Purdue researcher Shalini Low-Nam has received a five-year R01 grant from the National Institutes of Health (NIH) to investigate the molecular signals that control activation of chimeric antigen receptor (CAR) T cells, a type of engineered immune cell used in cancer immunotherapy. The work could help scientists develop safer and more effective CAR T cell therapies for cancer and other diseases.
Low-Nam is a member of the Purdue Institute for Cancer Research (PICR) and an assistant professor of chemistry in the James Tarpo Jr. and Margaret Tarpo Department of Chemistry in Purdue’s College of Science.
The project, funded by the National Institute of Allergy and Infectious Diseases, began Sept. 1 and will run through August 2031. The award provides $2.09 million of funding support.
CAR T cells are typically a patient’s own immune cells that have been genetically engineered with artificial receptors designed to recognize specific targets, such as biomolecules on the surface of cancer cells. When a CAR T cell collects sufficient binding information from a target, it becomes activated and releases toxic molecules that can destroy the target cell. The approach has transformed treatment for some blood cancers, but significant challenges remain and, as yet, no CAR T cell therapy is a first-line treatment option. Scientists still do not fully understand the molecular signals that determine when CAR T cells activate, how strongly they respond, or why they sometimes destroy unintended targets, typically healthy tissue.
Low-Nam’s team recently discovered that CAR T cells are remarkably sensitive, capable of responding to a small handful of binding interactions with a target cell. This sensitivity may help explain why CAR T cells sometimes generate off-target toxicity and harmful side effects. The researchers also found that the T cell receptor, the normal pathogen detector naturally present on these immune cells, appears to play an unexpectedly important role in regulating their activity. When the team disrupted the natural receptor, CAR T cell activation dropped sharply, suggesting that interactions between the natural and engineered receptors may be critical to how these therapies work.
Using approaches from biophysics, biochemistry and cell biology, the researchers will examine how the natural and engineered receptors are organized and communicate within individual cells, how their signaling affects the cells’ ability to kill targets and which interactions lead to the most potent responses. The work will draw on a specialized laboratory platform that tracks the interactions experienced by individual immune cells and measures how those interactions influence their behavior. The team also plans to use machine learning to identify patterns that influence CAR T cell performance.
By defining the mechanisms that control CAR T cell activation, the research could provide scientists with new strategies for engineering immune cells that more effectively destroy intended targets while minimizing unwanted effects. The findings could also advance fundamental understanding of how T cells function, with potential implications for cancer immunotherapy, autoimmune diseases and other engineered cell therapies.
The research reflects the discovery-driven science at the heart of the PICR’s mission. As one of only eight National Cancer Institute-designated Basic Laboratory Cancer Centers in the United States, the PICR focuses on understanding the biological processes that drive cancer and using that knowledge to lay the groundwork for new approaches to prevention, detection and treatment. Investigations like Low-Nam’s help establish the scientific understanding needed to improve existing therapies and develop new ones.
The newly funded work builds on research supported through earlier pilot funding from the PICR and the Ralph W. and Grace M. Showalter Research Trust. The first CAR T cell system that the Low-Nam lab studied was designed at Purdue in the laboratory of the late Philip Low, a longtime professor and cancer institute member.
The PICR’s pilot grant programs provide early-stage funding to help researchers explore promising ideas, generate preliminary findings and build the scientific case for larger, externally funded research projects. Low-Nam’s award illustrates how these investments can help advance innovative research toward sustained federal support.