Cytotoxicity of fourth-generation anti-Trop2 CAR-T cells against breast cancer

Somboonpatarakun, C., Phanthaphol, N., Suwanchiwasiri, K., Ramwarungkura, B., Yuti, P., Poungvarin, N., Thuwajit, P., Junking, M. and Yenchitsomanus, P.-T. (2024) Cytotoxicity of fourth-generation anti-Trop2 CAR-T cells against breast cancer. International Immunopharmacology, 129, 111631. (doi: 10.1016/j.intimp.2024.111631) (PMID:38359664)

Abstract

The treatment of breast cancer (BC) remains a formidable challenge due to the emergence of drug resistance, necessitating the exploration of innovative strategies. Chimeric antigen receptor (CAR)-T cell therapy, a groundbreaking approach in hematologic malignancies, is actively under investigation for its potential application in solid tumors, including BC. Trophoblast cell surface antigen 2 (Trop2) has emerged as a promising immunotherapeutic target in various cancers and is notably overexpressed in BC. To enhance therapeutic efficacy in BC, a fourth-generation CAR (CAR4) construct was developed. This CAR4 design incorporates an anti-Trop2 single-chain variable fragment (scFv) fused with three costimulatory domains –CD28/4-1BB/CD27, and CD3ζ. Comparative analysis with the conventional second-generation CAR (CAR2; 28ζ) revealed that anti-Trop2 CAR4 T cells exhibited heightened cytotoxicity and interferon-gamma (IFN-γ) production against Trop2-expressing MCF-7 cells. Notably, anti-Trop2 CAR4-T cells demonstrated superior long-term cytotoxic functionality and proliferative capacity. Crucially, anti-Trop2 CAR4-T cells displayed specific cytotoxicity against Trop2-positive BC cells (MDA-MB-231, HCC70, and MCF-7) in both two-dimensional (2D) and three-dimensional (3D) culture systems. Following antigen-specific killing, these cells markedly secreted interleukin-2 (IL-2), tumor necrosis factor-alpha (TNF-α), IFN-γ, and Granzyme B compared to non-transduced T cells. This study highlights the therapeutic potential of anti-Trop2 CAR4-T cells in adoptive T cell therapy for BC, offering significant promise for the advancement of BC treatment strategies.

• Item Type: Articles
• Additional Information: This research and innovation activity received financial support from various sources, including the Thailand Research Fund (TRF) (Grant no. IRN58W0001), and the Center of Excellence on Medical Biotechnology (CEMB), under the aegis of the S and T Postgraduate Education and Research Development Office, Office of Higher Education Commission (OHEC) in Thailand (Grant no. CB-61–006-01). CS received support from Mahidol University (Grant no. R016520008), while MJ was the recipient of Siriraj Chalermphrakiat Grants.
• Keywords: Cellular immunotherapy, Female, Receptors, Antigen, T-Cell - metabolism, Chimeric antigen receptor (CAR), Breast Neoplasms, Immunotherapy, Adoptive - methods, Adoptive T cell therapy, Breast cancer, Trophoblast cell surface antigen 2 (Trop2), Humans, Cell Line, Tumor, T-Lymphocytes, Interferon-gamma - metabolism
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Phanthaphol, Miss Nattaporn

Creator Roles

Phanthaphol, N.: Investigation, Methodology, Validation, Writing – review and editing

• Authors: Somboonpatarakun, C., Phanthaphol, N., Suwanchiwasiri, K., Ramwarungkura, B., Yuti, P., Poungvarin, N., Thuwajit, P., Junking, M., and Yenchitsomanus, P.-T.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: International Immunopharmacology
• Publisher: Elsevier
• ISSN: 1567-5769
• ISSN (Online): 1878-1705
• Published Online: 14 February 2024