Enhancing the effectiveness of γδ T cells by mRNA transfection of chimeric antigen receptors or bispecific T cell engagers

• Published in: Molecular therapy. Oncolytics Vol. 29; pp. 145 - 157
• Main Authors: Becker, Scott A., Petrich, Brian G., Yu, Bing, Knight, Kristopher A., Brown, Harrison C., Raikar, Sunil S., Doering, Christopher B., Spencer, H. Trent
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15-06-2023; American Society of Gene & Cell Therapy; Elsevier
• Subjects: bispecific T cell engager; cancer immunotherapy; CAR T cells; electroporation; gamma delta T cells; Original; electroporation; gamma delta T cells; CAR T cells; cancer immunotherapy; bispecific T cell engager
• ISSN: 2372-7705; 2372-7705
• DOI: 10.1016/j.omto.2023.05.007

Adoptive cell therapy (ACT) utilizing γδ T cells is becoming a promising option for the treatment of cancer, because it offers an off-the-shelf allogeneic product that is safe, potent, and clinically effective. Approaches to engineer or enhance immune-competent cells for ACT, like expression of chimeric antigen receptors (CARs) or combination treatments with bispecific T cell engagers, have improved the specificity and cytotoxic potential of ACTs and have shown great promise in preclinical and clinical settings. Here, we test whether electroporation of γδ T cells with CAR or secreted bispecific T cell engager (sBite) mRNA is an effective approach to improve the cytotoxicity of γδ T cells. Using a CD19-specific CAR, approximately 60% of γδ T cells are modified after mRNA electroporation and these cells show potent anticancer activity in vitro and in vivo against two CD19-positive cancer cell lines. In addition, expression and secretion of a CD19 sBite enhances γδ T cell cytotoxicity, both in vitro and in vivo, and promotes killing of target cells by modified and unmodified γδ T cells. Taken together, we show that transient transfection of γδ T cells with CAR or sBite mRNA by electroporation can be an effective treatment platform as a cancer therapeutic.
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The use of γδ T cells as a cancer immunotherapy offers a promising approach for adoptive cell therapy. Engineering γδ T cells using mRNA electroporation to express chimeric antigen receptors and bispecific T cell engagers improves their anticancer activity and has the potential to be an effective cancer treatment.