Effective antitumor activity of 5T4‐specific CAR‐T cells against ovarian cancer cells in vitro and xenotransplanted tumors in vivo

Abstract

Ovarian cancer is considered to be the most lethal gynecologic malignancy, and despite the development of conventional therapies and new therapeutic approaches, the patient's survival time remains short because of tumor recurrence and metastasis. Therefore, effective methods to control tumor progression are urgently needed. The oncofetal tumor‐associated antigen 5T4 (trophoblast glycoprotein, TPBG) represents an appealing target for adoptive T‐cell immunotherapy as it is highly expressed on the surface of various tumor cells, has very limited expression in normal tissues, and spreads widely in malignant tumors throughout their development. In this study, we generated second‐generation human chimeric antigen receptor (CAR) T cells with redirected specificity to 5T4 (5T4 CAR‐T) and demonstrated that these CAR‐T cells can elicit lytic cytotoxicity in targeted tumor cells, in addition to the secretion of cytotoxic cytokines, including IFN‐γ, IL‐2, and GM‐CSF. Furthermore, adoptive transfer of 5T4 CAR‐T cells significantly delayed tumor formation in xenografts of peritoneal and subcutaneous animal models. These results demonstrate the potential efficacy and feasibility of 5T4 CAR‐T cell immunotherapy and provide a theoretical basis for the clinical study of future immunotherapies targeting 5T4 for ovarian cancer.

CAR-T Cells in the Treatment of Ovarian Cancer: A Promising Cell Therapy

“…Moreover, adoptive transfer of TPBG-CAR-T cells significantly delayed tumor formation in peritoneal and subcutaneous animal model xenografts. These results demonstrate the potential therapeutic effect and feasibility of immunotherapy with TPBG-CAR-T cells and provide a theoretical basis for future clinical trials of OC immunotherapy [ 34 ].…”

“…TPBG is a potential target for adoptive T-cell immunotherapy because it is highly expressed on the surface of various tumor cells and has low expression in normal tissues. Guo et al [ 34 ] produced second-generation CAR-T cells specific for TPBG and showed that TPBG-CAR-T cells could induce lytic cytotoxicity and production of cytotoxic cytokines, including interferon gamma (IFNG), interleukin-2 (IL-2), and granulocyte-macrophage colony-stimulating factor. Moreover, adoptive transfer of TPBG-CAR-T cells significantly delayed tumor formation in peritoneal and subcutaneous animal model xenografts.…”

Understanding CAR T cell therapy and its role in ovarian cancer and peritoneal carcinomatosis from ovarian cancer

“…5T4 plays a role in tumor development and spread, and its expression correlates with poorer clinical outcomes. The selective tumor expression pattern of 5T4 together with its tumor-initiating and tumor-spreading role makes this molecule an attractive target for CAR T cell therapy ( 71 , 75 ).…”

“…Oncofetal TAA 5T4-targeted CAR T cell therapy was tested by Guo et al. ( 75 ). They developed second-generation human CAR T cells that showed specific concentration-dependent cytotoxicity against 5T4+ cells and significantly higher secretion of cytotoxic cytokines in vitro .…”

The role of interferons in ovarian cancer progression: Hinderer or promoter?

“…Effective transduction of patient T cells with anti-5T4 CAR and antigen-specific secretion of IFN-γ was produced by the co-culture of CAR-T cells and matched autologous tumor catabolites. And IFN-γ production correlated with tumor cell surface 5T4 expression levels ( 122 , 123 ). In addition, CAR-T therapy modulated the differentiation of T cells through IFN-γ affecting tumor immunity ( 124 ).…”