Icahn School of Medicine at Mount Sinai
Jalal Ahmed, MD, PhD
Targeting the tumor microenvironment to advance CAR T cell therapy for lung cancer
LCRF Pilot Grant Program
Lung cancer remains the leading cause of death from cancer. These data compel us to develop novel approaches to address this challenging disease. Chimeric Antigen Receptors (CAR) are engineered receptors that can redirect the killing activity of T cells to targets of interest and have had dramatic results in the treatment of B cell leukemia. However, the application of this technology to lung cancer remains challenging in part due to suppressive tumor microenvironments that are seen even at the earliest stages of disease. Early tumors are infiltrated with immunosuppressive cells including macrophages and T regulatory cells, and have a reduction in effector T cells. Furthermore, radiation therapy can alter tumor microenvironments and stun the growth of tumors. These observations raise the potential for a synergy from combination of radiation therapy and CAR T cell therapy to kill lung tumors. To test this hypothesis, Dr. Ahmed will use a genetic engineering protocol using CRISPR/Cas9 technology that can produce mouse CAR T cells with high efficiencies. This approach will allow him to test CAR T cells in a novel mouse model with an intact immune system and tumor microenvironment. He will use this model to determine if radiotherapy can modify the inflammatory state of the tumor microenvironment and improve CAR T cell killing of lung tumors. Ultimately, Dr. Ahmed hopes to demonstrate the potential of this CAR T cell-lung cancer platform to test novel combination therapies. In future work, he will apply this model to further dissect the ways in which the tumor microenvironment blocks attack from immune cells, to test new CAR T cell combination therapies, as well as to test the safety and efficacy of a multitude of novel CAR technologies that are under active development.