Cancers & # 39; change spots & # 39; to avoid immunotherapy

Cancers can make the task of new immunotherapies more difficult to visualize by "modifying their spots" and deactivating a key molecule on the cell surface that would otherwise be recognized by the treatment.

The researchers discovered that they could badyze samples of patients with bowel cancer to determine which ones best responded to immunotherapy by evaluating the molecular changes within tumors miniatures developed in the laboratory.

Using the mini-tumors, the researchers identified existing drugs that could possibly be used in combination with immunotherapy to make it work for many more patients.

The team at the Institute of Cancer Research in London and the Royal Marsden NHS Foundation Trust believe their findings could help increase the effectiveness of the antibody-based drug cibisatamab and offer ways to determine if patients will respond to immunotherapy in the laboratory.

The study is published today (Monday) in the Journal for cancer immunotherapy and was funded by Cancer Research UK and the NIHR Biomedical Research Center of the Institute for Cancer Research (ICR) and the Royal Marsden.

Immunotherapy is proving to be an exciting new way of treating cancer for a subset of patients, but there is currently no way to distinguish who will benefit from those who will not, or to increase the number of respondents.

Cibisatamab is a promising new immunotherapy that acts as an intermediate between cancer cells and the immune system.

An "arm" attaches to a molecule called carcinoembryonic antigen (CEA) that is found on the surface of several types of cancer cells and is so common in the cancer of the intestine that it is used to test the disease. The other arm stops and activates a type of immune cell called T cell, which can then attack the tumor.

The ICR and Royal Marsden team, however, found that many laboratory-developed mini-colon cancers were able to hide from treatment.

Cibisatamab has shown promising results in preliminary trials, but researchers wanted to know why some bowel cancers were resistant to treatment and find ways to make it work for more patients.

They took biopsy samples from eight bowel cancer patients and used an innovative new technique, developed at ICR, to develop miniature replicas of their tumors in the laboratory.

The team discovered that there were three groups of cells: those with high levels of ACE on the surface of most cancer cells of the tumor, those with low levels of erythrocytes. ACE on most cells and those with a mixture.

Treatment with cibisatamab reduced growth by 96% in tumors with a high concentration of CEA, but only 20% with low CEA and 53% in tumors with a mixed CEA concentration.

With the help of specialized equipment, the researchers separated the individual cells with high or low ECA and let them settle for a month to become tumors. They discovered that CEA levels had changed in recurring tumors, suggesting that the cells could quickly switch to a different state and that they might well be hiding from immunotherapy.

However, by closely examining the active genes in the mini-tumors, they discovered that cells with low levels of CEA on their surface had increased activity in the TND gene pathway – targeted by several new drugs in development.

The treatment of small bowel cancer tumors via the WNT pathway, targeting drugs known as tankyrase inhibitors and porcupine inhibitors, has increased CEA levels – increasing their vulnerability to the disease. immunotherapy.

Dr. Marco Gerlinger, Head of Translational Oncogenomics in the London Institute of Cancer Research and Oncology Consultant at Royal Marsden, said:

"Cancer is very effective at hiding the immune system.The latest successful immunotherapies act as a matchmaker to bring the immune system closer to cancer, so that it can see it and attack it."

"Our study found that bowel cancer prevented the most recent immunotherapies, that is, changing the stain by altering the level of a key molecule on the surface of the cells, so that they become more difficult to recognize.

"We used a new technique of growing miniature replicas of tumors to develop a way to determine if patients would respond to immunotherapy." And, best of all, we were able to identify an existing inhibitor of the WNT pathway. that could be used to reverse this process We hope that this could in the future help immunotherapies work in more patients, making cancer cells more visible to immune cells. "

Professor Paul Workman, director of the London Cancer Institute, said:

"As we move away from the unique treatment of cancer, it is essential to be able to identify the patients most likely to respond to a drug and do everything in our power to avoid resistance to treatment for so long." as possible.

"This research reveals that cancers may be hiding from a promising new type of immunotherapy." While the work is still in its infancy, it could be used to develop a test to determine who is the most likely to react to the drug, and indicates possible combinations of drugs that may prevent or delay resistance. "

Dr. Andrew Beggs, British colon cancer specialist at Cancer Research, said:

"Mini-tumors developed in the laboratory have the potential to transform the way we test drugs before clinical trials.From a very small biopsy, we can recreate the tumor in the laboratory to better reflect the cancer of the body." 39, a patient that with the traditional methods of cell culture.

"This study is an example of the creation of mini colon cancer tumors, called organoids, to guide future research on experimental immunotherapy, and we can also use organoids to learn more about how cancers can respond to drugs, by simultaneously testing multiple treatments for potential vulnerabilities Organoid models are increasingly being used in this way to help researchers study, develop and refine potential treatments to be tested in clinical trials. "