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Efficacy and Safety of Glycosphingolipid SSEA-4 Targeting CAR-T Cells in an Ovarian Carcinoma Model
Hector J Monzo1, Kerttu Kalander1,2, Marko M Hyytiäinen1
1Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
Abstract:
Chimeric antigen receptor (CAR) T-cell immunotherapies for solid tumors face critical challenges such as heterogeneous antigen expression. We characterized stage-specific embryonic antigen-4 (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 preclinically in vitro and in vivo for antitumor response and safety. SSEA-4 CAR-T cells effectively eliminated SSEA-4-positive cells in all the tested cancer cell lines, whereas SSEA-4-negative cells lines were not targeted. In vivo efficacy and safety studies using NSG mice and the high-grade serous ovarian cancer cell line OVCAR4 demonstrated a remarkable and specific antitumor response at all the 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, the severity of toxicity was reduced with a delayed onset when lower CAR T-cell doses were used. Our data demonstrate the efficacy of anti-SSEA-4 CAR T-cell 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.
Insights
Stage-specific embryonic antigen-4 (SSEA-4) CAR T-cell therapy shows promise for solid tumors. Careful dose management is crucial to balance efficacy and mitigate potential toxicity in this novel cancer immunotherapy.
Area of Science:
- Immunotherapy
- Oncology
- Cellular Therapy
Background:
- Chimeric antigen receptor (CAR) T-cell therapies face challenges in solid tumors due to heterogeneous antigen expression.
- Stage-specific embryonic antigen-4 (SSEA-4), a cell-surface glycolipid, is expressed during embryogenesis and in several cancer types, making it a potential tumor-associated antigen.
Purpose of the Study:
- To characterize SSEA-4 as a target for CAR T-cell therapy.
- To evaluate the preclinical efficacy and safety of anti-SSEA-4 CAR T-cells in vitro and in vivo.
Main Methods:
- Generation of anti-SSEA-4 CAR T-cells.
- In vitro assessment of CAR T-cell activity against SSEA-4-positive and SSEA-negative cancer cell lines.
- In vivo efficacy and safety studies in NSG mice using the OVCAR4 high-grade serous ovarian cancer cell line.
Main Results:
- Anti-SSEA-4 CAR T-cells demonstrated effective and specific elimination of SSEA-4-positive cancer cells in vitro.
- Significant antitumor response observed in vivo in ovarian cancer models across various CAR T-cell doses.
- Dose-dependent toxicity observed, with higher doses causing health deterioration; lower doses showed reduced toxicity and delayed onset.
Conclusions:
- Anti-SSEA-4 CAR T-cell therapy is effective against SSEA-4-expressing solid tumors.
- Clinical translation requires safety strategies, including dose limitation and combinatorial antigen recognition, to manage potential toxicities.
