Abstract
Mesothelin (MSLN) is an attractive antigen for chimeric antigen receptor (CAR) T therapy and the epitope selection within MSLN is essential. In this study, we constructed two types of CARs targeting either region I of MSLN (meso1 CAR, also known as a membrane-distal region) or region III of MSLN (meso3 CAR, also known as a membrane-proximal region) using a modified piggyBac transposon system. We reported that, compared with meso1 CAR T cells, meso3 CAR T cells express higher levels of CD107α upon activation and produce increased levels of interleukin-2, TNF-α, and IFN-γ against multiple MSLN-expressing cancer cells in vitro. In a real-time cell analyzer system and a three-dimensional spheroid cancer cell model, we also demonstrated that meso3 CAR T cells display an enhanced killing effect compared with that of meso1 CAR T cells. More importantly, in a gastric cancer NSG mice model, meso3 CAR T cells mediated stronger antitumor responses than meso1 CAR T cells did. We further identified that meso3 CAR T cells can effectively inhibit the growth of large ovarian tumors in vivo. Collectively, our study provides evidences that meso3 CAR T-cell therapy performs as a better immunotherapy than meso1 CAR T-cell therapy in treating MSLN-positive solid tumors.
Highlights
Chimeric antigen receptor (CAR) T-cell therapy is an immunotherapeutic strategy which genetically modifies T cells expressing a cell-surface antigen to promote T-cell function and persistence
CAR targeting to membrane-distal region (MDR) and membraneproximal region (MPR) epitopes of MSLN, respectively, using the non-viral PB transposon system
We suggest that MSLN MPR is a better epitope to target than MDR for CAR T design
Summary
Chimeric antigen receptor (CAR) T-cell therapy is an immunotherapeutic strategy which genetically modifies T cells expressing a cell-surface antigen to promote T-cell function and persistence. The remarkable efficacy of CD19-CAR T against hematologic malignancies encourages the exploration of CAR T therapies in solid tumors.[1,2,3]. A majority of CAR T studies utilize viral vectors to deliver CAR transgenes into T cells, owing to the high efficiency[4,5,6,7]. To generate high efficiency of CAR T cells, it is crucial to choose appropriate antigens to eliminate tumor cells with minimum toxicity. Mesothelin (MSLN) is becoming a promising antigen, because of its low expression on normal tissues and high expression on various solid tumors[10]. MSLN is a cell-surface glycoprotein with normal expression in peritoneum, pleura, and pericardium, Official journal of the Cell Death Differentiation Association
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