Abstract
Engineered T cell receptor T (TCR-T) cell therapy has facilitated the generation of increasingly reliable tumor antigen-specific adaptable cellular products for the treatment of human cancer. TCR-T cell therapies were initially focused on targeting shared tumor-associated peptide targets, including melanoma differentiation and cancer-testis antigens. With recent technological developments, it has become feasible to target neoantigens derived from tumor somatic mutations, which represents a highly personalized therapy, since most neoantigens are patient-specific and are rarely shared between patients. TCR-T therapies have been tested for clinical efficacy in treating solid tumors in many preclinical studies and clinical trials all over the world. However, the efficacy of TCR-T therapy for the treatment of solid tumors has been limited by a number of factors, including low TCR avidity, off-target toxicities, and target antigen loss leading to tumor escape. In this review, we discuss the process of deriving tumor antigen-specific TCRs, including the identification of appropriate tumor antigen targets, expansion of antigen-specific T cells, and TCR cloning and validation, including techniques and tools for TCR-T cell vector construction and expression. We highlight the achievements of recent clinical trials of engineered TCR-T cell therapies and discuss the current challenges and potential solutions for improving their safety and efficacy, insights that may help guide future TCR-T studies in cancer.
Highlights
While tumor-infiltrating lymphocyte (TIL) and endogenous T-cell therapy (ETC) therapies rely on the isolation and in vitro expansion of T cells derived from tumor or peripheral blood, respectively, T cell receptor T (TCR-T) and chimeric antigen receptors (CAR)-T therapies use genetic modification of T lymphocytes to endow them with tumor antigen specificity [1]
We summarize the tumor antigens currently being targeted with engineered T Cell Receptors (TCR)-T therapies and evaluate the clinical efficacy of current clinical trials
HPV-E7, human papillomavirus 16 (E7); HPV-E6, human papillomavirus 16 (E6); KRAS, Kirsten rat sarcoma virus; MAGE, melanomaassociated antigen; LMP2, latent membrane protein 2; TAC, protachykinin-1; Melanoma antigen recognized by T-cells 1 (MART-1), melanoma antigen recognized by T cells-1; Epstein-Barr virus (EBV), Epstein–Barr virus; gp100, glycoprotein 100; human endogenous retroviral (HERV)-E, human endogenous retrovirus group E; HA-1H, a 29-mer peptide derived from histocompatibility antigen; TP53, tumor protein 53; WT1, Wilm’s Tumor-1 transcription factor; PRAME, preferentially expressed antigen in melanoma; AFP, alpha-fetoprotein; NY-ESO-1, New York esophageal squamous cell carcinoma-1
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. CAR-T therapies use single chain variable fragment (scFv) chimeric antigen receptors (CAR) that can directly recognize tumor cell surface antigens without the requirement for MHC restriction, which is one major limitation of TCR-directed immunotherapies [2]. These CAR constructs can incorporate the intracellular domains of several different co-stimulatory molecules, which can facilitate T cells’ activation, proliferation, and effector functions. TCR-T cells have targeted neoantigens generated by somatic mutations in tumor DNA, which are more tumor-specific but are less shared by cancer patients [5] These engineering approaches can successfully redirect T cells’ specificity to selectively target tumor-associated antigens. We provide perspectives on the key goals and objectives for future research, which include the personalized identification of therapeutic tumor-specific TCRs and potential modifications to improve TCR signaling and effector function
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