TCR-T cell therapy: current development approaches, preclinical evaluation, and perspectives on regulatory challenges.

Golikova, Elena A.; Alshevskaya, Alina A.; Alrhmoun, Saleh; Sivitskaya, Natalia A.; Sennikov, Sergey V.

TCR-T cell therapy represents a promising advancement in adoptive immunotherapy for cancer treatment. Despite its potential, the development and preclinical testing of TCR-T cells face significant challenges. This review provides a structured overview of the key stages in preclinical testing, including in silico, in vitro, and in vivo methods, within the context of the sequential development of novel therapies. This review aimed to systematically outline the processes for evaluating TCR-T cells at each stage: from in silico approaches used to predict target antigens, assess cross-reactivity, and minimize off-target effects, to in vitro assays designed to measure cell functionality, cytotoxicity, and activation. Additionally, the review discusses the limitations of in vivo testing in animal models, particularly in accurately reflecting the human tumor microenvironment and immune responses. Performed analysis emphasizes the importance of these preclinical stages in the safe and effective development of TCR-T cell therapies. While current models provide valuable insights, we identify critical gaps, particularly in in vivo biodistribution and toxicity assessments, and propose the need for enhanced standardization and the development of more representative models. This structured approach aims to improve the predictability and safety of TCR-T cell therapy as it advances towards clinical application.

T cell receptors; CELLULAR therapy; T cells; ANIMAL experimentation; CYTOTOXINS

Journal of Translational Medicine, 2024, Vol 22, Issue 1, p1

1479-5876

Academic Journal

10.1186/s12967-024-05703-9