T Cells Expressing a Modified FcγRI Exert Antibody-Dependent Cytotoxicity and Overcome the Limitations of CAR T-cell Therapy against Solid Tumors

• DOI: 10.1158/2326-6066.cir-22-0423
• Publication Date: 2023-04-18T17:32:25Z
• Authors: Diana Rasoulounir...; Nadine Santana-Magal; Amit Gutwillig; Leen Farhat-Younis; Lior Tal; Sarah Amar; Michael Milyavsky; Siva Sai Naga Anu...; Neta Solomon; Hana Shpilt; Shahar Dotan; Noam Pilpel; Claudia Waskow; Meora Feinmesser; Peleg Rider; Yaron Carmi
• Keywords: Cancer Immunotherapy; Fc receptor

Abstract The pioneering design of chimeric antigen receptor (CAR) T-cell therapy demonstrated the potential reprogramming immune system. Nonetheless, exhaustion, toxicity, and suppressive microenvironments limit their efficacy in solid tumors. We previously characterized a subset tumor-infiltrating CD4+ T cells expressing FcγRI receptor. Herein, we detail engineering receptor, based on structure, allowing to target tumor using antibody intermediates. These showed effective specific cytotoxicity only when an appropriate was added. Only target-bound antibodies activated these cells, while free were internalized without activation. Their cytotoxic activity correlated protein density, therefore targeting with high density sparing normal low or no expression. This activation mechanism prevented premature exhaustion. Furthermore, during antibody-dependent secreted attenuated cytokine levels compared CAR thereby enhancing safety profile. eradicated established melanomas, infiltrated microenvironment, facilitated host cell recruitment immunocompetent mice. In NOD/SCID gamma mice infiltrate, persist, eradicate As opposed therapies, which require changing across different types cancer, our engineered remain same types, injected changes. Overall, generated highly flexible capable binding wide range affinity, preserving specificity tumor-associated antigens single manufacturing process.