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A Real-time Potency Assay for Chimeric Antigen Receptor T Cells Targeting Solid and Hematological Cancer Cells
Published on: November 12, 2019
New CEACAM-targeting 2A3 single-domain antibody-based chimeric antigen receptor T-cells produce anticancer effects in
Iga Jancewicz1, Magdalena Śmiech1, Magdalena Winiarska1,2
14Cell Therapies S.A., 59C Bojkowska Street, 44-100, Gliwice, Poland.
Abstract:
Recently, a breakthrough immunotherapeutic strategy of chimeric antigen receptor (CAR) T-cells has been introduced to hematooncology. However, to apply this novel treatment in solid cancers, one must identify suitable molecular targets in the tumors of choice. CEACAM family proteins are involved in the progression of a range of malignancies, including pancreatic and breast cancers, and pose attractive targets for anticancer therapies. In this work, we used a new CEACAM-targeted 2A3 single-domain antibody-based chimeric antigen receptor T-cells to evaluate their antitumor properties in vitro and in animal models. Originally, 2A3 antibody was reported to target CEACAM6 molecule; however, our in vitro co-incubation experiments showed activation and high cytotoxicity of 2A3-CAR T-cells against CEACAM5 and/or CEACAM6 high human cell lines, suggesting cross-reactivity of this antibody. Moreover, 2A3-CAR T-cells tested in vivo in the BxPC-3 xenograft model demonstrated high efficacy against pancreatic cancer xenografts in both early and late intervention treatment regimens. Our results for the first time show an enhanced targeting toward CEACAM5 and CEACAM6 molecules by the new 2A3 sdAb-based CAR T-cells. The results strongly support the further development of 2A3-CAR T-cells as a potential treatment strategy against CEACAM5/6-overexpressing cancers.
Insights
New chimeric antigen receptor (CAR) T-cells targeting CEACAM5 and CEACAM6 show potent anti-cancer activity. This breakthrough offers a promising new immunotherapy for solid tumors like pancreatic cancer.
Area of Science:
- Immunotherapy
- Oncology
- Molecular Biology
Background:
- Chimeric antigen receptor (CAR) T-cell therapy is a breakthrough in hematooncology.
- Identifying suitable targets for CAR T-cells in solid tumors remains a challenge.
- CEACAM family proteins are implicated in pancreatic and breast cancer progression.
Purpose of the Study:
- To evaluate the antitumor properties of novel CEACAM-targeted 2A3 single-domain antibody-based CAR T-cells.
- To assess the efficacy of 2A3-CAR T-cells against CEACAM5 and CEACAM6 expressing cancers.
- To investigate the potential of 2A3-CAR T-cells as a therapeutic strategy for solid tumors.
Main Methods:
- Development of 2A3 single-domain antibody-based CAR T-cells.
- In vitro assessment of CAR T-cell activation and cytotoxicity against CEACAM-expressing cell lines.
- In vivo evaluation of 2A3-CAR T-cell efficacy in a pancreatic cancer xenograft model (BxPC-3).
Main Results:
- 2A3-CAR T-cells demonstrated cross-reactivity and high cytotoxicity against CEACAM5 and CEACAM6 expressing cell lines.
- In vivo studies showed high efficacy of 2A3-CAR T-cells against pancreatic cancer xenografts.
- The study identified enhanced targeting of CEACAM5 and CEACAM6 by 2A3 sdAb-based CAR T-cells.
Conclusions:
- 2A3-CAR T-cells exhibit significant antitumor activity against CEACAM5/6-overexpressing solid tumors.
- This novel CAR T-cell therapy shows promise for treating pancreatic and potentially other CEACAM-related cancers.
- Further development of 2A3-CAR T-cells is warranted for clinical application in CEACAM-driven malignancies.
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