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Electroporation of NKG2D RNA CAR Improves Vγ9Vδ2 T Cell Responses against Human Solid Tumor Xenografts
Wei Xia Ang1,2, Yu Yang Ng1,2, Lin Xiao1
1Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore.
Abstract:
Vγ9Vδ2 T cell-based anticancer immunotherapy has shown some promise in early-phase clinical trials but there is still large room for improvement. Using the extracellular domain of the human NKG2D, a stimulatory receptor expressed by Vγ9Vδ2 T cells, we constructed NKG2D ligand-specific chimeric antigen receptors (CARs). We adopted a non-viral CAR approach via mRNA electroporation to modify Vγ9Vδ2 T cells and demonstrated that, upon interaction with the NKG2D ligand-positive cancer cells, the CARs substantially enhanced the cytotoxic activity of the modified cells toward multiple cultured solid tumor cell lines, including those resistant to Zometa treatment. Repeated doses of the CAR-expressing cells resulted in tumor regression in mice with established tumors, extending median survival time by up to 132% as compared to the PBS control group. The findings suggest clinical potential for RNA CAR-modified Vγ9Vδ2 T cells to treat a wide variety of NKG2D ligand-expressing cancers.
Insights
Engineered Vγ9Vδ2 T cells using RNA chimeric antigen receptors (CARs) show enhanced anticancer activity. This novel immunotherapy approach led to significant tumor regression and improved survival in preclinical models, suggesting broad clinical potential.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- Vγ9Vδ2 T cell immunotherapy shows promise but requires enhancement for broader efficacy.
- NKG2D is a key stimulatory receptor on Vγ9Vδ2 T cells crucial for recognizing target cells.
Purpose of the Study:
- To develop and evaluate NKG2D ligand-specific chimeric antigen receptors (CARs) for Vγ9Vδ2 T cell immunotherapy.
- To assess the efficacy of RNA-based CAR modification in enhancing Vγ9Vδ2 T cell anticancer activity against solid tumors.
Main Methods:
- Constructed NKG2D ligand-specific CARs using the extracellular domain of human NKG2D.
- Utilized a non-viral approach with mRNA electroporation to modify Vγ9Vδ2 T cells.
- Tested modified cells against various solid tumor cell lines and in a mouse tumor model.
Main Results:
- CAR-modified Vγ9Vδ2 T cells exhibited significantly enhanced cytotoxic activity against NKG2D ligand-positive cancer cells, including Zometa-resistant lines.
- Repeated administration of CAR-expressing cells led to substantial tumor regression in mice.
- Median survival time in treated mice increased by up to 132% compared to controls.
Conclusions:
- RNA CAR-modified Vγ9Vδ2 T cells represent a promising strategy for enhancing anticancer immunotherapy.
- This approach demonstrates potential for treating a wide range of cancers expressing NKG2D ligands.
