Efficacy and safety of glycosphingolipid SSEA-4 targeting CAR-T cells in an ovarian carcinoma model

HJ Monzo,M Hyytiäinen,E Elbasani,K Kalander, J Wall, L Moyano-Galceran, J Tanjore-Ramanathan, J Jukonen,P Laakkonen,A Ristimäki, JW Carlson,K Lehti,S Salehi,P Puolakkainen,C Haglund,H Seppänen,S Leppä, PM Ojala

Molecular Cancer Therapeutics(2022)

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摘要
AbstractChimeric antigen receptor (CAR) T-cell immunotherapies for solid tumors face critical challenges such as heterogeneous antigen expression. We characterized SSEA-4 cell-surface glycolipid as a target for CAR-T cell therapy. SSEA-4 is mainly expressed during embryogenesis but is also found in several cancer types making it an attractive tumor-associated antigen. Anti-SSEA-4 CAR-T cells were generated and assessed pre-clinicallyin vitroandin vivofor anti-tumor response and safety. SSEA-4 CAR-T cells effectively eliminated SSEA-4 positive cells in all tested cancer cell lines whereas SSEA-4 negative cells lines were not targeted.In vivoefficacy and safety studies using NSG mice and the high-grade serous ovarian cancer cell line OVCAR4 demonstrated a remarkable and specific anti-tumor response at all CAR-T cell doses used. At high T cell doses, CAR-T cell-treated mice showed signs of health deterioration after a follow-up period. However, severity of toxicity was reduced with delayed onset when lower CAR-T cell doses were used. Our data demonstrate the efficacy of anti-SSEA-4 CAR-T therapy; however, safety strategies, such as dose-limiting and/or equipping CAR-T cells with combinatorial antigen recognition should be implemented for its potential clinical translation.
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ovarian carcinoma model
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