It is not common for a failed clinical trial to lead to a scientific breakthrough. Researchers have found a new strategy to avoid the side effects of cancer immunotherapy. When patients in the UK began to have negative side effects in a cancer immunotherapy trial, researchers at the cancer immunotherapy center of the La Jolla Institute of Immunology (LJI) and the University of Liverpool looked back, examined the data and used patient samples to determine the cause of the error.
Three dimensional rendering of T cells attacking cancer cells. Source: La Jolla Institute of Immunology
Their findings, published today (May 4, 2022) in the journal Nature, provide key clues to the causes of many dangerous side effects of immunotherapy - and point out more effective strategies for treating patients with solid tumors.
Professor vijayanand of the La Jolla Institute of Immunology (LJI) and ottensmeier of the University of Liverpool are both doctors and scientists. Ottensmeier is an oncologist who treats patients with solid tumors. Over the past decade, he has seen more and more patients thrive on the progress of immunotherapy, which works with the immune system to kill cancer.
In the field of oncology, immunotherapy has completely changed our view of treatment. We can provide patients with immunotherapy, and even deal with metastatic and diffuse diseases. If it goes well, we can even tell them that their cancer has been cured, which is a shocking change. Unfortunately, only about 20% to 30% of solid cancer patients receiving immunotherapy can achieve long-term remission. Some people don't see any changes after immunotherapy, but some people have serious problems with their lungs, intestines and even skin during treatment. These side effects can be debilitating or even fatal, and these patients are forced to stop receiving immunotherapy.
Important lessons from clinical trials
Researchers at LJI and the University of Liverpool used samples from a recent clinical trial in the UK for patients with head and neck cancer. These patients received an oral cancer immunotherapy called pi3kd inhibitor. At that time, pi3kd inhibitors had been shown to be effective in B-cell lymphoma, but they had not been tested in solid tumors.
Pi3kd inhibitors are new products in the field of cancer immunotherapy, but they are promising in inhibiting the ability of "regulatory" T cells (Tregs). Tregs usually try to prevent other T cells (called effector T cells) from targeting the body's own tissue. Oncologists inhibit Tregs in tumors so that effector T cells can release and produce CD8 + T cells that kill cancer.
"If there is an oral pill that can relieve Tregs, it will be a huge asset for oncologists," vijayanand said.
Unfortunately, 12 of the 21 patients in the trial had to stop treatment early because they developed colitis, which is called colitis. "We don't think this drug is toxic, so why does this happen?" Vijayanand said.
Dr. Simon eschweiler, LJI lecturer, took the lead in thinking back about how the treatment of pi3kd inhibitors affected the immune cells of these patients. Using single-cell genome sequencing, he showed that pi3kd inhibitors also prevented the protection of colon by a specific subgroup of Treg cells in the process of increasing antitumor T cells in tumors. Without the work of Tregs, pathogenic T cells called Th17 and TC17 cells enter and cause inflammation and colitis.
Obviously, these cancer patients were given larger doses of pi3kd inhibitors than they needed, and immunotherapy unbalanced the delicate composition of immune cells in the intestine.
Eschweiler said that the pathways leading to the toxicity seen in the new study may be widely applicable to other organs hosting Treg like cells and other immunotherapies targeting Treg cells, such as anti-CTLA-4.
The new administration strategy may save lives. The research team found that intermittent administration may be an effective treatment strategy, which combines sustained antitumor immunity and reduced toxicity.
Researchers are now designing a human clinical trial to test intermittent dosing strategies in humans.
Professor LJI and chief scientific officer Dr Mitchell Kronenberg said: "this study shows how you can see what's behind the toxicity of these patients from clinical research to mouse research," and his laboratory led most of the mouse model work of the new study.
How to explain the lack of toxicity in B-cell lymphoma test? Eschweiler said that in previous studies, lymphoma patients had previously received several treatments, resulting in a decline in overall immunity. This means that patients with lymphoma do not have the same type or degree of immune response after receiving pi3kd inhibition. At the same time, patients with head and neck cancer are untreated. Their immune system was not damaged, so immune related adverse events occurred faster and more obvious.
Overall, the new study shows that it is necessary to study not only personalized therapies, but also personalized treatment doses and schedules.
As ottensmeier explained, a decade ago doctors offered only one form of immunotherapy. It's either helpful or not. Today, doctors have a rapidly growing library of immunotherapies to choose from.
Vijayanand and ottensmeier were among the first researchers to use single-cell genome sequencing tools to determine which treatment combinations are most effective for individual patients and the best schedule for giving these treatments. In a 2021 study in Nature Immunology, this pair of studies showed the potential importance of giving immunotherapy in a specific order.
"If you design your clinical trials well and apply complex genomics, you have a lot to learn," vijayanand said. "You can find out what happened and go back to the patient."