New strategy to avoid side effects of immunotherapy

The immunotherapy is a type of treatment that stimulates the body’s natural defenses to fight Cancer. For this, it uses substances produced by the body or in the laboratory to improve the functioning of your body. immunity system and destroy the cancer cells. However, there is no lack secundary effects.

This week the magazine Nature collect data from a clinical trial II trial in the UK showing how the experimental cancer drug AMG319The PI3Kδ inhibitoris effective in people with Head and neck tumors. However, adverse immune-related outcomes led to discontinuation of treatment.

The researchers, experts from Cancer Immunotherapy Center at the La Jolla Institute (USA) and the University of Liverpool (UK), analyzed the data and worked with patient samples to see what had gone wrong.

These types of inhibitors are new to the cancer immunotherapy scene. But they show promise for their ability to disable regulatory T cells (Tregs), whose job is to stop other T cells, called effector T cells, from reaching the body’s own tissues. Oncologists try to ‘turn off’ the Tregs inside tumors so that effector T cells can break free and generate cancer-killing CD8+ T cells.

“The study examines how PI3Kδ inhibition removes Tregs from cancer and healthy tissue. This unblocks the anti-tumor responses of T cells, but also causes adverse effects related to the immune system, for example, in the colon”, explains to SINC Christian H. Ottensmeierof the British institution.

“Having an oral pill that can remove the braces – the Tregs – can be a big plus for oncologists,” he says. Pandurangan Vijayanandprofessor at the La Jolla Institute of Immunology, co-director of the new research with Ottensmeier.

Limited success of immunotherapies

Despite initial failure, their findings provide critical clues as to why many immunotherapies trigger dangerous side effects and point to a better treatment strategy. dosage to treat patients with solid tumors. “This work demonstrates the importance of learning from early-stage clinical trials,” says Vijayanand.

“We were able to characterize how the biology of adverse effects occurs, and specifically that elimination of Tregs by a PI3k delta inhibitor can activate protective immunity against cancer, as well as immune responses in the gut,” adds Ottensmeier.

The specialist from the United Kingdom has seen in the last ten years the progress that has occurred thanks to advances in immunotherapies: “This type of therapy has revolutionized the way of conceiving the treatment of cancer. We can give it to patients even with metastatic and disseminated disease, and only three years later tell them the cancer is cured. It’s an incredible change.”

Immunotherapy has revolutionized the way of conceiving cancer treatment. We can give it to patients even with metastatic and disseminated disease, and only three years later tell them the cancer is cured. It’s an amazing change

Christian H. Ottensmeier, author

However, only 20-30% of solid cancer patients who receive immunotherapies go into long-term remission. Some people don’t see any change after treatment, but others develop serious problems with their lungs, intestines, and even their skin. These side effects can be debilitating, even fatal, and patients are forced to stop taking it.

In this studio, 12 of 21 patients of the study had to stop treatment early because they developed a inflammation in the colon (colitis). “We thought this drug would not be toxic, so why was this happening?” asks Vijayanand.

Experts point out that patients with head and neck cancer have not received prior treatment, so their immune system has not been compromised. This made related adverse effects faster and more pronounced.

How it affects immune system cells

Experts worked to see exactly how the treatment influences these patients’ immune cells. Using single-cell genomic sequencing, they showed that, in the process of increasing tumor-fighting T cells, the PI3Kδ inhibitor also blocked a specific subset of Treg cells to protect the colon.

Without the Tregs, the pathogenic T cells, called Th17 and Tc17, went ahead and caused inflammation and colitis. “It was clear that patients in the cancer trial received a higher dose of PI3Kδ inhibitor than they needed, and the immunotherapy unbalanced the delicate composition of immune cells in the gut,” the authors write.

The team found that intermittent dosing may be a valid treatment strategy that combines a antitumor immunity performed with a reduced toxicity. The researchers are now designing a human clinical trial to test this strategy.

Optimize doses to save lives

Although more research is needed, the authors conclude that it is necessary to reduce the dose or modify the PI3Kδ treatment regimen to induce an antitumor immune response in solid tumors, limiting adverse effects associated with reduced T-regulatory cell function in healthy tissues.

“We found that adverse events can be eliminated by changing the inhibitor regimen while maintaining the antitumor effect. Therefore, we believe that this will be a generic approach in any solid cancer where regulatory T cells from cancer tissue have a role,” insists Ottensmeier.

“Ten years ago, doctors could only offer one type of immunotherapy that helped or didn’t help the patient. Today, they have a rapidly growing library of these therapies,” concludes Ottensmeier.