Distinct waves of T cells generated by each dose of combination immunotherapy

A new tool for tracking patterns of immune health over time has revealed how a pair of checkpoint inhibitor therapies work together to recruit new cancer-fighting T cells with each infusion. Findings from the use of the new tool, developed by researchers at the University of Pennsylvania Perelman School of Medicine and Penn Medicine’s Abramson Cancer Center (ACC), were published today in Cancer Cell. The study challenges fundamental assumptions about how a common combination of immunotherapy drugs activates different types of T cells to defeat cancer and could help researchers more accurately measure the immune response in future clinical trials.

Immunotherapy has made huge strides in improving survival for advanced melanoma over the past decade, although researchers are still working to understand why some patients’ cancers respond better than others and to develop treatments that have fewer side effects. This study focused on a specific immunotherapy combination that has become the mainstay of melanoma treatment: PD-1 and CTLA-4 checkpoint inhibitors.

A new understanding of the T cell response

Immune checkpoint inhibitors work by freeing T cells to find and kill cancer cells. This type of combination immunotherapy was thought to work by equipping an army of T cells to recognize and fight the cancer throughout the course of treatment. In a sense, the idea was that if this group of T cells stayed strong long enough, they would conquer the cancer, but if they were too depleted, they would lose the battle. The study, which analyzed data from 36 patients receiving immunotherapy for advanced melanoma, found that the combination therapy produces waves of new T cells—known as a clonal response—with each dose, rather than continuously boosting the same pool of T cells.

We found that after each infusion, you have a new immune response, with a new group of T cells coming in to fight the cancer. Think of these T cells as an army: for many cancer patients, even when tumors are growing, skilled T-lymphocyte fighters try to slow the advance of hostile cancer cells. We call them ‘exhausted T cells’ because they have been fighting for so long, but they are elite because they can survive in a hostile environment and know how to recognize and fight cancer cells.”

Alexander Huang, MD, senior author, assistant professor of Hematology-Oncology and investigator at the Tara Miller Melanoma Center at ACC

The conventional thinking was that certain immune checkpoint blockade therapies would boost exhausted T cells, instantly rejuvenating them. However, these new data suggest that immune checkpoint blockade is actually bringing new recruits out of the barracks to fight cancer. Instead, there comes a time when the new T-cell recruits have been dispatched and the barracks are empty, and this is when immune checkpoint blockade can become less effective.

Previous research has shown that exhausted T cells, the elite fighters, come from a source called progenitor cells. Anti-PD-1 immunotherapy taps into this source and eventually depletes the supply. In the current study, researchers found that this anti-CTLA-4 therapy complements PD-1 checkpoint inhibitors by replenishing the supply of progenitor-depleted T cells, adding more elite fighters to the ranks.

Evaluation of the immune response over time

To make these discoveries, the team developed a new algorithm called Cyclone to track immune response and patterns over time by following the unique receptors on individual T cells. By examining blood samples from the same patients, taken at different points during their treatment, the researchers were able to see which T cells moved, remained or disappeared during each patient’s nine-week treatment.

This approach also allows researchers to assess the magnitude of the response, including how many and which type of immune cells are activated over time as patients undergo treatment. In comparison, other current single-cell methods of studying the immune response provide more of a narrow “snapshot” in time.

“We envision that this more precise immune monitoring method could be applied to clinical trials in a number of ways,” Huang said. “For example, it could help researchers better understand how new drugs affect the immune system, or understand the appropriate dose needed to produce the necessary biological effect, without having to push to find the ‘maximum tolerated dose’ ” and potentially expose patients to unnecessary toxicity. .”

The research team plans to apply Cyclone in upcoming clinical trials for new cancer immunotherapy approaches, including neoadjuvant studies where T cells can be monitored in both blood samples and tumors, and new immunotherapy combinations, such as drugs targeting PD-1 and LAG-3, a new type of treatment with checkpoint inhibitors.

The study’s lead author was Kevin Wang, a medical student in Huang’s lab. The study was supported by the National Institutes of Health, including Wistar/Penn SPORE in Skin Cancer, (K08CA230157, R01CA273018, RO1CA258113, P50CA174523, P50CA261608, P30CA01025, and P30CA010152 0CA016087), the Tara Miller Foundation ma, the Parker Institute for Cancer Immunotherapy and the Pew-Stewart Fellows Program in Cancer Research.