T cells genetically engineered to overcome death signaling enhance adoptive cancer immunotherapy
Tori N. Yamamoto, Ping-Hsien Lee, Suman K. Vodnala, Devikala Gurusamy, Rigel J. Kishton, Zhiya Yu, Arash Eidizadeh, Robert Eil, Jessica Fioravanti, Luca Gattinoni, James N. Kochenderfer, Terry J. Fry, Bulent Arman Aksoy, Jeffrey E. Hammerbacher, Anthony C. Cruz, Richard M. Siegel, Nicholas P. Restifo, and Christopher A. KlebanoffJournal of Clinical Investigation, January 29, 2019
Summary of work
One of the major challenges in adoptive cell therapy for cancer: getting engineered T-cells to multiply and live longer so that they can effectively tackle tumors over time, particularly solid tumors. PICI investigator Christopher Klebanoff, MD, of Memorial Sloan Kettering Cancer Center, shows in this paper that genetically blocking the activation of Fas – a major signaling pathway that instructs cells to self-destruct – could be a solution to this problem. The researchers engineered the T-cells to have a dominant negative receptor, which effectively turns off the Fas pathway and leads to superior longevity and cancer-killing power.
Why this is impactful to patients
This paper demonstrates a novel strategy for keeping tumor-killing CAR-T cells alive longer, preventing them from becoming “exhausted” once administered to cancer patients. The potential for applying this to treatment of solid cancers, notoriously difficult to treat with immunotherapy, is particularly exciting. “This appears to be a new and promising approach for improving T-cell persistence and therapeutic efficacy for CAR-T,” said PICI Clinical Scientist Jingying Xu, PhD. “It will be exciting to see this strategy get further explored in the clinic.”