Cancer Therapy With TCR-Engineered T Cells: Current Strategies, Challenges, and Prospects

Abstract

To redirect T cells against tumor cells, T cells can be engineered ex vivo to express cancer-antigen specific T cell receptors (TCRs), generating products known as TCR-engineered T cells (TCR T). Unlike chimeric antigen receptors (CARs), TCRs recognize HLA-presented peptides derived from proteins of all cellular compartments. The use of TCR T cells for adoptive cellular therapies (ACT) has gained increased attention, especially as efforts to treat solid cancers with ACTs have intensified. In this review, we describe the differing mechanisms of T cell antigen recognition and signal transduction mediated through CARs and TCRs. We describe the classes of cancer antigens recognized by current TCR T therapies and discuss both classical and emerging pre-clinical strategies for antigen-specific TCR discovery, enhancement, and validation. Finally, we review the current landscape of clinical trials for TCR T therapy and discuss what these current results indicate for the development of future engineered TCR approaches.

Clinical cancer immunotherapy: Current progress and prospects

“…MART TCR-T, gp100 TCR-T, and TCR-T targeting MAGE-A3 or MAGE-A4 have achieved positive results in clinical trials. However, safe use in the clinic should consider the type of antigen and TCR affinity ( 66 , 67 ). In a clinical trial of nine patients treated with TCR-T, 56% (5/9) of patients experienced an OR, one of which was a CR.…”

Emerging Trends in Immunotherapy for Cancer

“…TCR-based adoptive cellular therapy uses genetically manipulated lymphocytes that are targeted against specific tumor antigens. This approach utilizes the ability of TCRs to recognize the tumor-specific antigens presented by the major histocompatibility complex (MHC) present on the surface of malignant cells [ 159 , 160 , 161 ]. Typically, TCR-based therapy requires methodical and well-coordinated steps that include patient’s HLA (human leukocyte antigen) typing, selection of tumor-specific antigen, leukapheresis, manufacturing of transduced TCR product, lymphodepletion, and delivery to the patient [ 159 , 160 , 161 ] ( Figure 3 A).…”

“…Most cell-based immunotherapies face challenges in delivering an effective pool of anti-tumor effector cells. However, the ex vivo production of up to billions of activated lymphocytes with known antigen selectivity and potency allows TCR therapy to overcome this obstacle [ 159 , 161 ]. TCR-based therapy utilizes a variety of immune cells, but T cells and NK cells are used most frequently [ 159 ].…”

Gene-modified T cell therapy for cancer: Current challenges and potential solutions

“…The TCR expressed by the exogenous gene binds CD3 molecules in a non-covalent bond, forming a TCR-CD3 complex expressed on the cell membrane, which further recognizes the HLA-antigen peptide complex. Unlike CAR-T cells, TCR-T cells can recognize HLA peptides derived from intracellular proteins and kill target cells in HLA-restricted dependent manner [96][97][98] . The expression of cancer/testis antigens is silent in normal tissues, except in reproductive system, but is significantly increased in tumor tissues, including melanoma-associated antigen (MAGEA)-3, MAGEA-4, MART-1, gp100, and New York esophageal squamous cell carcinoma (NY-ESO-1), which are considered attractive targets for TCR-T cell therapy [99] .…”

“…The persistence and expansion of antigen specific T cells in vivo are related to the response to TCR-T cell therapy [98,106] . The function of tumor antigen-specific T cells expressing exhaustion marker in the tumor is impaired [107] .…”