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

Diana Rasoulouniriana, Nadine Santana-Magal, Amit Gutwillig, Leen Farhat-Younis, Lior Tal, Sarah Amar, Michael Milyavsky, Siva Sai Naga Anurag Muddineni, Neta Solomon, Hana Shpilt, Shahar Dotan, Noam Pilpel, Claudia Waskow, Meora Feinmesser, Peleg Rider, Yaron Carmi*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

The pioneering design of chimeric antigen receptor (CAR) T-cell therapy demonstrated the potential of reprogramming the immune system. Nonetheless, T-cell exhaustion, toxicity, and suppressive microenvironments limit their efficacy in solid tumors. We previously characterized a subset of tumor-infiltrating CD4þ T cells expressing the FcgRI receptor. Herein, we detail engineering of a receptor, based on the FcgRI structure, allowing T cells to target tumor cells using antibody intermediates. These T cells showed effective and specific cytotoxicity only when an appropriate antibody was added. Only target-bound antibodies activated these cells, while free antibodies were internalized without activation. Their cytotoxic activity was correlated to target protein density, therefore targeting tumor cells with high antigen density while sparing normal cells with low or no expression. This activation mechanism prevented premature exhaustion. Furthermore, during antibody-dependent cytotoxicity these cells secreted attenuated cytokine levels compared with CAR T cells, thereby enhancing their safety profile. These cells eradicated established melanomas, infiltrated the tumor microenvironment, and facilitated host immune cell recruitment in immunocompetent mice. In NOD/SCID gamma mice the cells infiltrate, persist, and eradicate tumors. As opposed to CAR T-cell therapies, which require changing the receptor across different types of cancer, our engineered T cells remain the same across tumor types, while only the injected antibody changes. Overall, we generated a highly flexible T-cell therapy capable of binding a wide range of tumor cells with high affinity, while preserving the cytotoxic specificity only to cells expressing high density of tumor-associated antigens and using a single manufacturing process.

Original languageEnglish
Pages (from-to)792-809
Number of pages18
JournalCancer immunology research
Volume11
Issue number6
DOIs
StatePublished - 1 Jun 2023

Funding

FundersFunder number
Dotan Foundation
Emerson Collective Foundation
Israel Cancer Research Fund
Israel Science Foundation2262/18

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