Researchers at the University of Pennsylvania Perelman School of Medicine and Penn Medicine’s Abramson Cancer Center have developed a new tool for monitoring immune health patterns over time, which has revealed how a pair of checkpoint inhibitor therapies work together to recruit new cancer-fighting T cells with each infusion. The study challenges fundamental assumptions about how a common immunotherapy drug combination activates different types of T cells to defeat cancer and could help researchers more precisely measure immune response in future clinical trials. The research, published in Cancer Cell, focused on PD-1 and CTLA-4 checkpoint inhibitors, which have become a mainstay of melanoma treatment.
Traditionally, it was believed that combination immunotherapy equips an army of T cells to recognize and fight cancer throughout the treatment. The study identified that the combination therapy actually produces waves of new T cells with each dose, known as a clonal response, rather than continually strengthening the same pool of T cells. The immune checkpoint blockade therapies bring in new recruits from the barracks to fight the cancer, rather than directly rejuvenating exhausted T cells. The study found that anti-CTLA-4 therapy complements PD-1 checkpoint inhibitors by replenishing the supply of progenitor-exhausted T cells, adding elite fighters to the ranks.
To track immune response and patterns over time, the research team developed a new algorithm called Cyclone, which follows the unique receptors from individual T cells. By analyzing blood samples from patients at different points throughout their treatment, the researchers were able to see which T cells moved, remained, or disappeared over a nine-week course of treatment. This approach offers a more precise method of immune monitoring that could help researchers understand how new drugs impact the immune system, determine appropriate dosage, and minimize patient exposure to unnecessary toxicity during clinical trials.
The research team plans to apply the Cyclone algorithm in upcoming clinical trials for new cancer immunotherapy approaches, including neoadjuvant studies where T cells can be tracked in both blood and tumor samples, and new immunotherapy combinations targeting PD-1 and LAG-3. The lead author of the study was Kevin Wang, a medical student in the laboratory of senior author Alexander Huang, MD. The study was supported by the National Institutes of Health, the Wistar/Penn SPORE in Skin Cancer, the Tara Miller Melanoma Foundation, the Parker Institute for Cancer Immunotherapy, and the Pew-Stewart Scholars Program in Cancer Research. Huang has performed consulting work for Immunai and received research funding from Bristol Myers Squibb and Merck.
