Immunotherapy could act against bowel cancers resistant to important targeted treatment

Patients with bowel cancer who have stopped responding to a widely used targeted drug could benefit from immunotherapy, reveals a major new study.

Scientists found that intestinal tumors that initially reacted to cetuximab before developing resistance became more visible to the immune system, making them potentially vulnerable to immunotherapies.

A phase II clinical trial has already begun to test the potential benefit of immunotherapy in patients who have stopped responding to cetuximab.

A team from the Institute of Cancer Research in London and the Royal Marsden NHS Foundation Trust has revealed the various complex mechanisms by which bowel cancers have become resistant to cetuximab. Their study could not only lead to new therapeutic approaches, but also to tests to determine which patients are likely to develop resistance to cetuximab as quickly as possible.

The research is published in the prestigious journal Cancer cell today and has been largely funded by Cancer Research UK, with additional help from the biomedical research center of the INDH at the Institute of Cancer (ICR) and the Royal Marsden.

The researchers studied tumor samples from 35 people with advanced bowel cancer who had been treated in a clinical trial on cetuximab conducted by the ICR and the Royal Marsden.

Cetuximab is effective in some people with advanced bowel cancer – but the treatment works only in about half of the patients, and most of them will eventually stop responding to as their cancer becomes resistant to drugs. Once intestinal tumors become resistant to cetuximab, treatment options are very limited, and new treatments are absolutely necessary.

The new study provides a detailed picture of the many ways in which intestinal cancers can elude cetuximab treatment, either initially or through acquired drug resistance.

Surprisingly, the researchers could only find genetic modifications that could explain the development of drug resistance in 36% of the tumors they studied.

However, in five out of seven patients who had stopped responding to cetuximab, tumors had been heavily infiltrated by non-cancerous cells from supporting tissues around the tumor, which fed the cancer cells and helped them grow. during treatment.

This discovery adds to our understanding of the complex nature of cancer evolution, in which tumors often adopt genetic strategies to evade treatment or alter their environment as a non-genetic approach to the development of drug resistance. .

The research team then studied the different types of immune cells in tumor samples before and after cetuximab treatment, with the goal of finding new ways to fight against drug-resistant cancers.

The researchers found that, on average, anti-cancer immune cells were six times more active in tumors that had become cetuximab-resistant than those that had not reacted to the drug initially.

Researchers believe that cetuximab kills cancer cells to send signals that attract immune cells to the tumor – and their results suggest that immunotherapies designed to reduce the effects of the immune system may be effective in these cancers.

Researchers at ICR and Royal Marsden have launched a Phase II clinical trial involving the combination of two immunotherapy drugs, nivolumab and relatlimab, in patients with severe heart failure. an advanced bowel cancer whose tumors have stopped responding to a combination of cetuximab and chemotherapy.

The new study also identified six new genetic mechanisms that can cause cetuximab resistance in patients. These results could lead to the development of better tests to select patients who will not respond to cetuximab from the start, or will stop doing so quickly – so that they can be identified quickly and, as far as possible, switch to alternative treatments.

The new research fits into the ICR's ambitious strategy to understand and overcome cancer evolution and drug resistance through the world's first "Darwinian" drug discovery program.

ICR, a charity and research institute, raises last £ 15m of £ 75m investment in new Cancer Research Center to host research program , which aims to create a new generation of "anti-evolution" treatments. .

Dr. Marco Gerlinger, team leader in translational oncogenomics at the Cancer Institute, London, and medical oncology consultant at the Royal Marsden NHS Foundation Trust, said:

"In our new study, we shed light on the complex biology underlying the ability of bowel cancers to evade treatment with the targeted drug, cetuximab.

"Most intestinal cancers are" immune deserts "- so it's extremely exciting to see that cetuximab attracts immune cells into these tumors.In ICR and Royal Marsden, we have already started a clinical trial of immunotherapy in people whose intestinal tumors have become resistant, cetuximab and chemotherapy: I'm eager to see if immunotherapy can release immune cells and reduce tumors.

"Our findings could also lead to better tests so that people with changes in their tumor that mean that it is unlikely that they respond to cetuximab – or likely to stop responding – can be spared by unnecessary treatments. "

Professor David Cunningham, Director of the NIHR Biomedical Research Center of the Royal Marsden NHS Foundation Trust and the Institute of Cancer, London, said:

"This research underlines how important it is to understand the evolution of cancer, especially when it is a direct effect of treatment." In this study, the antibody cetuximab has made colorectal cancer tumors potentially sensitive to immunotherapy, and this discovery could have implications for the treatments we offer patients with this disease. "

Rachel Shaw, Head of Research Information at Cancer Research UK, said:

"Bowel cancer is the fourth most common cancer in the UK, and the second-largest cancer cancer, and resistance to treatment remains a major part of the challenge, so it's essential that we find new cancer. ways to treat this disease.

"Although cetuximab works well for many people, most of them will no longer respond to treatment." The details of how cetuximab modifies the biology of intestinal tumors has allowed us to better understand what may be to be the next stage of treatment, look forward to seeing the results of the trial ".

Professor Sir Mel Greaves, who will badume the duties of director of cancer evolution at the ICR's new Cancer Drug Discovery Center, said: "Cancers are a moving target that is constantly adapting and evolving in their environment to survive, progress and avoid treatments This intriguing study shows that cancers do not always need to accumulate genetic changes to become drug-resistant. also change their behavior and their immediate environment in a complex and subtle way to make treatments ineffective.

"By unraveling the mechanisms that underlie the evolution and adaptation of cancer in response to drugs, our research aims to open up new treatment strategies – in this case, through the use of the drug. Immune therapy in the treatment of bowel cancers becoming more visible to the immune system.This is an approach that lies at the heart of the pioneering ICR projects aimed at creating a new generation of anti-evolution treatments, once we have raised the final £ 15 million to complete our Cancer Drug Research Center. "

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