Adverse effects of cancer immunotherapy are under way in a new strategy

Adverse effects of cancer immunotherapy are under way in a new strategy ...

It is not often that a failed clinical investigation leads to a scientific breakthrough.

Researchers at the La Jolla Institute for Immunology (LJI)Center for Cancer Immunotherapy and the University of Liverpool examined patient samples and determined what was wrong.

Their findings, published recently in Nature, give us a clear explanation for why many immunotherapies trigger fatal side effects, and highlight the need for a better treatment of patients with severe tumors.

ProfessorPandurangan Vijayanand, M.D., Ph.D., who led the new research withChristian H. Ottensmeier, a professor at the University of Liverpool, The Clatterbridge Cancer Centre NHS Foundation Trust, and an adjunct professor at LJI, believes this work is proof that early stage clinical trials are important.

Limited success with immunotherapies

Both Vijayanand and Ottensmeier are physician scientists, and Ottensmeier is an oncologist who treats solid tumor patients. In just the last decade, he has seen more and more patients thrive thanks to advances in immunotherapies, which work with the immune system to kill cancers.

Immunotherapy has revolutionized the way we think about treatment, according to Ottensmeier. In the medical world, patients may receive immunotherapies, even if they have metastatic and spreading disease, and three years later they may leave the country and say that their cancer is healed. This is a remarkable transformation.

Only around 20 to 30 percent of solid cancer patients receiving immunotherapy are put in short-term remission. Some individuals see no change after immunotherapy, but others develop serious issues in their lungs, bowel, and even skin during therapy. These side effects can be debilitating, but these patients are forced to stop receiving the immunotherapy.

Important lessons from a clinical trial

Patients with head and neck cancers were treated with an oral cancer immunotherapy called a PI3K inhibitor. At the time, PI3K inhibitors had proven effective for B cell lymphomas, but had not yet been tested in solid tumors.

PI3K inhibitors are new to the cancer immunotherapy industry, but they offer their ability to inhibit regulatory T cells (Tregs) (Tregs). Tregs normally try to prevent other effector T cells from targeting the body''s own tissues. Oncologists instill Tregs inside tumors, allowing effector T cells to let loose and produce cancer-killing CD8+ cells.

The Tregscan is a great asset for oncologists, according to Vijayanand, because it can take off the brakes.

Twelve of the 21 patients in the trial had to terminate treatment early because they developed inflammation in the colon, a condition called colitis. We thought this medication would not be toxic, therefore why was this happening? Vijayanand reports.

Snacks on the job, pathogenic T cells, called Th17 and Tc17 cells, sparked inflammation and colitis, according to LJI instructor Simon Eschweiler.

Patients in the cancer trial had received a higher PI3K inhibitor dosage than they needed, and immunotherapy had reduced the composition of immune cells in the gut.

According to Eschweiler, the pathway that leads to the toxicity observed in the new study may be broadly applicable to other organisms harboring similar Treg cells, as well as to other anti-CTLA-4 therapies.

New dosing strategy may save lives

The team believes that intermittent dosing might be a valid treatment strategy that combines sustained anti-tumor immunity and reduced toxicity.

The researchers are now developing a human clinical trial to test the human dosage strategy.

Mitchell Kronenberg, a LJI professor and chief scientific officer, has shown how you can go from a clinical review to a mouse study to discover what drives the dangers of toxicity in these patients.

How to explain the lack of toxicity in the treatment of B cell lymphomas? Eschweiler claims that lymphoma patients in previous studies had been given several therapies leading to an overall immunocompromised state. This means the lymphoma patients didnt have the same typeor the same magnitudeof immune response upon PI3K inhibition. However, the head and neck cancer patients were treated-naive. Their immune system was not compromised, therefore the immune-related adverse events were both more rapid and more pronounced.

The report demonstrates the importance of not only personalized therapies, but also personalized therapy doses and schedules.

ten years ago, doctors had only one type of immunotherapy to offer. It either helped a patient or it did. Doctors today have a rapidly growing library of immunotherapies to choose from.

Vijayanand and Ottensmeier are among the first individuals to employ single-cell genomic sequencing tools to identify which therapeutic combinations are most effective in individual patients, and the best time to administer these therapies. In a 2021Nature Immunology study, the pair demonstrated the possibility of giving immunotherapies in a specific sequence.

Vijayanand claims that if you design well your clinical trials and utilize advanced genomics, you have a lot to learn. You can then determine what''s happening and return to the patients.

This study has been a remarkable collaborative effort, according to Ottensmeier. It has taken a group of medical oncologists, surgeons, research nurses, our patients, and scientists together on two sides of the pond.

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