In cancer immunotherapy trials, when patients started experiencing adverse side effects, researchers reviewed data and studied patient samples to determine what went wrong.
3D image of T cells attacking cancer cells
When patients in the UK started experiencing adverse side effects in a cancer immunotherapy trial, researchers from the La Jolla Institute for Immunology (LJI) Cancer Immunotherapy Centre and the University of Liverpool reviewed the data and gave patients Samples were studied to find out what went wrong.
Their findings, recently published in the journal Nature, provide key clues as to why many immunotherapies cause dangerous side effects, and provide insights into Treating patients with solid tumors offers better strategies.
“This work shows the importance of learning from early clinical trials,” said Pandurangan, La Jolla Institute for Immunology (LJI) Professor Vijayanand said.
Immunotherapy has limited success
Vijayanand and Ottensmeier are both internal medicine scientists, and Ottensmeier is the attending oncologist who treats patients with solid tumors. In just the past decade, he has seen more and more patients improve due to advances in immunotherapy. Immunotherapy works by working with the immune system to kill cancer.
“In oncology, immunotherapy has revolutionized the way we think about treatment,” says Ottensmeier. “We can give patients immunotherapy, even for metastatic and transmissible disease, and then just 3 years later wave goodbye and tell them the cancer is cured. It’s an amazing change.”
Unfortunately, only about 20% to 30% of solid cancer patients receive long-term remission after immunotherapy. Some people see no change after immunotherapy, but others develop severe problems in the lungs, intestines, and even skin during treatment. These side effects can be debilitating and even fatal, and these patients are forced to stop receiving immunotherapy.
Important lessons from clinical trials
The LJI and University of Liverpool researchers used samples from a recent clinical trial in patients with head and neck cancer in the UK. The patients received a type of oral cancer immunotherapy called a PI3Kδ inhibitor. At the time, PI3Kδ inhibitors had been shown to be effective in B-cell lymphomas, but had not been tested in solid tumors.
PI3Kδ inhibitors are new drugs in the field of cancer immunotherapy, but they have the ability to inhibit “regulatory” T cells (Treg). Treg cells normally try to prevent other T cells, known as effector T cells, from attacking the body’s own tissues. Oncologists suppress Tregs within tumors, so effector T cells can release and generate cancer-killing CD8+ T cells.
Vijayanand said: “Having an oral tablet that relieves Treg symptoms is a huge asset for oncologists.”
Unfortunately, 12 of the 21 patients in the trial had to stop treatment early due to inflammation of the colon (colitis) . “We don’t think the drug would be toxic, so why is this happening?” Vijayanand said.
LJI instructor Dr. Simon Eschweiler spearheaded the study of how PI3Kδ inhibitor treatment affects the immune cells of these patients. Using single-cell genome sequencing, he showed that in increasing tumor-fighting T cells in tumors, PI3Kδ inhibitors also blocked specific subsets of Treg cells that protect the colon. Without the involvement of Treg, pathogenic T cells called Th17 and Tc17 enter and cause inflammation and colitis.
It is clear that cancer trial patients were given larger doses of PI3Kδ inhibitors than they needed, and immunotherapy reduced immune cells in the gut. Subtle composition imbalance.
Eschweiler said the pathways that lead to toxicity identified in the new study may be broadly applicable to other organs that have Treg-like cells, as well as to other organs that target Treg cells. immunotherapy, such as anti-CTLA-4.
New medication strategy may save lives
The team found that intermittent dosing may be an effective therapeutic strategy that combines sustained anti-tumor immunity with reduced toxicity.
The researchers are currently designing a human clinical trial to test this intermittent dosing strategy in humans.
LJI Professor and Chief Scientific Officer Dr. Mitchell Kronenberg said: “This study illustrates how to move from clinical studies to mouse studies to understand these The reasons behind patient toxicity.” His lab led most of the mouse model work for the new study.
How could the lack of toxicity in the B-cell lymphoma trial be explained? In previous studies, patients with lymphoma had been treated several times, Eschweiler said. , leading to overall low immune function. This means that lymphoma patients do not have the same type or the same size of immune response to PI3Kδ inhibition. Meanwhile, head and neck cancer patients are untreated. Their immune systems were not compromised, so immune-related adverse events were more rapid and apparent.
Overall, this new study shows that it’s not just personalizing therapy, but also the dose and schedule of personalized therapy .
Ottensmeier explained that a decade ago doctors could only offer one type of immunotherapy. Either it helps the patient or it doesn’t. Doctors today have a rapidly growing arsenal 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 were most effective for individual patients, and The optimal schedule for giving these treatments. In a 2021 study in Nature ImmunologyIn their study, the two showed the potential importance of administering immunotherapy in a specific order.
Vijayanand said: “If you design your clinical trials and apply complex genomics, you still have a lot to learn. You can get Know what’s going on and get back to the patient.”
References
Intermittent PI3Kδ inhibition sustains anti-tumour immunity and curbs irAE