Electroporation of NKG2D RNA CAR Improves Vγ9Vδ2 T Cell Responses against Human Solid Tumor Xenografts

Ang, Wei Xia; Ng, Yi Zhen; Xiao, Lin; Chen, Can; Li, Zhendong; Chi, Zhixia; Tay, Johan Chin-Kang; Tan, Wee Kiat; Zeng, Jieming; Toh, Han Chong; Wang, Shu

doi:10.1016/j.omto.2020.04.013

Cited by 36 publications

(22 citation statements)

References 45 publications

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“…mRNA CARs are also used for retargeting of γδ T cells [ 168 , 169 ], NKT cells [ 170 ] and NK cells [ 135 , 171 , 172 ]. Besides the classical CAR construct containing an scFv as a targeting moiety, CARs featuring the extracellular domain of natural killer group 2D (NKG2D) have been engineered to recognize tumor cells that express high levels of NKG2D ligands.…”

Section: Mrna-encoded Antigen Receptorsmentioning

confidence: 99%

mRNA therapeutics in cancer immunotherapy

et al. 2021

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Synthetic mRNA provides a template for the synthesis of any given protein, protein fragment or peptide and lends itself to a broad range of pharmaceutical applications, including different modalities of cancer immunotherapy. With the ease of rapid, large scale Good Manufacturing Practice-grade mRNA production, mRNA is ideally poised not only for off-the shelf cancer vaccines but also for personalized neoantigen vaccination. The ability to stimulate pattern recognition receptors and thus an anti-viral type of innate immune response equips mRNA-based vaccines with inherent adjuvanticity. Nucleoside modification and elimination of double-stranded RNA can reduce the immunomodulatory activity of mRNA and increase and prolong protein production. In combination with nanoparticle-based formulations that increase transfection efficiency and facilitate lymphatic system targeting, nucleoside-modified mRNA enables efficient delivery of cytokines, costimulatory receptors, or therapeutic antibodies. Steady but transient production of the encoded bioactive molecule from the mRNA template can improve the pharmacokinetic, pharmacodynamic and safety properties as compared to the respective recombinant proteins. This may be harnessed for applications that benefit from a higher level of expression control, such as chimeric antigen receptor (CAR)-modified adoptive T-cell therapies. This review highlights the advancements in the field of mRNA-based cancer therapeutics, providing insights into key preclinical developments and the evolving clinical landscape.

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Section: Mrna-encoded Antigen Receptorsmentioning

confidence: 99%

mRNA therapeutics in cancer immunotherapy

et al. 2021

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“…The control construct was generated by replacing the anti-BCMA scFv sequence with the EGFP coding sequence. A 1 st generation NKG2D CAR, NKG2Dz, constructed in our previous study [ 25 ] was included for CAR activity comparison.…”

Section: Resultsmentioning

confidence: 99%

Vγ9Vδ2 T cells expressing a BCMA—Specific chimeric antigen receptor inhibit multiple myeloma xenograft growth

Zhang

et al. 2022

PLoS ONE

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Vγ9Vδ2 T cells are immune effector cells capable of killing multiple myeloma (MM) cells and have been tested in clinical trials to treat MM patients. To enhance the MM cell killing function of Vγ9Vδ2 T cells, we introduced a BCMA-specific CAR into ex vivo expanded Vγ9Vδ2 T cells through electroporation of the CAR-encoding mRNA. The modified Vγ9Vδ2 T cells displayed a high cytolytic activity against BCMA-expressing MM cell lines in vitro, while sparing BCMA-negative cells, including normal B cells and monocytes. Subsequently, we intravenously injected KMS-11 human MM cells to generate a xenograft mouse model. The treatment of the tumor-bearing mice with Zometa and anti-BCMA CAR- Vγ9Vδ2 T cells resulted in a significant reduction of tumor burden in the femur region, as well as the overall tumor burden. In association with the decrease in tumor burden, the survival of the MM cell-inoculated mice was markedly prolonged. Considering the potential of Vγ9Vδ2 T cells to be used as off-the-shelf products, the modification of these cells with a BCMA-specific CAR could be an attractive option for cancer immunotherapy against bone marrow cancer MM.

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“…Only when CD3 and its costimulatory signal receptors were involved did CAR-γδT cells become activated and release cytokines [107]. In addition, CAR-γδT cells targeting CD19 [17,108], NKG2D [109], gp100/HLA-A2 [100], carcinoembryonic antigen (CEA), and HER2 [41] have antitumor effects on corresponding tumor cells in vivo and in vitro.…”

Section: Car T Engineered Strategiesmentioning

confidence: 99%

γδT cells: alternative treasure in antitumor immunity

Zhang

Chen

et al. 2022

Explor Immunol

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In recent decades, abundant methods for targeted tumor cell immunotherapy have been developed. It was recently discovered that excellent curative effects observed in hematological tumors cannot be achieved in solid tumors, as serious side effects will occur. These are all derived from engineered adaptive immune cells, the use of which will bring limitations. γδT cells have a unique ability to respond to a variety of tumor cells while linking innate immunity and adaptive immunity, and thus, they are an ideal source of therapeutic allogeneic cells. This review introduces strategies that can optimize the clinical application of γδT cells to provide novel ideas for adoptive immunotherapy in the future.

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Electroporation of NKG2D RNA CAR Improves Vγ9Vδ2 T Cell Responses against Human Solid Tumor Xenografts

Cited by 36 publications

References 45 publications

mRNA therapeutics in cancer immunotherapy

mRNA therapeutics in cancer immunotherapy

Vγ9Vδ2 T cells expressing a BCMA—Specific chimeric antigen receptor inhibit multiple myeloma xenograft growth

γδT cells: alternative treasure in antitumor immunity

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