Evaluation of combination mTOR agonist and CD147-IL15-CAR-NK cell therapy in transgenic human CD147 Hepatocellular Carcinoma models

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Presentation Time: 11:30 AM - 12:45 PM
Poster Board Number: B161
Abstract ID: 4477

Presenting Author:
Minh Ma , PhD candidate at Rutgers New Jersey Med. Sch., Rutgers Grad. Sch. of Biomed. Sci.

Abstract:

Hepatocellular carcinoma (HCC) is one of the deadliest solid tumor cancers. While chimeric antigen receptor (CAR)-natural killer (NK) cells have shown remarkable results in treating refractory leukemias, there are currently no effective CAR-NK cells for solid tumors. We developed primary CD147-CAR-NK cells that effectively kill immortalized and primary HCC tumor cells (Tseng, et al., 2020). However, significant therapeutic challenges remain: NK cells do not persist in a suppressive tumor microenvironment (TME); NOD Scid gamma (NSG) do not recapitulate HCC progression; and the mechanisms of CD147-CAR-NK cells in HCC remain obscure. Our data from knocking out CD147 in HCC cell lines suggest that the immunosuppressive mediators are regulated by CD147, which contribute to HCC tumorigenesis while inhibit CD147-CAR-NK cell functions through mTOR suppression. Restoration of the mTOR signaling using a small molecule show an increased efficacy of CD147-CAR-NK cells across all HCC models in human CD147 transgenic NSG mice (hCD147tg-NSG). Adding the ability to secrete IL-15 by CD147-CAR-NK cells (CD147-IL15-CAR-NK) enhance persistence and anti-tumor activity by exhibiting increased lymphocyte function-associated antigen 1 (LFA-1) activation, a critical factor in the immunological synapse (IS) formation. Altogether, we focus on the mTOR signaling and LFA-1 activation to study the mechanism of improved therapeutic efficacy of CD147-CAR-NK cells in HCC in immunocompetent hCD147tg mice.