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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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Cancer research highlights from 2023

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By Mayo Clinic staff

Researchers at Mayo Clinic Comprehensive Cancer Center spent 2023 studying the biology of cancer and new ways to predict, prevent, diagnose and treat the disease. Their discoveries are creating hope and transforming the quality of life for people with cancer today and in the future. Here are some highlights from their research over the past year:

Mayo Clinic researchers link ovarian cancer to bacteria colonization in the microbiome.

A specific colonization of microbes in the reproductive tract is commonly found in people with ovarian cancer, according to a study from the Mayo Clinic  Center for Individualized Medicine . Published in  Scientific Reports  and led by  Marina Walther-Antonio, Ph.D. , a Mayo Clinic researcher, and Abigail Asangba, Ph.D., the discovery strengthens the evidence that the bacterial component of the microbiome — a community of microorganisms that also consists of viruses, yeasts and fungi — is an important indicator for early detection, diagnosis and prognosis of ovarian cancer . The study also suggests that a higher accumulation of pathogenic microbes plays a role in treatment outcomes and could be a potential indicator for predicting a patient's prognosis and response to therapy.  Read more .

Artificial intelligence is forging a new future for colorectal cancer and other digestive system diseases.

Colonoscopy remains the gold standard in detecting and preventing colorectal cancer , but the procedure has limitations. Some studies suggest that more than half of post-colonoscopy colon cancer cases arise from lesions missed at patients' previous colonoscopies. In 2022, Michael Wallace, M.D. , a Mayo Clinic gastroenterologist, published the results  of an international, multicenter study testing the impact of adding artificial intelligence (AI) to routine colonoscopies. His team, including James East, M.D. , a Mayo Clinic gastroenterologist, and other researchers from the U.S., the U.K., Italy, Germany and Ireland, found that incorporating AI into colonoscopies reduced the risk of missing polyps by 50%.  Read more .

A big step forward: Bringing DNA sequencing data to routine patient care.

The Tapestry study , an extensive genomic sequencing clinical research study, aims to complete exome sequencing (sequencing the protein-coding regions of a genome) for 100,000 Mayo Clinic patients. The results will be integrated into patients’ electronic health records for three hereditary conditions, and the amassed data will contribute to a research dataset stored within the Mayo Clinic Cloud on the Omics Data Platform. The overall hope of Tapestry is to accelerate discoveries in individualized medicine to tailor prevention, diagnosis and treatment to a patient's unique genetic makeup. It is poised to advance evidence that exome sequencing, when applied to a diverse and comprehensive general population, can proficiently identify carriers of genetic variants that put them at higher risk for a disease, allowing them to take preventive measures.  Read more .

Patients with multiple tumors in one breast may not need a mastectomy.

Patients who have multiple tumors in one breast may be able to avoid a mastectomy if surgeons can remove the tumors while leaving enough breast tissue, according to research led by the  Alliance in Clinical Trials in Oncology  and  Mayo Clinic Comprehensive Cancer Center . Patients would receive breast-conserving therapy — a  lumpectomy  followed by whole-breast  radiation therapy — rather than mastectomy . The study is published in the  Journal of Clinical Oncology . Historically, women with multiple tumors in one breast have been advised to have a mastectomy. Now, patients can be offered a less invasive option with faster recovery, resulting in better patient satisfaction and cosmetic outcomes, says  Judy Boughey, M.D. , lead author, Mayo Clinic breast surgical oncologist and the W.H. Odell Professor of Individualized Medicine. Read more .

Staging pancreatic cancer early with minimally invasive surgery shows positive results in patient prognosis.

A study published in the  Journal of the American College of Surgeons  reveals that performing a minor surgical procedure on patients newly diagnosed with  pancreatic cancer  helps to identify cancer spread early and determine the stage of cancer. The researchers add that the surgery ideally should be performed before the patient begins chemotherapy. "This is an important study because it supports that staging laparoscopy may help determine a patient's prognosis and better inform treatment so that patients avoid unhelpful or potentially harmful surgical therapy," says  Mark Truty, M.D. , a Mayo Clinic surgical oncologist who led the research.  Read more .

Mayo Clinic study reveals proton beam therapy may shorten breast cancer treatment.

In a trial published in  The Lancet Oncology , Mayo Clinic Comprehensive Cancer Center researchers uncovered evidence supporting a shorter treatment time for people with breast cancer . The study compared two separate dosing schedules of pencil-beam scanning proton therapy , known for its precision in targeting cancer cells while preserving healthy tissue to reduce the risk of side effects. The investigators found that both 25-day and 15-day proton therapy schedules resulted in excellent cancer control while sparing surrounding non-cancerous tissue. Further, complication rates were comparable between the two study groups. "We can now consider the option of 15 days of therapy for patients based on the similar treatment outcomes observed," says  Robert Mutter, M.D. , a Mayo Clinic radiation oncologist and physician-scientist. Read more .

Harnessing the immune system to fight ovarian cancer.

Mayo Clinic research is biomanufacturing an experimental, cell-based ovarian cancer vaccine and combining it with immunotherapy to study a "one-two punch" approach to halting ovarian cancer progression. This research begins with a blood draw from people with advanced  ovarian cancer  whose tumors have returned after standard surgery and chemotherapy. White blood cells are extracted from the blood, biomanufactured to become dendritic cells and returned to the patient. Dendritic cells act as crusaders that march through the body, triggering the immune system to recognize and fight cancer. "We're building on an earlier phase 1 clinical trial  that showed promising results  in terms of survival after the dendritic cell-based vaccine," says  Matthew Block, M.D., Ph.D. , co-principal investigator and Mayo Clinic medical oncologist. "Of the 18 evaluable patients in the phase 1 study, 11 had cancer return, but seven of them — 40% — have been cancer-free for almost 10 years. We typically expect 90% of patients in this condition to have the cancer return."  Read more .

New gene markers detect Lynch syndrome-associated colorectal cancer.

Researchers from Mayo Clinic Comprehensive Cancer Center and Mayo Clinic Center for Individualized Medicine have discovered new genetic markers to identify Lynch syndrome-associated colorectal cancer with high accuracy. Studies are underway to determine if these genetic markers are in stool samples and, if so, how this could lead to a non-invasive screening option for people with  Lynch syndrome . The research was published in Cancer Prevention Research , a journal of the American Association for Cancer Research. "This is an exciting finding that brings us closer to the reality that clinicians may soon be able to offer a non-invasive cancer screening option to patients with the highest risk of getting cancer," says  Jewel Samadder, M.D. , co-lead author of the paper and a Mayo Clinic gastroenterologist. Read more .

Mayo Clinic prepares to biomanufacture a new CAR-T cell therapy for B-cell blood cancers.

Mayo Clinic research has developed a new type of  chimeric antigen receptor-T cell therapy (CAR-T cell therapy)  aimed at killing B-cell blood cancers that have returned and are no longer responding to treatment. This pioneering technology, designed and developed in the lab of  Hong Qin, M.D., Ph.D. , a Mayo Clinic cancer researcher, killed B-cell tumors grown in the laboratory and tumors implanted in mouse models. The preclinical findings are published in  Cancer Immunology, Immunotherapy . "This study shows our experimental CAR-T cell therapy targets several blood cancers, specifically chronic lymphocytic leukemia," says Dr. Qin. "Currently, there are six different CAR-T cell therapies approved for treatment of relapsed blood cancers. While the results are impressive, not everyone responds to this treatment. Our goal is to provide novel cell therapies shaped to each patient's individual need."  Read more .

Related Posts

Dr. Jonathan Schwartz discusses medulloblastoma treatment for children, the latest advances, and what families should look for in a care team.

Dr. Mark Tyson discusses new and developing bladder cancer treatment options and what you should know when seeking bladder cancer care.

Mayo Clinic researchers are collaborating to develop CAR-T cell therapy for solid tumors in thyroid cancer.

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12 cancer research breakthroughs of 2021

13th December 2021

2021 has been a fantastic year for science with the rollout of the coronavirus vaccine happening at unprecedented speed thanks to the hard work of people around the world. And all through this turbulent time, cancer researchers have been hard at work too. Here’s the 12 big cancer research breakthroughs made by our scientists in 2021.

Diet, obesity and immunotherapy

Our scientists in Spain uncovered how a fat molecule found in palm oil, called palmitic acid, alters the cancer genome, and increases the likelihood cancer will spread . The researchers have started developing therapies that interrupt this process and say a clinical trial could start in the next couple of years.

Researchers in Italy discovered a new way to treat acute leukaemia by engineering immune cells taken from healthy donors and using them to target and destroy blood cancer cells . The team hope this could be the start for a new way to treat leukaemia in the future.

In Spain, researchers made a discovery that could help protect against diet-induced obesity and its related health issues . They found that by blocking a protein present in fatty tissue of obese mice could provide protection from weight gain caused by a high fat diet. Their findings could have major implications for obesity related diseases such as cancer.

Bubbles, brain tumours and preventing bowel cancer

Our scientists in London developed a new way to deliver drugs that can shut down cancer-promoting mutations in neuroblastoma . The findings show that the new delivery method, which uses tiny bubbles to deliver their cargo directly to the tumour cells, could form the basis for a new treatment for this common childhood cancer.

In Ireland, researchers supported by a collaboration between Worldwide Cancer Research and The Brain Tumour Charity discovered how a genetic mutation causes diffuse midline glioma – a childhood brain cancer also known as DIPG. Their discovery shows that it is possible to reverse the effects of the mutation to slow cancer growth.

Researchers in the Netherlands discovered a better understanding of how bowel cancer develops and identified a new way to prevent it. The research has now resulted in a clinical trial that will aim to repurpose a psychiatric drug as a new preventive cancer treatment in a group of people that – without intervention – are virtually 100% likely to develop bowel cancer in their lifetime.

New treatments and clinical trials

Our scientists in France discovered how the tissue surrounding breast cancer tumours can prevent immune cells from reaching and destroying cancer cells . Their findings could lead to better ways to diagnose breast cancer and new ways to improve immunotherapy.

Researchers in Spain co-funded by AECC FC found a potential new way to treat highly aggressive pancreatic cancer . Their findings pave the way to design new treatment combinations that could kill cancer cells while also making them more susceptible to chemotherapy.

We found out that research we funded in 2005 helped to launch clinical trials testing a promising new treatment option for people with bowel cancer . The research revealed how a specific group of immune cells in the body can ‘mask’ the immune responses normally triggered to fight the cancer and have now sparked clinical trials testing a drug that can remove these cells, unmask the immune system, and open the tumour for attack. It’s hoped that this treatment could help prevent the disease from returning and improve survival rates for those with bowel cancer.

Starting new cancer cures

In Argentina, scientists made an exciting new discovery that could lead to the start of new clinical trials for prostate cancer . Their findings reveal a new treatment strategy that helps make immunotherapy work more effectively to kill off the most aggressive types of prostate cancer.

An international study shone a light on the impact the coronavirus pandemic had on the lives of people with liver cancer. Rates of liver cancer in the UK have increased by more than two and a half times since the early 1990s and continue to rise. Liver cancer now affects more than 6,000 people each year in the UK and only about 1 in 8 people survive for 5 years or longer after their diagnosis.

And finally, we were delighted to be able to commit to funding £4.5m on 23 new research projects that will start in 2022! These innovative new ideas from scientists all over the world are crucial for us to end cancer by starting new cancer cures of the future.

Further reading

I can’t bear the thought of losing yet another loved one to cancer

When Rachel was young, she was told that her auntie had been really ill with something called cancer. This is her story of how her family has been impacted by the disease.

17 November 2021

How dietary fats help cancer to spread around the body

Researchers in Spain have discovered how fats found in palm oil can help cancer spread and have developed new drugs to stop it from happening.

10 November 2021

Why haven't we cured pancreatic cancer yet?

Pancreatic cancer is a type of cancer that has seen some improvements in survival rates but it continues to be one of the most difficult types of cancer to diagnose and treat. Find out more here.

08 November 2021

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Recent developments in cancer research: Expectations for a new remedy

1 Department of Surgery and Science, Kyushu University, Fukuoka Japan

Qingjiang Hu

Yuta kasagi, masaki mori.

Cancer research has made remarkable progress and new discoveries are beginning to be made. For example, the discovery of immune checkpoint inhibition mechanisms in cancer cells has led to the development of immune checkpoint inhibitors that have benefited many cancer patients. In this review, we will introduce and describe the latest novel areas of cancer research: exosomes, microbiome, immunotherapy. and organoids. Exosomes research will lead to further understanding of the mechanisms governing cancer proliferation, invasion, and metastasis, as well as the development of cancer detection and therapeutic methods. Microbiome are important in understanding the disease. Immunotherapy is the fourth treatment in cancer therapy. Organoid biology will further develop with a goal of translating the research into personalized therapy. These research areas may result in the creation of new cancer treatments in the future.

Cancer research has made remarkable progress and new discoveries are beginning to be made. In this review, we will introduce and describe the latest novel areas of cancer research: exosomes, microbiomes, immunotherapy, and organoids.

1. INTRODUCTION

The cancer research field has developed significantly through use of new equipment and technology. One example of new technology is Next‐Generation Sequencing (NGS). Also known as high‐throughput sequencing, NGS is the catch‐all term used to describe a number of different modern nucleic acid sequencing technologies. These methods allow for much quicker and cheaper sequencing of DNA and RNA compared with the previously used Sanger sequencing, and as such have revolutionized the study of genomics and molecular biology. NGS also allows for easier detection of mutations in cancer samples, leading to development of many new agents that can be used to treat patients. For example, if the RAS gene status is detected as wild type in a colorectal cancer patient, then an anti‐EGFR antibody, such as cetuximab or panitumumab, can be used for treatment.

A liquid biopsy, also known as fluid biopsy or fluid phase biopsy, is the sampling and analysis of non‐solid biological tissue, primarily blood. 1 It is being used as a novel way to detect cancer. Like a traditional biopsy, this type of technique is mainly used as a diagnostic and monitoring tool for diseases, and also has the added benefit of being largely noninvasive. Therefore, liquid biopsies can be performed more frequently, allowing for better tracking of tumors and mutations over a duration of time. This technique may also be used to validate the effectiveness of a cancer treatment drug by taking multiple liquid biopsy samples in the span of a few weeks. It may also prove to be beneficial for monitoring relapse in patients after treatment.

Novel devices and drugs have also been developed and used for cancer treatment. For surgery procedures, robotic‐assisted laparoscopic surgery has evolved and made it possible to visualize the fine movement of the forceps in three dimensions. This method is now used in esophageal, gastric, and rectal cancer surgeries in Japan. 2 , 3 , 4

Recently, immunotherapy became an additional method for treating cancer patients. The discovery of the immune checkpoint by Dr Honjo led to the development of immune checkpoint inhibitors. 5 Despite these developments, gastrointestinal cancers are still a major problem in need of new treatment methods. In this review, we introduce and describe four new areas of cancer research that may contribute to cancer treatment in the future: exosomes, microbiome, immunotherapy, and organoids.

2. AN APPLICATION OF EXOSOME RESEARCH IN CANCER THERAPY

An exosome is a small particle that is secreted by cells. Its size can range from 50 to 150 nm and has a surface consisting of proteins and lipids that originate from the cell membrane. Additionally, proteins and nucleic acids, such as DNA, microRNAs, and mRNAs, can be found inside the exosome as its “cargo.” 6 Recently, many researchers have discovered that exosomes are involved in the mechanisms of various diseases. As mentioned above, various functional compounds, such as microRNAs, mRNAs, and proteins, can be contained within exosomes. 7 , 8 Many cells use secretion of exosomes to communicate with one another, and these exosomes can even reach distant cells. Cancer cells can also secrete exosomes that contain molecules beneficial to cancer growth. For example, microRNAs found in cancer exosomes can modulate gene expression to induce angiogenesis in the tumor microenvironment, which supports metastasis. 9 Exosomes released from cancer cells can also reportedly break the blood‐brain barrier, which makes it contribute to brain metastasis. 10 , 11 Cancer cells themselves are similarly affected by the exosomes secreted by the surrounding normal cells. 12 In one case, the exosomes secreted by bone marrow‐delivered mesenchymal stem cells can force cancer cells into a dormant state. 13 These dormant cancer cells become resistant to chemotherapy and are involved in long‐term disease recurrence. Thus, exosomes are deeply involved in cancer proliferation, invasion, and metastasis, as well as in the formation of the tumor microenvironment and pre‐metastatic niche. 13 Further research on cancer‐related exosomes is ongoing.

Knowledge of exosomes can be applied to cancer treatment. If the secretion of exosomes from cancer cells can be prevented, then signal transduction supporting the formation of the tumor microenvironment and pre‐metastatic niche can be blocked. Work focusing on the removal of cancer exosomes is now ongoing. 14

Exosomes can also be utilized for cancer diagnosis. Exosomes secreted by many cell types are found in various body fluids, such as blood and urine. Capturing and analyzing exosomes from cancer cells can be used to detect the presence of disease. 15 Obtaining blood or urine from patients is not very invasive or painful. Since many molecules, such as various proteins, DNA, and microRNAs, can be found in exosomes from normal cells, it is important to distinguish them from cancer‐related ones. If exosomes are to be used for cancer diagnosis, then specific biomarkers need to be discovered. Additionally, the development of a method to detect these exosomes must be done. Currently, exosome detection methods for exosomes abundantly found in the serum of colorectal and pancreatic cancer patients, as well as exosomes found in the urine of bladder cancer patients, are being developed. 16 , 17 Thus, further understanding of the mechanisms governing cancer proliferation, invasion, and metastasis, as well as the development of cancer detection and therapeutic methods, is significantly affected by exosome research.

3. MICROBIOME IN CANCER RESEARCH

A large number of microorganisms inhabit the human body. These microorganisms include bacteria, viruses, and fungi. Among them, bacteria have the most important relationship with the human body. Bacteria can live anywhere within the human body, including the digestive tract, respiratory system, and oral cavity. 18 , 19 , 20 In particular, bacteria in the digestive tract are rich in type and number, 21 with possibly 1000 types and more than 100 trillion individual bacterial cells present. 22 , 23 The overall population of various bacteria found in the human intestine is referred to as the “intestinal flora.” Recently, the terms “microbiota” or “microbiome” have also been widely used.

Recent advancements with NGS have led to a much more precise understanding of the intestinal microbiome. 24 The bacteria in the human microbiome mainly belong to four phyla: Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteri. Of these, Firmicutes and Bacteroidetes are the most dominant species. It is reported that microbiome vary depending on age and race. 25 , 26 Dysbiosis is a condition in which the diversity of the microbiome is reduced. Dysbiosis is reportedly involved in various diseases such as inflammatory bowel disease, colorectal cancer, obesity, diabetes, and allergic diseases. 27 , 28 , 29 For example, bacteria such as Atopobium parvulum and Actinomyces odontolyticus increase in number during the early stages of colorectal cancer (adenomas or intramucosal cancers) and decrease in number during cancer progression. 30 This suggests that a specific microbiome is associated with early stages of colorectal cancer development, which may be useful knowledge for early cancer detection.

Various studies have also been conducted to elucidate the relationship between the microbiome and the human immune system. 31 The IgA antibody, which is one of the most important elements in the intestinal immune system, is believed to play a role in the elimination of pathogens and maintenance of the intestinal environment. The IgA antibody recognizes, eliminates, and neutralizes pathogenic bacteria and toxins. It also maintains a symbiotic relationship by recognizing and binding to the normal microbiome of the host. 32 Mice lacking a microbiome have reduced production of the IgA antibody. A microbiome is required for IgA antibody differentiation. Recent studies have identified W27IgA antibodies that have the ability to bind to various bacteria. 33 Oral administration of a W27IgA antibody to enteritis model mice suppressed enteritis by altering the microbiome. This W27IgA antibody can recognize a part of the amino acid sequence of serine hydroxymethyl transferase, which is a metabolic enzyme involved in bacterial growth. The W27IgA antibody can suppress the growth of E coli by binding to them. However, the W27IgA antibody does not bind to bacteria that suppress enteritis, such as bifidobacteria and lactic acid bacteria. 33 Thus, the microbiome is deeply involved in human intestinal immunity. Recently, it is having been established that the microbiome is not only involved in intestinal immunity, but also in the systemic immune system.

As the analysis of the microbiome progresses, the pathophysiology of various diseases, such as cancers, and its relationship with the regulatory function of the human immune system will be further elucidated. It has been demonstrated that F nucleatum plays a role in the development and progression of colon adenomas and colorectal cancer. It is also related to lymph node metastases and distant metastasis. 34 , 35 Also, microbiome is associated with hepatocellular carcinoma. 36 Studying microbiome will give us some clue in the development and remedy for gastrointestinal cancers (Table  1 ).

Gastrointestinal cancer and their related microbiome

4. THE RISE OF IMMUNOTHERAPY IN CANCER TREATMENT

For many years, surgery, chemotherapy, and radiation therapy were the main methods of cancer treatment. In addition to these therapies, immunotherapy has recently attracted great attention worldwide (Table  2 ). 37 , 38 Under normal circumstances, a cancer antigen will activate the patient's immune system to attack the cancer cells. However, sometimes the immune system does not recognize the cancer cells as non‐self, or it simply fails to attack them. This can result in the development and progression of cancer.

Immune checkpoint inhibitors

Although therapies that activate the immune system against cancer cells have been studied for a long time, the use of the patient's own immune system for cancer treatment was not established. Recently, the effectiveness of both immune checkpoint inhibition therapy and chimeric antigen receptor (CAR)‐T cell therapy has proved to be promising. 39 , 40 Immunotherapy has moved to the forefront of cancer treatment strategies.

There are two major reasons why proving the efficacy of cancer immunotherapies was difficult for some time. First, cancer immunity is strongly suppressed. Signal transduction from immune checkpoint compounds, such as PD‐1 and CTLA4, strongly inhibits cytotoxic T cells (CTLs). 38 This checkpoint mechanism can prevent the immune system from attacking cancer cells. The development of immune checkpoint inhibitors has arisen from the discovery of this mechanism. Inhibition of immune checkpoint molecules with neutralizing antibodies can release the suppression of cancer‐specific CTLs, activate immunity, and promote cancer elimination. The effectiveness of immune checkpoint antibodies has been confirmed and clinically applied to many solid cancers such as melanoma, 41 lung cancer, 42 urothelial cancer, 43 gastric cancer, 44 and esophageal cancer. 45 In addition to PD‐1 and CTLA4, new immune checkpoint molecules, such as LAG3, TIGIT, and SIRPA, are also being actively studied. 46 , 47 , 48 Although this therapy is promising, the cancer cases who respond to these therapies are limited. This is because use of this therapy requires the presence of cancer‐specific CTLs in the patient's body. To maximize the therapeutic effect, it is desirable to select appropriate cases and develop useful biomarkers.

The second difficulty for immunotherapy is that T cells do not recognize specific cancer cell antigens and immune accelerators are too weak. One goal of CAR‐T cell therapy is to strengthen the immune accelerator by administering CTLs to the patient's body that recognize specific cancer cell‐specific antigens. A CAR is prepared by fusing a single chain Fv (scFv), derived from a monoclonal antibody that recognizes a specific antigen expressed by cancer cells, with CD3z and costimulatory molecules (CD28, 4‐1BB, and others). Next, the CAR is introduced to the T cells obtained from a cancer patient and CAR‐T cells are made. CAR‐T cells recognize the specific antigen of the cancer cells and are activated to damage these cells. CAR‐T cells recognize cancer‐specific antigens with high antibody specificity and attack the respective cancer cells with strong cytotoxic activity and high proliferative activity. CAR‐T therapy is effective in blood cancers such as B‐cell acute lymphoblastic leukemia and myeloma. 49 , 50 While CAR‐T cell therapy has a high therapeutic effect, a frequent and serious adverse event called cytokine release syndrome has been observed in some patients. 51 , 52 The development of a technique for suppressing the occurrence of cytokine release syndrome is anticipated. In addition, the development of CAR‐T cell therapies for solid tumors is ongoing.

Recently, there was new progress made in treating gastrointestinal cancer patients. For MSI‐H colorectal cancer, the combination therapy with nivolumab and ipilimumab was approved. From the nivolumab plus ipilimumab cohort of CheckMate‐142, progression‐free survival rates were 76% (9 months) and 71% (12 months); respective overall survival rates were 87% and 85% which were quite high. This new treatment will benefit MSI‐H colorectal cancer patients. 53

Thus, it is expected that further understanding of cancer immune mechanisms and the development of various immunotherapies will contribute to great progress in cancer treatment.

One problem for immunotherapy is that there is no certain predictive biomarker. It was thought that the expression of PD‐1 or PD‐L1 would predict the effect. However, this was not the case. To find a new biomarker, we assessed the cytolytic activity (CYT) score. The CYT score is a new index of cancer immunity calculated from the mRNA expression levels of GZMA and PRF1. We are now evaluating CYT score in gastric cancer patients (data not published). The development in the biomarker search will benefit many gastrointestinal cancer patients.

5. ADVANTAGES FOR USING ORGANOIDS IN CANCER RESEARCH

The three‐dimensional (3D) organoid system is a cell culture‐based, novel, and physiologically relevant biologic platform. 54 An organoid is a miniaturized and simplified version of an organ that is produced in vitro in 3D and shows realistic microanatomy. With only one to a few cells isolated from tissue or cultured cells as the starting material, organoids are grown and passaged in a basement membrane matrix, which contributes to their self‐renewal and differentiation capacities. 54 , 55 The technique used for growing organoids has rapidly improved since the early 2010s with the advent of the field of stem cell biology. The characteristics of stem, embryonic stem cells (ES cells), or induced pluripotent stem cells (iPS cells) that allow them to form an organoid in vitro are also found in multiple types of carcinoma tissues and cells. Therefore, cancer researchers have applied ES cells or iPS cells in their field. 56 , 57 , 58

Organoid formation generally requires culturing stem cells or their progenitor cells in 3D. 54 , 55 The morphological and functional characteristics of various types of carcinoma tissue have been recapitulated in organoids that were generated from single‐cell suspensions or cell aggregates. These suspensions or aggregates were isolated from murine and human tissues or cultured cells, as well as from cancer stem cells propagated in culture. The structures of the organoids show the potential of cancer stem cell self‐renewal, proliferation, and differentiation abilities, and also provide insights into the roles of molecular pathways and niche factors that are essential in cancer tissues. 56 , 57 , 59 , 60 , 61 , 62 The organoid system also has been utilized for studying multiple biological processes, including motility, stress response, cell‐cell communications, and cellular interactions that involve a variety of cell types such as fibroblasts, endothelial cells, and inflammatory cells. These interactions are mediated via cell surface molecules, extracellular matrix proteins, and receptors in the microenvironment under homeostatic and pathologic conditions.

Although the organoid system is a complex and not effortless procedure that requires specific media, supplements, and many tricky techniques, 58 , 63 application of this system has been extended to a variety of cell types from different carcinomas (colorectal, pancreatic, prostate, breast, ovary, and esophageal cancers). 56 , 57 , 59 , 60 , 61 An organoid is generally induced within a few days to weeks, and is faster and less costly than the murine xenograft assay. Furthermore, applying novel genetic manipulations (e.g. CRISPR‐Cas9) can be carried out in the organoid system. 64 , 65

Kasagi et al modified keratinocyte serum‐free medium to grow 3D organoids from endoscopic esophageal biopsies, immortalized human esophageal epithelial cells, and murine esophagi. Esophageal 3D organoids serve as a novel platform to investigate regulatory mechanisms in squamous epithelial homeostasis in the context of esophageal cancers. 64

We anticipate that many experimental results that utilize the organoid system will be published in the future.

The 3D organoid system has emerged in the past several years as a robust tool in basic research with the potential to be used for personalized medicine. 66 By passaging dissociated primary structures to generate secondary 3D organoids, this system can be performed using live tissue pieces obtained from biopsies, operative‐resected specimens, or even frozen tissues. This method has the potential to transform personalized therapy. For example, in the case of cancer recurrence, an effective chemotherapy can be selected by testing the chemotherapeutic sensitivity of cancer‐derived organoids from an individual patient's tissue stocks. In many cases, a patient's organoid accumulation is helpful for testing the sensitivity of novel therapeutic agents for treating carcinoma. 66 Hence, it appears that organoid biology will further develop with a goal of translating the research into personalized therapy.

6. SUMMARY AND FUTURE DIRECTIONS

This review describes four new cancer‐related studies: exosomes, microbiome, immunotherapy, and organoids (Figure  1 ).

The summary of the four cancer research areas. In this figure the summary of the four cancer research areas is shown: exosome, microbiome, immunotherapy, and organoid research

Since exosomes are released in blood or urine, if the capturing system is established, it will be a less invasive test to diagnose cancer. In the present, the presence of circulating tumor DNA (ctDNA) is one of the tools to detect the minimal residual disease. However, since ctDNA is only DNA, it is difficult to spread to cancer research. In that respect, as exosomes include not only DNA but also other nucleic acids and proteins, this will be a new tool for cancer research such as the diagnosis of early cancer.

Microbiome may lead to improved cancer diagnosis and treatment. Detecting a specific microbiome in a gastrointestinal tract may predict a specific cancer. And changing microbiome in some way may result in preventing cancer development.

Organoids may help address the problem of drug resistance, and also lead to the development of personalized therapy. However, producing organoids takes time and testing the drug resistance may take more time. If we could overcome these problems, the research into organoids can contribute to overcoming cancer.

As shown in Table  3 , many new studies and findings are reported into this field of research. These four novel cancer research areas will make many contributions to the diagnosis and treatment of cancer.

Recent studies on exosome, microbiome, immunotherapy, and organoids

Conflict of Interest: All the authors have no conflict of interest to disclose.

ACKNOWLEDGMENTS

We thank Dr Hirofumi Hasuda and Dr Naomichi Koga for their help in preparing this manuscript. We also thank J. Iacona, PhD, from Edanz Group for editing a draft of this manuscript.

Ando K, Hu Q, Kasagi Y, Oki E, Mori M. Recent developments in cancer research: Expectations for a new remedy . Ann Gastroenterol Surg . 2021; 5 :419–426. 10.1002/ags3.12440 [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]

Cancer patients often do better with less intensive treatment, research shows

Scaling back treatment for three kinds of cancer can make life easier for patients without compromising outcomes, doctors reported at the world’s largest cancer conference .

It’s part of a long-term trend toward studying whether doing less — less surgery, less chemotherapy or less radiation — can help patients live longer and feel better. The latest studies involved ovarian and esophageal cancer and Hodgkin lymphoma.

Thirty years ago, cancer research was about doing more, not less. In one sobering example, women with advanced breast cancer were pushed to the brink of death with massive doses of chemotherapy and bone marrow transplants. The  approach didn’t work  any better than chemotherapy and patients suffered.

Now, in a quest to optimize cancer care, researchers are asking: “Do we need all that treatment that we have used in the past?”

It’s a question, “that should be asked over and over again,” said Dr. Tatjana Kolevska, medical director for the Kaiser Permanente National Cancer Excellence Program, who was not involved in the new research.

Often, doing less works because of improved drugs.

“The good news is that cancer treatment is not only becoming more effective, it’s becoming easier to tolerate and associated with less short-term and long-term complications,” said Dr. William G. Nelson of Johns Hopkins School of Medicine, who was also not involved in the new research.

Latest news on cancer treatment

• Cancer-fighting antibodies inject chemo directly into tumor cells, upping effectiveness.
• Long-term study shows 'remarkable' treatment helps patients with deadly nonsmoking-related lung cancer.
• FDA approves groundbreaking treatment for advanced melanoma.

Studies demonstrating the trend were discussed over the weekend at an American Society of Clinical Oncology conference in Chicago. Here are the highlights:

Ovarian cancer

French researchers found that it’s safe to avoid removing lymph nodes that appear healthy during surgery for advanced ovarian cancer. The study compared the results for 379 patients — half had their lymph nodes removed and half did not. After nine years, there was no difference in how long the patients lived and those with less-extreme surgery had fewer complications, such as the need for blood transfusions. The research was funded by the National Institute of Cancer in France.

Esophageal cancer

This German study looked at 438 people with a type of cancer of the esophagus that can be treated with surgery. Half received a common treatment plan that included chemotherapy and surgery on the esophagus, the tube that carries food from the throat to the stomach. Half got another approach that includes radiation too. Both techniques are considered standard. Which one patients get can depend on where they get treatment.

After three years, 57% of those who got chemo and surgery were alive, compared to 51% of those who got chemo, surgery and radiation. The German Research Foundation funded the study.

Hodgkin lymphoma

A comparison of two chemotherapy regimens for advanced Hodgkin lymphoma found the less intensive treatment was more effective for the blood cancer and caused fewer side effects.

After four years, the less harsh chemo kept the disease in check in 94% of people, compared to 91% of those who had the more intense treatment. The trial included 1,482 people in nine countries — Germany, Austria, Switzerland, the Netherlands, Denmark, Sweden, Norway, Australia and New Zealand — and was funded by Takeda Oncology, the maker of one of the drugs used in the gentler chemo that was studied.

The Associated Press

Cancer patients often do better with less intensive treatment, new research finds

S caling back treatment for three kinds of cancer can make life easier for patients without compromising outcomes, doctors reported at the world’s largest cancer conference.

It’s part of a long-term trend toward studying whether doing less — less surgery , less chemotherapy or less radiation — can help patients live longer and feel better. The latest studies involved ovarian and esophageal cancer and Hodgkin lymphoma.

Thirty years ago, cancer research was about doing more, not less. In one sobering example, women with advanced breast cancer were pushed to the brink of death with massive doses of chemotherapy and bone marrow transplants. The approach didn’t work any better than chemotherapy and patients suffered.

Now, in a quest to optimize cancer care, researchers are asking: “Do we need all that treatment that we have used in the past?”

It’s a question, “that should be asked over and over again,” said Dr. Tatjana Kolevska, medical director for the Kaiser Permanente National Cancer Excellence Program, who was not involved in the new research.

Often, doing less works because of improved drugs.

“The good news is that cancer treatment is not only becoming more effective, it’s becoming easier to tolerate and associated with less short-term and long-term complications,” said Dr. William G. Nelson of Johns Hopkins School of Medicine, who was also not involved in the new research.

Studies demonstrating the trend were discussed over the weekend at an American Society of Clinical Oncology conference in Chicago. Here are the highlights:

OVARIAN CANCER

French researchers found that it’s safe to avoid removing lymph nodes that appear healthy during surgery for advanced ovarian cancer. The study compared the results for 379 patients — half had their lymph nodes removed and half did not. After nine years, there was no difference in how long the patients lived and those with less-extreme surgery had fewer complications, such as the need for blood transfusions. The research was funded by the National Institute of Cancer in France.

ESOPHAGEAL CANCER

This German study looked at 438 people with a type of cancer of the esophagus that can be treated with surgery. Half received a common treatment plan that included chemotherapy and surgery on the esophagus, the tube that carries food from the throat to the stomach. Half got another approach that includes radiation too. Both techniques are considered standard. Which one patients get can depend on where they get treatment.

After three years, 57% of those who got chemo and surgery were alive, compared to 51% of those who got chemo, surgery and radiation. The German Research Foundation funded the study.

HODGKIN LYMPHOMA

A comparison of two chemotherapy regimens for advanced Hodgkin lymphoma found the less intensive treatment was more effective for the blood cancer and caused fewer side effects.

After four years, the less harsh chemo kept the disease in check in 94% of people, compared to 91% of those who had the more intense treatment. The trial included 1,482 people in nine countries — Germany, Austria, Switzerland, the Netherlands, Denmark, Sweden, Norway, Australia and New Zealand — and was funded by Takeda Oncology, the maker of one of the drugs used in the gentler chemo that was studied.

The Associated Press Health and Science Department receives support from the Howard Hughes Medical Institute’s Science and Educational Media Group. The AP is solely responsible for all content.

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At-home saliva test could help diagnose prostate cancer sooner

1 June 2024

A new saliva test for identifying men at high risk of prostate cancer could help find more cases of the disease earlier, when doctors have a better chance of treating it successfully.

The researchers behind the BARCODE 1 study, which we helped fund, say their test could help “turn the tide” on prostate cancer.

Although it is the second biggest cancer killer of men in the UK, taking around 12,000 lives a year, there is no national screening programme for prostate cancer . This is because the only current option, the prostate-specific antigen (PSA) blood test , is too inaccurate.

Instead of measuring the amount of PSA in blood, the new spit test sorts people into groups by looking through the DNA in their saliva samples for a range of small genetic changes linked to prostate cancer. The results of the trial suggest that this approach works better. The men the new test puts in its highest risk group are more likely to have prostate cancer than men with raised PSA levels.

The new test also falsely identified prostate cancer fewer times than the PSA test does, and picked up a higher proportion of aggressive cancers.

“With this test, it could be possible to turn the tide on prostate cancer,” said Ros Eeles, a professor at the Institute of Cancer Research and a consultant at the Royal Marsden NHS Foundation Trust, which jointly led the research. ”We have shown that a simple, cheap spit test to identify men at higher risk due to their genetic makeup is an effective tool to catch the cancer early.”

Eeles is presenting the results of BARCODE 1 at the annual American Society of Clinical Oncology meeting in Chicago. She ties her work to a long legacy of research into the genetic markers of prostate cancer.

“Building on decades of research into the genetic markers of prostate cancer, our study shows that the theory does work in practice – we can identify men at risk of aggressive cancers who need further tests, and spare the men who are at lower risk from unnecessary treatments.”

From PSA testing to polygenic risk scoring

In the study, spit samples were used to calculate prostate cancer polygenic risk scores (PRSs) for more than 6,000 European men. All participants were recruited through their GP surgeries when they were between 55 and 69 – an age at which risk of prostate cancer is increased.

Their PRSs were based on 130 genetic variations – many hereditary – shown to be linked with prostate cancer through studies into the DNA of hundreds of thousands of men.

For BARCODE 1, the men with the highest 10% of risk scores were invited to further screening. Following an MRI and a prostate biopsy, 187 of them (40% of the total) were diagnosed with prostate cancer. That’s a significant jump from the 25% of men identified by PSA tests who actually have prostate cancer. Moreover, 147 (78%) of the men diagnosed thanks to the new saliva test had a ‘normal’ PSA level, which would usually indicate that no further screening is required.

The researchers also took a closer look at how the prostate cancers picked up by their new test behaved (which can be assessed by looking at how abnormal they appear, measured by grade ). PSA testing picks up many people who have cancers that grow too slowly to cause any significant health impacts, meaning that men may undergo unnecessary MRI scans, invasive biopsies, and treatments. Importantly, then, the new spit test identified a higher proportion of aggressive cancers – which are fast growing and likely to spread – than the PSA test. Of the 187 cancers detected in BARCODE 1, 55% were aggressive cancers, compared with 36% of those identified by a PSA test in a recent study.

The PRS test is also more accurate than an MRI scan for men who score in the highest 10% for genetic risk.

Naser Turabi, our director of evidence and implementation, put the findings into context.

“Right now, there’s no reliable method to detect aggressive prostate cancer, but this study brings us a step closer to finding the disease sooner in those people who need treatment,” he said. “It’s encouraging to see that genetic testing might help to guide a more targeted approach to screening based on someone’s risk of developing prostate cancer. More research is now needed to confirm if this tool can save lives from the disease so that it can be rolled out to improve diagnosis.”

Since BARCODE 1 started, an international research team has identified more genetic variants associated with prostate cancer risk in men of Asian and African ancestry. The ICR team intend to trial a saliva test for this population to ensure polygenic risk scoring can benefit all men. They are also comparing the saliva test to other potential screening options as part of the ongoing TRANSFORM trial.

This research was funded by the European Research Council, the Bob Willis Fund, Cancer Research UK, The Peacock Trust and the National Institute for Health and Care Research (NIHR) Biomedical Research Centre (BRC) at The Royal Marsden and The Institute of Cancer Research (ICR).

Amazing news, I pray this will be commercially available soon in Ireland, we are years behind in Ireland with genetic testing.

Does that mean no more biopsies? (Breathes sigh of relief) Uses in detection for other cancers?

fantastic reseach

Excellent Idea as I think many men are embarrassed I feel it would stop a lot of worry

This hopefully a game changer and fully on board. Unfortunately men are simply not being heard or seen by there GP , just simply not good enough four week wait, zero to do with covid, many many people young old falling through the inadequacy’s from all cancers.

I would like to thank you so very much for this amazing research you are carrying out. I personally have had prostate cancer but I was treated successfully if this can save more men from dying from this horrible disease it is a truly life changing moment.

If test preliminary test need to be rolled out to a larger test group, I’d be happy to take part. To many men die unnecessarily due to this cancer so this is a great step forward.

The sooner we adopt this method of screening in the UK then the better for all men, regardless of age or ethnicity. I expect the UK won’t be adopting this screening method for at least 5 years because of all the “usual” red tape plus demands for lengthy UK based clinical trial to validate it’s efficacy and worth to the NHS.

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June 4, 2024

Gene variants and breast cancer risk in Black women

At a glance.

• In the largest study of its kind, researchers identified genetic variants that appear to boost breast cancer risk among females of African ancestry.
• The findings could help improve risk prediction in this population and lead to more targeted therapies and prevention strategies.

Breast cancer is the most often diagnosed cancer in many parts of the world, including the U.S. More than 310,000 new cases are expected nationwide this year.

Black women tend to develop breast cancer at a younger age than White women. Black women are also more likely than Whites to die from the disease, and they are twice as likely to develop an aggressive subtype called triple-negative breast cancer. But despite the increased risks faced by women of African descent, most large-scale genetic studies of breast cancer to date have focused on women of European ancestry.

To better understand their unique genetic risks, a research team led by Dr. Wei Zheng of Vanderbilt University analyzed genetic data from over 40,000 females of African descent. About 18,000 had been diagnosed with breast cancer. The data were gathered as part of the NIH-funded African Ancestry Breast Cancer Genetic consortium, which combined data from 26 studies. Most participants (85%) were African Americans. The rest were from Barbados or Africa.

The researchers conducted a genome-wide association study (GWAS) to look for genetic variants that are found more often in participants with breast cancer than in those without. This is believed to be the largest GWAS study to date of breast cancer in this population. Results were reported in Nature Genetics on May 13, 2024.

The analysis pinpointed 12 genetic regions, or loci, associated with breast cancer. Three of these loci were linked to the aggressive triple-negative cancer. About 8% of the women carried two genetic copies of risk variants in all three of these loci. Such women, the researchers found, were 4.2 times more likely to be diagnosed with triple-negative breast cancer than women who had only one or no copies of the variants.

Because this type of cancer lacks specific cell receptors often seen with breast cancer (like estrogen or HER2 receptors), there are fewer targeted options for treatment. These findings may help researchers identify new treatment targets.

The researchers also confirmed many breast cancer risk variants that were found earlier in other populations. And they identified an uncommon risk variant in the gene ARHGEF38 , which had been previously linked to aggressive prostate and lung cancers.

The scientists used their findings to create polygenic risk scores (PRS) for breast cancer risk in females of African descent. PRS use genomic data to gauge the chance that a person will develop a certain medical condition. PRS created previously, using results from other populations, tend to perform poorly at predicting breast cancer risk for Black women. The new PRS, based on genomic data from African descendants, outperformed previous PRS at predicting breast cancer risk in this population.

The findings and data could lead to improved detection of breast cancer in this at-risk population and provide clues for potential treatment targets. Studies with even larger, more diverse populations will be needed to further improve the prediction of breast cancer risk.

“We have worked with researchers from more than 15 institutions in the U.S. and Africa to establish this large genetic consortium,” Zheng says. “Data put together in this consortium have been and will continue to be used by researchers around the world.”

—by Vicki Contie

Related Links

• Human Pangenome Boosts Accuracy and Reflects Diversity
• Technique May Improve Detection of Breast Tumors
• Test Predicts Whether Chemotherapy Will Help Early-Stage Breast Cancer Patients
• Advances in Breast Cancer: Screening and Treatment Get Personal
• Breast Cancer
• Polygenic Risk Scores

References:  Genome-wide association analyses of breast cancer in women of African ancestry identify new susceptibility loci and improve risk prediction. Jia G, Ping J, Guo X, Yang Y, Tao R, Li B, Ambs S, Barnard ME, Chen Y, Garcia-Closas M, Gu J, Hu JJ, Huo D, John EM, Li CI, Li JL, Nathanson KL, Nemesure B, Olopade OI, Pal T, Press MF, Sanderson M, Sandler DP, Shu XO, Troester MA, Yao S, Adejumo PO, Ahearn T, Brewster AM, Hennis AJM, Makumbi T, Ndom P, O'Brien KM, Olshan AF, Oluwasanu MM, Reid S, Butler EN, Huang M, Ntekim A, Qian H, Zhang H, Ambrosone CB, Cai Q, Long J, Palmer JR, Haiman CA, Zheng W. Nat Genet. 2024 May;56(5):819-826. doi: 10.1038/s41588-024-01736-4. Epub 2024 May 13. PMID: 38741014.

Funding:  NIH’s National Cancer Institute (NCI).

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Therapeutic products containing CD8 + and CD4 + T cells expressing CARs are effective at inducing remission in patients with cancer. How CD4 + CAR T cells contribute to the anti-tumor response has not been well established. A study uses syngeneic models and in vivo imaging to glean mechanistic insights into how CD4 + T cells target tumors.

• M. Eric Kohler
• Terry J. Fry

Venetoclax–obinutuzumab combinations are effective in fit patients with CLL

Taking the temperature of lung cancer antigens

Antigen presentation is fundamental to anti-tumor immunity, but our understanding of the physiological and molecular inputs to the process in different contexts remains limited. Two new studies explore the contribution of cell-intrinsic proteolytic mechanisms and cell-extrinsic hot and cold tumor microenvironments in shaping the antigenic landscape in lung cancer.

• Paul A. Stewart
• Alex M. Jaeger

A skull bone marrow niche for antitumour neutrophils in glioblastoma

A preprint by Lad et al. shows that tumour-associated neutrophils in glioblastoma originate from skull bone marrow and acquire an antigen-presenting cell phenotype intratumorally in the presence of local T cells.

• Austeja Baleviciute

Impaired RNA clearance

In this study, Insco et al. find patient-specific CDK13 mutations to impede RNA surveillance, leading to the accumulation and translation of prematurely terminated RNAs that drive malignancy in melanoma models.

Peptide-mediated CRISPR engineering of cells

An article in Nature Biomedical Engineering reports a simple and hardware-independent peptide-mediated delivery method for the CRISPR-mediated engineering of T cells.

• Nesma El-Sayed Ibrahim

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Progress in Cancer Research

Basic, molecular, epidemiologic, and clinical research are leading to improved cancer prevention, screening, and treatment. Decreasing cancer mortality death rates and increasing numbers of cancer survivors are important indicators of the progress we have made. As the leader of the National Cancer Program, NCI has played a major role in the progress that has been made by the cancer community. But work still needs to be done to reduce the burden of cancer for those who face a diagnosis.

Progress in research depends on the work of individual scientists and research institutions—universities and medical centers across the country, the NCI-designated cancer centers, the National Clinical Trials Network, the NCI Community Oncology Research Program—as well as collaborations between the private and public sector. In this section, we highlight the stories behind some notable milestones and present data about ongoing progress.

Annual Report to the Nation on the Status of Cancer

The Annual Report to the Nation on the Status of Cancer is an update of rates for new cases, deaths, and trends for the most common cancers in the United States.

Cancer Trends Progress Report

The Cancer Trends Progress Report summarizes the nation’s advances against cancer in relation to Healthy People targets set out by the Department of Health and Human Services.

Research Advances by Cancer Type

Find NCI’s collection of research advances for common cancers such as breast cancer, colorectal cancer, leukemia, lung cancer, and prostate cancer.

Stories of Discovery

Collection of stories that describe landmark developments in cancer prevention and treatment supported by NCI funding.

Milestones in Cancer Research and Discovery

During the past 250 years, we have witnessed many landmark discoveries in our efforts to make progress against cancer, an affliction known to humanity for thousands of years. This timeline shows a few key milestones in the history of cancer research.

Colorectal cancer rates for certain people have nearly doubled in Michigan, mystifying experts

The increase is not due to screening at an earlier age, doctors say.

When Jason Maman of Rochester Hills was diagnosed with colorectal cancer at age 46, it took months for the news to sink in. He never thought it would happen to him, but his physician knew immediately.

“Basically, for a year, I had symptoms,” said Maman, now 49, who was diagnosed in 2020. “It got to a point where I almost blacked out just going to the bathroom. The pain was so intense. I have a very high pain threshold, but that’s what scared me into finally going to see a doctor.”

Maman is an example of how colorectal cancer rates are surging in people younger than age 50 in Michigan. The incidence rate of these cancers — also called colon or rectal cancer, depending on where the cancer starts — has nearly doubled in Michigan for people younger than age 50 over the last 35 years, according to data tracked through 2020 by the Michigan Department of Health and Human Services. The rate of invasive colorectal cancer grew from 4.2 cases per 100,000 Michiganians below 50 in 1985 to 8 cases per 100,000 in 2020.

Experts said they can't pinpoint one reason for the uptick. A number of factors could be at play, from diet to inflammation in the colon, but that's not the entire story. And screenings at earlier ages don't explain why rates are going up in those under 50, at least two experts said.

“Sometimes we think that cancer is becoming more common because we're screening for it more and we're detecting it more,” said Dr. Samantha Hendren, surgical director of the colorectal cancer program at Michigan Medicine’s Rogel Cancer Center. “The increased risk of colorectal cancer in people under 50 was absolutely, 100% not due to increased screening in that younger population.”

Most colorectal cancers start as polyps in the lining of the colon or rectum. Polyps are typically benign, but some can turn into cancer over time, typically for a period of several years, according to the American Cancer Society.

Still, if caught early, colorectal cancer is treatable, said Dr. Harry Wasvary, a colon and rectal surgeon at Corewell Health's Royal Oak Hospital. Recent advancements in chemotherapy and radiation have improved results in later-stage colorectal cancer, too, he said.

“In the early stage, it's a very survivable process and that's the whole goal is either to prevent it with proper screening or ultimately catch it early for good outcomes,” Wasvary said.

For Maman, his cancer diagnosis couldn't have come at a worse time. Two weeks later, his wife was diagnosed with breast cancer and had to undergo radiation and an operation herself.

“You just had to react to things. You didn’t have time to sulk or be upset,” Maman said. “It was just total chaos for two years.”

But after 12 rounds of chemotherapy, 33 rounds of radiation and numerous operations, Maman has returned to the things he loves, such as playing guitar in a local band. Both he and his wife are now cancer-free and under surveillance, but Maman will have to live with a colostomy bag for the rest of his life. A colostomy bag is attached to a surgically created hole in the abdomen that allows waste to leave the body.

“I waited too long to get checked, so the tumor got too big, and they had to cut out so much material so there was no way to reverse the bag,” Maman said, who added, "... I'm not wanting to dwell on negative stuff. Life’s too short for that.”

Unexplained increase

The increase in colorectal cancer among Michigan's young people occurred while rates in all age groups above the age of 50 trended down during the same 35-year period, mirroring national trends as the disease is now the leading cause of cancer death in men and second for women under 50, according to the Colon Cancer Coalition .

Michigan Medicine’s Hendren said she's seen a dramatic increase in early-onset colorectal cancer patients throughout her career. The cancers doctors find also tend to be more advanced in colorectal patients under 50, she said.

Colorectal cancer rates have decreased in older populations thanks to improved screening, but experts have yet to confirm a reason for the increase in early-onset cases, Corewell Health's Wasvary said.

“We’re blaming it on lifestyle factors and basically anything that makes you out of shape, obese, diabetic, whether it be inactivity, lack of exercise, poor dietary habits,” Wasvary said. “All these things may contribute to … a pro-inflammatory process in the gut, and that enhanced inflammation is toxic to the lining of the colon and can increase the chances of getting colorectal cancer.”

Hendren said about 30% of the excess risk for early-onset colorectal cancer is related to an overall increase in obesity in the population, but this is still a minority of the total excess risk.

“I've seen lots of overweight patients who have colorectal cancer at a young age, but I've also seen normal weight patients who have developed colorectal cancer at a young age,” Hendren said. “There are clearly other environmental or lifestyle factors.”

Maman had no issues with his weight before his diagnosis. Jobs as a mechanic, landscaper and welder always kept him fit, so he said he never felt the need to get regular check-ups at the doctor.

Advocates call for more screening

The biggest barrier to screening for colorectal cancer is a lack of symptoms, Wasvary said. Young people feel that if they don’t experience any symptoms, there must be nothing wrong, he said.

“Most of the patients that present to us with colon cancer don't have any symptoms at all,” Wasvary said. “That's why you have to get the screening with the goal of finding small polyps that one-third of us have and removing them before they can grow to become something bigger later in life.”

Howard Brown of Birmingham was diagnosed with stage 3B colon cancer in 2016 after getting his routine colonoscopy at age 50 with no symptoms. Brown also said he had no family history of colon cancer, although this wasn’t his first time receiving a life-altering diagnosis.

Brown was also diagnosed with stage four non-Hodgkin’s T-cell accelerated lymphoma at the age of 23. After chemotherapy failed, he underwent a bone marrow transplant and an immunotherapy clinical trial and attained remission. He said if he had been screened for colon cancer earlier, he might have avoided the second diagnosis.

“If I would have been screened earlier … at 40, we wouldn't even be talking right now. I probably would have snipped the polyp and went on with my life or maybe even had stage one,” Brown said.

Unfortunately, two surgeries, 12 cycles of high-dose chemotherapy and a clinical trial did not prevent the cancer from progressing from stage three to four, so Brown began “salvage chemotherapy." He also joined a cancer support group through Colontown , an online community of colorectal patients, survivors and caregivers, through which he learned about a complicated procedure called cytoreductive hyperthermic intraperitoneal chemotherapy.

“It was so helpful for me to talk to other patients that were in the fight, right on the front lines,” Brown said. “It is a great place for you to become a smart patient.”

Physicians have seen no signs of cancer in Brown since 2019, about a year and a half after he had the procedure that involves surgically removing tumors and applying heated chemotherapy drugs inside the abdomen. He has become an advocate for colon cancer screening, speaking at medical schools, hospitals and conferences about his experience.

The recommended age for colorectal cancer screening in people with no extra risk factors has been lowered from 50 to 45 within the last five years, Hendren said. The biggest risk factor for anyone is having a family history of colorectal cancer.

Wasvary encouraged young people to be aware of any changes in bowel habits, including bleeding and weight loss that can’t be explained by other factors.

New research on the horizon

Recent cancer research has focused on the role of epigenetic mechanisms, or mechanisms that regulate gene expression or silencing, in disease development. New findings out of the Grand Rapids-based Van Andel Institute have at least one researcher hopeful that a novel combination of existing epigenetic drugs may help colorectal patients.

Scott Rothbart’s lab at the Van Andel Institute focuses on epigenetics, or how genes are turned on and off at specific times throughout development. Epigenetic regulatory mechanisms instruct cells to subspecialize into specific types, Rothbart said.

“In nearly all human cancers, epigenetic processes are misregulated, and the process that we study in the lab is called DNA methylation,” Rothbart said. “What happens in cancer is that DNA methylation contributes to the abnormal silencing of genes that regulate cell growth and proliferation.”

Tumor suppressor genes are often turned off in human cancers, allowing cancer cells to proliferate unchecked. DNA methylation also silences, or suppresses, viral elements of the human genome in healthy cells, Rothbart said. If re-expressed, the viral elements would trigger the body’s immune system into beginning to destroy its own cells.

“For cancer therapy, we can take advantage of this,” Rothbart said.

A class of epigenetic drugs called DNA hypomethylating agents inhibit DNA methylation. They can essentially trick the innate immune system into selectively attacking and clearing cancer cells, Rothbart said.

“These inhibitors have progressed through clinical trials and have a number of FDA approvals, but primarily for select hematological cancers, so cancers of the blood,” Rothbart said, referring to the Food and Drug Administration. “We sought to understand what is limiting the activity of these DNA hypomethylating agents in solid tumors.”

In a recently published study, Rothbart found that a separate enzyme called EZH2 helps cancer cells repress both tumor suppressor genes and viral elements and escape DNA hypomethylating agents.

“EZH2 is another really major target for cancer therapy. … EZH2 inhibitors have independently been developed as anti-cancer agents,” Rothbart said.

While the enzyme inhibitors have gained FDA approval for several cancers, they’ve never been combined with DNA hypomethylating agents, Rothbart said. A physician typically wouldn’t put a colorectal cancer patient on just an EZH2 inhibitor, but Rothbart said he thinks that colorectal cancer cells will become sensitive to the enzyme inhibitor after they are exposed to the DNA hypomethylating agents.

Preclinical models have focused on colorectal cancer and the next step is to combine the two drugs in a clinical trial, Rothbart said. His lab is working with partners at Johns Hopkins University in Baltimore to design one. While the field may still be far from a major clinical breakthrough, the research is a major step toward a novel approach to colon cancer therapy, Rothbart said.

Some colon cancer patients, such as 46-year-old Megan Koutsoubos, know the specific kind of mutation present in their cancer cells thanks to genetic testing. Koutsoubos of Bloomfield Hills was diagnosed with high-risk stage 3C colon cancer in 2022 but had no family history and no typical symptoms other than exhaustion, which she wrote off as a symptom of working full-time while raising three children.

Doctors operated on the tumor immediately, and Koutsoubos underwent eight months of chemotherapy before her bloodwork showed no evidence of disease. Unfortunately, five months later, additional scans showed the cancer had spread, and her diagnosis was moved to stage four and inoperable. She's been undergoing chemotherapy every two weeks for almost a year and will continue the treatment.

"Unless things change, I will be on chemo indefinitely," Koutsoubos said. "Either my body stops tolerating it ... it stops working, so the cancer starts growing, or they find something else — there's some sort of clinical trial or something like that, that might work better."

Koutsoubos has tolerated her current chemotherapy regimen pretty well for almost a year and has found ways to cope with her diagnosis, trying to be as positive as she can. Thanks to the genetic testing, she and her doctor are always keeping an eye out for clinical trials that may work, especially if her current chemotherapy regimen stops working.

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