TME) reflects a pre-existing anti-tumor immune response and is associated with a better prognosis and response to chemotherapy 1 . The immune response captured through immune-related tumor gene expression in microarray-based analyses also demonstrated that immune gene signatures were associated with a favorable clinical outcome, particularly in TNBC and Human Epidermal Growth factor Receptor 2 (HER2)-positive BC 2 , 3 . In using immunophenotyping analyses or transcriptomic approaches, different immune cell subsets were identified in the TME and their participation in a pro- or anti-tumor immune response has been demonstrated given their influence on BC clinical outcomes 4 . Among CD8+ T cells, the cytotoxic subpopulation is able to kill cancer cells and is associated with improved survival in patients, whereas the presence of immunosuppressive regulatory CD4+ T cells (Tregs) or macrophages is associated with a worse prognosis 4 .

The extent and composition of immune infiltrates are highly variable between BC subtypes and within each subtype 5 , 6 . Therefore, it is expected that not all BC patients would benefit from the same immunotherapeutic strategy to restore or elicit an anti-tumor immune response 5 . Predictive biomarkers are required to select patients and tailor therapies beyond the established BC subtypes. Programmed death-ligand 1 (PD-L1) immunohistochemistry (IHC) expression is the most widely used biomarker, but not sufficient, as it only appears to have predictive value in metastatic TNBC (mTNBC). Tumor mutational burden (TMB) is a marker of tumor foreignness and immunogenicity, as mutated antigens are recognized by T cells to initiate a cytotoxic response. Mutational load is highly variable in BC, and tumors that present high TMB may respond more favorably to ICI 7 . Tumor antigens have also been investigated in vaccination strategies, as demonstrated by the increasing number of clinical trials evaluating the preventive and therapeutic effects of cancer vaccines. Emerging modalities such as bispecific antibodies (BsAbs) or adoptive cell therapies involving TILs or chimeric antigen receptor T (CAR-T) cells are an area of current research.

This review describes recent advances in immunotherapy to treat BC and summarizes the challenges of implementing such treatments in a heterogeneous disease. We also present a comprehensive overview of the immunotherapeutic combinations currently investigated in clinical trials.

Clinical landscape and update of early results

The clinical development of immunotherapy in BC started more than 20 years ago, but it is only with the discovery of ICI that number of clinical trials testing immunotherapeutic strategies increased (Fig. 1A ) 8 . In January 2022, 745 immunotherapy-based trials enrolling patients with solid tumors, including BC, were identified on clinicaltrials.gov , with 450 (60.4%) exclusively dedicated to BC. Interestingly, our analysis shows a constant increase in the development of vaccines in the last 20 years, whereas more recent immunotherapeutic approaches increased exponentially since 2015 (Fig. 1A ).

Panels A – C show the number of clinical trials in breast cancer since early 2000, by immunotherapeutic approach ( A ), by trial setting ( B ), and by trial phase ( C ). Panel D shows the major immune targets. Only targets present in two or more trials are represented. The complete list of targets is available in online Supplementary Table 1 . Panel E shows the histogram of combination trials with PD-1/PD-L1 ICI backbone. ADC antibody-drug conjugates, ICI immune checkpoint inhibitors, mAbs monoclonal antibodies, Neo-adj neoadjuvant.

The number of trials is increasing both in the advanced setting and in early BC. In 2018, the number of neoadjuvant trials exceeded the number of adjuvant trials (Fig. 1B ), and a shift of phase 1 trials towards phase 2 and 3 trials is clearly observed (Fig. 1C ). Of note, the large phase 3 trials are sponsored by pharmaceutical companies, whereas the observed rise of phase 2 investigator-initiated studies indicates an enhanced global effort to investigate novel immunotherapy strategies.

The most studied co-inhibitory receptor is programmed death-1 (PD-1). Multiple monoclonal antibodies (mAbs) targeting PD-1 or its ligand PD-L1 have been developed (Fig. 1D ). Other molecules targeting immune checkpoints to prevent the inhibition of T cells (e.g., CTLA-4, LAG3, and TIGIT) or to stimulate T cells and increase their cytotoxic activity (e.g., OX-40 and 4-1BB) are being tested. HER2 represents the most studied target for vaccines but is also used by BsAbs and other directed therapies (Fig. 1D ). Recently, new combination strategies beyond ICI aiming to increase response rates (RR) and clinical benefit have been initiated with the hope of improving survival outcomes (Fig. 1E ).

Immune checkpoint combinations

Metastatic breast cancer.

In early phase trials, PD-1/PD-L1 ICI was primarily evaluated in monotherapy, enrolling heavily pretreated metastatic patients 9 . The response rates (RR) were only 5–20%, with increased efficacy in patients with PD-L1-positive TNBC, lower tumor burden, and non-visceral disease 10 . Nevertheless, few responders achieved long-lasting responses with survival benefit 11 , 12 . However, the KEYNOTE-119 trial, in which pembrolizumab monotherapy was compared to chemotherapy, failed to improve overall survival (OS) beyond the first line in mTNBC (Table 1 ) 13 .

Higher RR were observed with ICI combined with chemotherapy as first-line therapy in advanced TNBC, leading to randomized phase 3 trials in this setting 10 , 14 . The IMpassion130 trial demonstrated a gain of 2.5 months in progression-free survival (PFS) for patients treated with atezolizumab plus nab-paclitaxel whose tumors have PD-L1 ≥1% immune cells with the VENTANA SP142 immunohistochemistry (IHC) assay 15 . Based on these results, atezolizumab received accelerated approval from the United States Food and Drug Administration (FDA) in March 2019. However, FDA approval for atezolizumab was later withdrawn due to a lack of clinical benefit, because the final PFS and first OS interim analyses in the intention-to-treat (ITT) population did not cross the boundary for statistical significance 16 . The initially planned testing procedure was hierarchical, meaning that the analysis in the PD-L1 positive subgroup could be tested only if the primary endpoint in the overall cohort was met. Therefore, the OS results suggesting a survival benefit in the PD-L1 positive subgroup results must be interpreted with caution. Furthermore, the IMpassion131 trial enrolled a similar population but evaluated the combination of atezolizumab with paclitaxel (instead of nab-paclitaxel), and it also failed to demonstrate an improved outcome (neither PFS nor OS) even in the PD-L1-positive subgroup (Table 1 ) 17 . The use of immunosuppressive steroids for premedication to prevent hypersensitivity reactions with paclitaxel has been incriminated in these discordant results. In the ongoing IMpassion132 trial enrolling TNBC patients with early relapses (<12 months), the chemotherapy partners are carboplatin and gemcitabine or capecitabine 18 . In the KEYNOTE-355 trial, pembrolizumab was used in combination with paclitaxel, nab-paclitaxel, or gemcitabine plus carboplatin in first-line therapy for patients with mTNBC. The primary PFS results led to the approval of the drug by the FDA in November 2020 for patients with PD-L1-positive tumors 19 . Recently, the OS benefit was confirmed in patients with a PD-L1 combined positive score (CPS) ≥10 assessed by the IHC 22C3 pharmDx test 20 .

In luminal BC, the first attempts to combine ICI and chemotherapy were disappointing. In initial trials, no improved outcomes were reported, such as in a phase 2 study evaluating eribulin with or without pembrolizumab in metastatic luminal BC 21 . Results are expected from ongoing studies investigating the safety and efficiency of ICI in combination with endocrine therapies and Cyclin D Kinase 4/6 inhibitors (CDK4/6i). In preclinical models, CDK4/6i enhanced tumor antigen presentation, decreased Tregs proliferation, and modulated T cell activation by reducing the expression of inhibitory receptors such as PD-1 22 , 23 . The phase 1b trial, evaluating the combination of abemaciclib with pembrolizumab with or without endocrine therapy in ER-positive metastatic BC, with or without anastrozole, were complicated by increased hepatic toxicity, interstitial lung disease, and two toxic death in the triplet arm 24 . In contrast, the triple association of letrozole, palbociclib, and pembrolizumab was well tolerated in a phase 1/2 trial 25 .

In metastatic HER2-positive BC, the combination of trastuzumab with pembrolizumab showed a 15% RR in patients with trastuzumab-resistant PD-L1-positive tumors 26 . In combination with T-DM1, atezolizumab did not improve PFS but increased toxicity 27 .

Poly ADP ribose polymerase (PARP) inhibitors can lead to DNA damage and genomic instability, which could increase cancer cell immunogenicity and enhance the sensitivity to immunotherapies 28 . In BRCA-deficient BC, the combination of ICI with PARP inhibitors is under investigation. The RR (objective RR or disease control rate) was promising in two phases 2 trials evaluating the combination of durvalumab and olaparib or pembrolizumab and niraparib in first-line or pretreated patients with germline BRCA1 or BRCA2 mutations (Table 1 ) 29 , 30 .

Early breast cancer

Although many questions remain unanswered in the metastatic setting, several trials examined the use of immunotherapy in early BC. In theory, the early setting could be more appropriate for immunotherapy as the tumor burden is more limited, the biological background is more homogeneous, and the TME is less immunosuppressive and unimpacted by previous systemic treatments 31 . The majority of trials in early BC are now conducted in a neoadjuvant rather than in an adjuvant setting (Fig. 1B ) because it offers the advantage of evaluating the clinical and imaging response before surgery and the pathological response after surgery, the latter being a possible surrogate endpoint for the long-term clinical benefit 32 . Moreover, the presence of the primary tumor could serve as a source of neoantigens. Notably, in preclinical models, the neoadjuvant immunotherapeutic approach demonstrated enhanced efficacy compared with the adjuvant setting 33 .

Similarly, as with metastatic disease, the majority of neoadjuvant trials were conducted in the TNBC subtype. In the landmark phase 3 KEYNOTE-522 trial, stage II and III patients received neoadjuvant chemotherapy (NACT) associated with pembrolizumab or placebo concomitant with NACT and then continued in the adjuvant setting 34 . The pathological complete response (pCR) rates were superior in the experimental arm (64.8 vs. 51.2%), and the overall pCR benefit was more significant for patients with node-positive disease (∆ pCR rate of 20.6 vs. 6.3%) (Table 1 ). The estimated event-free survival (EFS) rate at 36 months favored the pembrolizumab-chemotherapy combination (HR = 0.63, 95% CI 0.48–0.82, absolute gain 7.7%) 34 . The combination of neoadjuvant pembrolizumab plus chemotherapy, followed by adjuvant pembrolizumab, is an FDA-approved regimen for early TNBC as of July 2021.

While the KEYNOTE-522 trial used paclitaxel with carboplatin followed by anthracycline with cyclophosphamide every 3 weeks, combined with an anti-PD-1, the neoadjuvant trials IMpassion031 and GeparNUEVO combined nab-paclitaxel with an anti-PD-L1 (atezolizumab or durvalumab) 35 , 36 , 37 . The NeoTRIPaPDL1 trial combined nab-paclitaxel with carboplatin without anthracyclines in the neoadjuvant setting 37 . In IMpassion031, the addition of atezolizumab to nab-paclitaxel followed by dose-dense anthracycline-based chemotherapy resulted in a significant increase in pCR rate: 41 vs. 58%, (∆ pCR rate 17%, 95% CI 6–27, one-side p  = 0.0044) (Table 1 ) 35 . However, NeoTRIPaPDL1 and GeparNUEVO trials could not demonstrate a substantial increase in pCR rates, highlighting the complexity of comparing different trials 37 , 38 . Even if there had been no difference in pCR rates in the GeparNUEVO trial, the addition of durvalumab to NACT significantly improved 3-year disease-free survival (DFS) and OS, questioning the validity of pCR as a surrogate endpoint in neoadjuvant immunotherapy trials (Table 1 ) 38 . Interestingly, pCR was only improved in patients treated in the window-of-opportunity part, in which durvalumab was given for 2 weeks before starting chemotherapy. Contrarily to the metastatic setting, PD-L1 IHC expression was not predictive of pCR, while TIL levels and dynamic TILs increase were associated with a better response in the retrospective analyses of KEYNOTE-173, GeparNuevo, and NeoTRIPaPDL1 trials 7 , 37 , 39 .

Less data were available for luminal and HER2-positive BC 40 , 41 , 42 . In phase 2 adaptively randomized I-SPY2 trial, adding pembrolizumab to NACT (weekly paclitaxel followed by doxorubicin-cyclophosphamide) was shown to be beneficial amongst patients with HER2-negative BC 40 . Pembrolizumab increased the pCR rate from 13 to 30% in luminal BC, which is a notable result given that in the metastatic setting, no benefit of ICI was found in this subtype. Nevertheless, compared to TNBC, the chemotherapy-ICI combination seems to generate lower pCR rates in luminal cancer, as expected, given its ‘colder’ immune phenotype. The ongoing phase 3 KEYNOTE-756 trial will shed light on the possible benefit of adding ICI to chemotherapy in grade III luminal BC 42 . The use of priming agents to elicit an immune response might be necessary to turn cold luminal BC into hot tumors 43 . For example, radiation therapy, which is a DNA-damaging agent, can be used to induce T cell priming via antigenic release and MHC-I upregulation. In addition, radiation activates innate immunity through several mechanisms, such as dendritic cells (DCs) activation 44 . This strategy is under evaluation in the Neo-CheckRay trial in luminal B MammaPrint high-risk BC 45 . The neoadjuvant chemotherapy-free strategy with ICI combined with endocrine therapy and CDK4/6i for luminal early BC resulted in increased hepatic toxicity 46 .

In HER2-positive BC, the randomized placebo-controlled phase 3 study IMpassion050 that evaluated the addition of atezolizumab to NACT and dual anti-HER2 blockade did not induce a significant increase in pCR rate in ITT nor PD-L1 positive population 47 . In addition, the median EFS, a secondary endpoint, was not reached in both arms 48 .

Fewer studies are being conducted in the adjuvant and post-neoadjuvant settings (Fig. 1B ). Indeed, larger sample sizes are required as well as a longer follow-up, therefore exposing more patients with potentially curable BC to a hypothetically effective and potentially toxic experimental treatment. Of note, the continuation of ICI after neoadjuvant chemotherapy is still unclear in the context of post-neoadjuvant therapies with capecitabine in TNBC and olaparib for patients with germline BRCA1 or BRCA2 mutations 49 , 50 .

Longer follow-up will help to better delineate the benefit versus harm ratio of ICI, which will ultimately dictate the optimal use of immunotherapeutic approaches in early BC. Although the safety profiles with ICI in BC clinical trials were comparable to clinical trials in other tumor types, the risk of long-term side effects in patients treated with curative intent should be taken into consideration as some immune-related adverse events (irAE) could be responsible for chronic diseases 51 , 52 . Moreover, some irAE should be carefully assessed in the perioperative period, particularly endocrine toxicity such as hypopituitarism with the potential risk of adrenal crisis during or after surgical intervention 51 , 53 .

Breast cancer vaccines

When the FDA approved trastuzumab in 1998 as the first monoclonal antibody for cancer treatment, the entire approach to cancer therapy changed. Ever since, there has been a relentless focus on HER2 as a predominant therapeutic target for HER2-positive cancers. However, despite the effectiveness of HER2 as a target for antibody-mediated receptor antagonism, it has met with conflicting and often perplexing results as a cancer vaccine target.

HER2 is a large molecule; therefore, most of the human HER2 cancer vaccines target one or more of the following three HER2-derived peptides: (1) E75 (Nelipepimut-S, NP-S, HER2 369–377, or NeuVax), an HLA-A2-restricted non-peptide derived from the extracellular domain of HER2 and designed to activate CD8+ T cells; (2) GP2 (HER2 654–662), another HLA-A2-restricted nonapeptide derived from the transmembrane domain of HER2 and also designed to activate CD8+ T cells in an HLA-A2-restricted manner; and (3) AE37 (HER2 776–790) an MHC class-II restricted 12-mer peptide derived from the intracellular domain of HER2 but modified by the addition of the four amino acids long Ii-Key peptide LRMK for enhancing the activation of CD4+ T cells 54 .

The results of phase 1/2 trials involving vaccination of BC patients with one or more of these HER2 peptides showed no significant clinical benefit, but exploratory subgroup analyses surprisingly indicated that patients with HER2-low-expressing tumors, including TNBC patients, may have derived a clinical benefit 55 , 56 . However, a subsequent phase 3 clinical trial involving E75 vaccination of patients, including TNBC patients, with node-positive HER2-low expressing breast tumors was stopped early when an interim analysis of the trial data showed that there was no significant difference in the primary endpoint of DFS between E75 vaccinated and placebo vaccinated subjects 57 .

Despite the confounding use of a HER2 vaccine in patients with HER2-low and HER2-negative BC, treatment of mTNBC with AE37 peptide vaccination has continued (NSABP FB-14). Moreover, a dendritic cell vaccine targeting HER2 and HER3, has been used to treat TNBC patients with brain metastases 58 . Further confusing the area, a recent meta-analysis of 24 clinical studies involving a total of 1704 vaccinated patients and 1248 control subjects found that E75 vaccination caused significant improvement in disease recurrence rate and DFS but no significant difference in OS 59 . One can only speculate how a vaccine targeting HER2 could possibly be effective in treating patients with HER2-negative tumors but not HER2-positive tumors, yet the confounding saga of HER2 vaccination continues.

The HER2 vaccine story certainly reveals the frustration that clinical investigators have had in finding a targeted treatment for TNBC, a BC subtype that expresses none of the traditional targets for BC therapy, including estrogen and progesterone receptors, and HER2. Moreover, TNBCs overexpress several non-HER2 tumor-associated antigens (TAAs), many of which have been the focus of numerous cancer vaccine clinical trials.

Perhaps the most commonly targeted non-HER2 TAAs for cancer vaccination have been the cancer-testis antigens (CTAs). These proteins are normally expressed in embryonic stem cells and testicular germ cells, minimally expressed in most other normal tissues but often expressed at high levels in many different tumors 60 . Several hundred CTAs have been identified, and many have served as targets in vaccination involving patients with TNBC 61 . Perhaps the most notable is cancer/testis antigen 1B (NY-ESO-1) 62 . Several other CTAs have been targeted in the vaccination of TNBC patients, including Wilms’ tumor protein (WT1) 63 , 64 the melanoma antigen gene protein-12 (MAGE-12), the folate receptor alpha (FRα), the T-box transcription factor brachyury 65 and the tumor suppressor transcription factor p53 66 .

One of the more interesting TAAs for targeting TNBC is Mucin 1 (MUC1), a hyperglycosylated, immunologically unavailable protein in many normal epithelial cells but a hypoglycosylated, immunologically available protein in several malignant tumors, including TNBC 67 . Several MUC1 vaccines have been tested in TNBC clinical trials. A number of cancer vaccines that target multiple TAAs have been developed for therapy against TNBC, including the PVX-410 vaccine that consists of peptides derived from the transcription factor X-box binding protein 1 (XBP1), the plasma cell marker syndecan-1 (CD138), and the NK cell receptor CD319 (CS1), as well as STEMVAC, a DNA vaccine encoding multiple peptides of CD105 (Endoglin), Y-box binding protein 1 (Yb-1), SRY-box 2 (SOX2), cadherin 3 (CDH3), and murine double minute 2 (MDM2) proteins. In addition, the vaccine-based immunotherapy regimen-2 (VBIR-2) has been used to treat patients with non-small cell lung cancer (NSCLC) and patients with TNBC, and apparently consists of several immunomodulators as well as multiple vaccinations against prostate-specific antigen (PSA), prostate-specific membrane antigen (PSMA), and prostate stem cell antigen (PSCA). Vaccination against PSMA and the preferentially expressed antigen in melanoma (PRAME) has also been used to treat TNBC patients 68 .

It is important to note that not all TNBC vaccines target TAA proteins. Indeed, tumor-associated carbohydrate (TAC) antigens that are frequently poor immunogens can be targeted using molecular mimic peptides or mimotopes that induce antibodies that cross-react with the human TAC antigen 69 . Such a mimotope vaccine called P10s-PADRE is currently being tested in clinical stage I-III TNBC patients. In addition, a vaccine that targets a non-protein hexasaccharide with a ceramide attached to its terminal glucose ring, the Globo H glycosphingolipid antigen, has reached phase 3 clinical trial status in patients with Globo H+ TNBC tumors 70 .

Despite decades of intense efforts using therapeutic cancer vaccines, the results have been modest or confounding at best. However, much has been learned about immunology in the past several decades, and recent cancer vaccine strategies may prove to be more effective than prior generations of cancer vaccines. Individual tumors have their own set of distinct mutations, many of which have the potential to be highly immunogenic for each individual patient. Such mutated proteins are called neoantigens, and recent clinical trials have focused on isolating these neoantigens and vaccinating individual TNBC test subjects with personalized neoantigen vaccines that include traditional vaccine/adjuvant combinations, vaccination with DNA-based vaccines, vaccination involving autologous dendritic cells, and even mRNA vaccination.

Finally, in light of the very successful prophylactic childhood vaccination program against infectious diseases, one may wonder why TNBC cancer vaccines have long been exclusively treatment vehicles 71 . Even when vaccines are used to prevent the recurrence of pre-existing tumors, they are still treatment vehicles. However, it has recently been proposed that vaccination against the human lactation protein, α-lactalbumin, may provide safe and effective primary prevention of TNBC because α-lactalbumin is a “retired” self-protein that is expressed exclusively in the breast only during late pregnancy and lactation but is expressed in >70% of TNBCs 72 . Thus, preemptive α-lactalbumin immunity provided to women at high risk for developing TNBC due to carrying mutations in their BRCA1 genes 73 may provide safe and effective primary prevention of TNBC as long as lactation is avoided. A phase 1 clinical trial to start this clinical testing process has very recently been initiated, with the first patient vaccinated in 2021. Thus, perhaps the focus of cancer vaccinations in the future may be to provide therapeutic immunity in a personalized manner to multiple neoantigens or to provide neoantigen or ‘retired’ self-protein immunity preemptively for the greatest effectiveness.

Other immunotherapeutic strategies under development

Adoptive cell therapies (ACTs) consist of identifying and isolating peripheral blood or tumor-resident T cells in order to modify, activate and expand these cells ex vivo before transferring them back into the patient 74 . ACTs can be classified into TIL-based therapies, T cell receptor (TCR) gene therapy, and CAR-T cells. The latter technology has already provided prolonged responses and remissions for patients with advanced hematological malignancies 75 .

First attempts to reintroduce autologous lymphokine-activated lymphocytes to treat patients with advanced solid tumors were undertaken years ago without relevant results in BC patients 76 . Of note, clinical trials evaluating ACTs were conducted in early phase trials enrolling a small number of patients, including very few with BC 77 . Recently, infusion of autologous activated lymphocytes against specific tumor antigens was demonstrated able to induce a long-lasting response in a patient with chemotherapy-refractory luminal metastatic BC treated with mutant-protein-specific TILs in conjunction with IL-2 and pembrolizumab 78 . In a study evaluating the feasibility of c-MET CAR-T cells, the best response was a stable disease for only one patient with ER-positive HER2-negative disease among the six patients with metastatic BC 79 . In solid tumors, the development of ACTs has been hampered by the heterogeneity of the antigenic landscape, the hostile TME conditions, and the lack of T cell infiltration in the tumor nests. Several strategies are under development to overcome these issues. Thus, promising CAR-T cell targets like HER2, MUC1, or Mesothelin have been identified for the treatment of BC patients 80 . The identification of neoantigens and the use of other immune cell types, such as NK cells or DCs offer new opportunities for ACTs.

Another challenge to develop ACTs is the toxicities related to lymphodepletion and to immune-mediated side effects such as neurotoxicity and cytokine release syndrome, two potentially lethal conditions. Cytokine release syndrome is a systemic inflammatory response with organ dysfunction that can be reversible if promptly diagnosed and managed 81 . In addition to the management of these toxicities, the complexity of manufacturing ACTs limits the development of cellular therapy programs in specialized cancer centers 82 .

Another type of engineered molecule are BsAbs designed to recognize two different epitopes or antigens on tumor cells and immune cells allowing immune recognition of these cancer cells 83 . A variety of BsAbs relevant to BC are in development 84 . Zanidatamab, BsAb, targets two different HER2 epitopes, in combination with chemotherapy, was well-tolerated, and has shown anti-tumor activity in heavily pretreated HER2-amplified metastatic BC patients 85 . In TNBC, BsAbs from a large panel of tissue agnostic targets such as CD3, CEACAM5, epithelial cell adhesion molecule (EpCAM), epithelial growth factor receptor (EGFR), mesothelin including Trop2 are under investigation 83 .

Conclusions and perspectives

Although the development of cancer immunotherapy in BC began more than 20 years ago, its integration into patient care was slower than in other tumor types. The current extensive clinical research landscape will hopefully change this situation and expand the use of ICI and other immunotherapies in BC beyond the TNBC subtype. As reviewed herein, the number of clinical trials evaluating multiple immunotherapeutic strategies is increasing across all BC subtypes. The FDA approval of ICI plus chemotherapy in TNBC will provide real-world data that will help to better evaluate the benefit of this therapeutic strategy in underrepresented in landmark clinical trials populations, specifically Black patients. Comprehensive translational research and the use of biomarkers will help avoid the development of “add-on designs” which adds a new immune drug to a clinically established modality without leading to the development of adequate strategies for each individual patient. Indeed, the first results from biomarker analyses in immunotherapy TNBC trials highlight the heterogeneity of this disease and the urgent need to better characterize the TME to tailor immunotherapeutic approaches 37 , 86 . The predictive value of several biomarkers, including TIL levels, presence of tertiary lymphoid structures, or expression of immune gene signatures, is under investigation and has already been retrospectively evaluated in some clinical trials 7 , 37 , 87 . Only PD-L1 IHC expression is currently used to select TNBC patients for ICI in the metastatic setting. Moreover, its use in clinical practice remains controversial and complicated by the availability of several mAb and scoring systems and by the limited inter-observer agreement of PD-L1 scoring 88 . Blood-based biomarker research is ongoing, and liquid biopsies may become a noninvasive alternative to tissue biopsies in predicting and monitoring treatment responses.

Immunotherapy is associated with unique and sometimes severe irAEs that will require multidisciplinary collaborative efforts to offer adequate management of the increasing number of patients treated with ICI and to treat emerging toxicity from new immune-modulating agents and ACTs 82 . Another challenge for developing immunotherapy is to define an adequate response assessment, as the pattern of responses to ICI is different from that due to chemotherapeutic agents. Immune Response Evaluation Criteria in Solid Tumors (iRECIST) to better capture the benefit of immunotherapy have been developed, but most trials are still using the conventional RECIST 89 . In BC, pCR after NACT is a surrogate endpoint for a long-term clinical outcome, which might be less appropriate to capture long-term immune memory responses that could sustain therapeutic effects and prevent relapses, as recently suggested by the results of the GeparNUEVO study 32 , 38 . The development of adequate endpoints and new imaging techniques to measure the immune response could refine our approach to tumor response assessment and our criteria predictive of benefit from a given therapy.

Future clinical investigations will also need to address the question of de-escalation strategies for patients with long-term benefits. The excellent outcome observed in the absence of chemotherapy in patients with high TILs, and early-stage TNBC has led to the design of neoadjuvant immunotherapy trials omitting chemotherapy (e.g., NCT04427293) 90 . For non-responders, the improved understanding of tumor-immune interactions and the contribution of the TME, notably with the help of the latest technologies such as single-cell analyses and spatial transcriptomics, may provide new drug targets and strategies to overcome resistance 91 , 92 .

In summary, the clinical research landscape of immunotherapy in BC is expanding with novel investigational therapies aimed at initiating, restoring, or triggering patients’ immune responses against tumor cells. Innovative drugs combinations have already demonstrated an improved outcome for some BC patients, and these new therapeutic strategies will gradually be integrated into clinical treatments.

Reporting summary

Further information on research design is available in the Nature Research Reporting Summary linked to this article.

Data availability

The data used for the Fig. 1 design are available in supplementary table 1 . Data extracted from https://clinicaltrials.gov/ with research terms “breast”, “nivolumab”, “pembrolizumab”, “avelumab”, “atezolizumab”, “durvalumab”, “ipilimumab”, “tremelimumab”, “CAR-T”, “Bispecific”, “Vaccine”, “immunotherapy”, “4-1BB”, “OX-40”, “LAG”, “TIGIT”, “PD-1”, “PD-L1”, and “NK cells”. Data extracted on January 14, 2022.

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The authors thank Prof. Christos Sotiriou for the helpful discussions. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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V.D.: Conceptualization, formal analysis, investigation, resources, writing—original draft, visualization, writing—review and editing, and validation. A.D.C.: Formal analysis, investigation, resources, writing—original draft, data research, writing— review and editing, and validation. X.W.: Formal analysis, investigation, resources, writing—original draft, writing—review and editing, and validation. M.P.-G.: Writing—review and editing and validation. V.K.T.: Investigation, writing—original draft, writing—review and editing, and validation. E.R.: Writing—original draft, writing—review and editing, and validation. L.B.: Conceptualization, writing—original draft, visualization, writing—original draft, and validation. All co-authors, after proofreading, approved the final version of the manuscript.

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V.D. and X.W. declare no competing financial or non-financial interests. The following authors declare no competing non-financial interests but the following competing financial interests: A.d.C.: Investigator-initiated trial (funds paid to institution): AstraZeneca. M.P.-G.: Board Member (Scientific Board): Oncolytics; Consultant (honoraria): AstraZeneca, Camel-IDS, Crescendo Biologics, G1 Therapeutics, Genentech, Huya, Immunomedics, Lilly, Menarini, MSD, Novartis, Odonate, Oncolytics, Periphagen, Pfizer, Roche, Seattle Genetics, Immutep, NBE Therapeutics, SeaGen; Research grants to her Institute: AstraZeneca, Lilly, MSD, Novartis, Pfizer, Radius, Roche-Genentech, Servier, Synthon (outside the submitted work). V.K.T.: Funding from the Department of Defense Breakthrough Award, Level 3 Clinical Trial for Primary Immunoprevention of Triple-Negative Breast Cancer, Anixa Biosciences, Inc. V.K.T. holds personal equity in Anixa Biosciences, Inc. ER: Investigator-initiated trial (funds paid to institution): AstraZeneca, BMS, Roche, Replimmune. Consultancy/advisory board: AstraZeneca, Merck, Roche, Pierre Fabre. L.B.: Investigator-initiated trial (funds paid to institution): AstraZeneca. L.B. is supported by the Belgian “Fondation Contre le Cancer”.

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Debien, V., De Caluwé, A., Wang, X. et al. Immunotherapy in breast cancer: an overview of current strategies and perspectives. npj Breast Cancer 9 , 7 (2023). https://doi.org/10.1038/s41523-023-00508-3

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