Interrogating and targeting co-inhibitory and co-stimulatory molecules in CAR T-cell Therapies

Adoptive cell therapies (ACT) with chimeric antigen receptors (CARs) hold promise for treating cancer, yet several challenges must be overcome to achieve this goal. Clinical evidence attributes treatment failure and resistance to insufficient functional T-cell persistence, antigen escape, and a suppressive tumor microenvironment replete with inhibitory, but not costimulatory, molecules. Investigating response and relapse mechanisms and effectively targeting tumor resistance mediators are urgently needed to improve current ACT. We found that CAR-T cells can express or acquire immune regulatory ligands associated with impaired T-cell function. However, the functional impact of these pathways on CAR-T activity remains largely unknown. We hypothesize that these intrinsic and tumor-derived regulatory signals limit CAR-T function and that rationally engineered synthetic receptors can redirect inhibitory interactions into productive costimulatory signals to improve antitumor efficacy across ACT platforms. Aim 1 will define how intrinsic immune regulatory ligand expression affects CAR-T function under varying antigen-stimulation conditions. Aim 2 will determine how tumor-derived ligand acquisition by CAR-T cells affects Tcell function using complementary in vitro and in vivo models. To enhance T-cell persistence and function, we developed a synthetic costimulatory platform that integrates immune regulatory ligand engagement with productive T-cell costimulation. Aim 3 will determine the mechanism of action and therapeutic benefit of this platform in hematologic and solid tumor models. Our multidisciplinary approach combines basic immunology with translational immunoengineering to overcome ACT barriers. We aim to advance next-generation engineered T cells and expand the scope of ACT, improving the survival and quality of life of cancer patients. Project Number: 1R37CA300795-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Mohamad Hamieh | Institution: WEILL MEDICAL COLL OF CORNELL UNIV, NEW YORK, NY | Award Amount: $716,183 | Activity Code: R37 | Study Section: Cellular Immunotherapy of Cancer Study Section[CIC] View on NIH RePORTER: https://reporter.nih.gov/project-details/11368643