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Preclinical Activity of Embryonic Annexin A2-Specific Chimeric Antigen Receptor T Cells Against Ovarian Cancer
Leonard Leong1,2, Heng Liang Tan1, Simeon Cua1
1Bioprocessing Technology Institute (BTI), Agency for Science, Technology and Research (A*STAR), Singapore 138668, Singapore.
Abstract:
Chimeric antigen receptors (CARs) have found clinical success in B cell malignancies, but a dearth of potential targets limits their wider clinical application, especially in solid tumours. Here, we describe the development of an anti-annexin A2 CAR, CAR(2448), derived from an antibody found to have activity against epithelial ovarian cancer cell lines. The spacer length of CAR(2448) was optimised based on in vitro cytotoxic activity against ovarian cancer (OC) cell lines via a real-time cytotoxicity assay. The longer spacer CAR(2448)L T cells exhibit significant effector activity, inducing inflammatory cytokine release and cytotoxicity against OC cell lines. Furthermore, CAR(2448)L-BBz T cells induced enhanced survival in an in vivo OC xenograft model and reduced tumour volume by 76.6%. Our preclinical studies of CAR(2448) suggest its potential for the unmet need of novel strategies for the treatment of ovarian cancer.
Insights
Researchers developed a novel chimeric antigen receptor (CAR) targeting annexin A2 for ovarian cancer treatment. This CAR therapy demonstrated significant efficacy in preclinical models, offering a promising new strategy for ovarian cancer.
Area of Science:
- Immunotherapy
- Oncology
- Molecular Biology
Background:
- Chimeric antigen receptor (CAR) therapies show success in B cell malignancies.
- Limited target availability hinders CAR application, particularly in solid tumors.
- Annexin A2 is a potential target identified for epithelial ovarian cancer.
Purpose of the Study:
- To develop and optimize a novel CAR targeting annexin A2 for ovarian cancer.
- To evaluate the in vitro and in vivo efficacy of the anti-annexin A2 CAR.
- To assess the potential of this CAR therapy for treating ovarian cancer.
Main Methods:
- Development of an anti-annexin A2 CAR (CAR(2448)) derived from an active antibody.
- Optimization of CAR spacer length based on in vitro cytotoxicity assays against ovarian cancer cell lines.
- Assessment of CAR T cell effector functions, cytokine release, and in vivo tumor reduction in xenograft models.
Main Results:
- The longer spacer CAR(2448)L T cells exhibited significant in vitro cytotoxic activity and inflammatory cytokine release against ovarian cancer cell lines.
- CAR(2448)L-BBz T cells demonstrated enhanced survival in an in vivo ovarian cancer xenograft model.
- Tumor volume was reduced by 76.6% in the in vivo model.
Conclusions:
- Preclinical studies indicate CAR(2448) is a promising candidate for ovarian cancer immunotherapy.
- This novel CAR targets annexin A2, addressing an unmet need in ovarian cancer treatment.
- Further development of CAR(2448) holds potential for a new therapeutic strategy against ovarian cancer.
