Engineered TCR-T Cell Immunotherapy in Anticancer Precision Medicine: Pros and Cons

Abstract

This review provides insight into the role of engineered T-cell receptors (TCRs) in immunotherapy. Novel approaches have been developed to boost anticancer immune system, including targeting new antigens, manufacturing new engineered or modified TCRs, and creating a safety switch for endo-suicide genes. In order to re-activate T cells against tumors, immune-mobilizing monoclonal TCRs against cancer (ImmTAC) have been developed as a novel class of manufactured molecules which are bispecific and recognize both cancer and T cells. The TCRs target special antigens such as NY-ESO-1, AHNAKS2580F or ERBB2H473Y to boost the efficacy of anticancer immunotherapy. The safety of genetically modified T cells is very important. Therefore, this review discusses pros and cons of different approaches, such as ImmTAC, Herpes simplex virus thymidine kinase (HSV-TK), and inducible caspase-9 in cancer immunotherapy. Clinical trials related to TCR-T cell therapy and monoclonal antibodies designed for overcoming immunosuppression, and recent advances made in understanding how TCRs are additionally examined. New approaches that can better detect antigens and drive an effective T cell response are discussed as well.

Prognostic Biomarkers in Uveal Melanoma: The Status Quo, Recent Advances and Future Directions

“…It is a construct composed of a soluble affinity-enhanced HLA-A*02:01–restricted T-cell receptor specific for the glycoprotein 100 (gp100) peptide YLEPGPVTA which is fused to an anti-CD3 single-chain variable fragment [ 376 , 378 ]. Thus, ImmTACs like Tebentafusp, are able to target any protein presented as a peptide–HLA complex on the surface of the target-cell, including intracellular antigens [ 379 , 380 ]. The binding of ImmTAC molecules to their target-cell surface specific peptide–HLA complexes initiates the recruitment and activation of polyclonal T cells, mediated through CD3, which efficiently leads to the release of cytokines and other cytolytic mediators to the target cells [ 379 , 380 ].…”

“…Thus, ImmTACs like Tebentafusp, are able to target any protein presented as a peptide–HLA complex on the surface of the target-cell, including intracellular antigens [ 379 , 380 ]. The binding of ImmTAC molecules to their target-cell surface specific peptide–HLA complexes initiates the recruitment and activation of polyclonal T cells, mediated through CD3, which efficiently leads to the release of cytokines and other cytolytic mediators to the target cells [ 379 , 380 ]. In a recent phase 3 clinical trial involving 378 previously untreated HLAA*02:01–positive metastatic UM patients, stratified based on lactate dehydrogenase (LDH) levels, treatment with Tebentafusp was associated with a higher PFS and a 1-year OS of 73%, while in the control group (single agent pembrolizumab, ipilimumab, or dacarbazine) the observed 1-year OS was only 59% [ 376 ].…”

Implications of Antigen Selection on T Cell-Based Immunotherapy

“…Severe toxicities have also been observed in transgenic TCR clinical trials, i.e., severe colitis in patients receiving anti-human CEA TCR [ 92 ] and severe mental changes, coma, and death in patients receiving anti-MAGE-A3 TCR (later found to be the result of cross-reactivity with MAGE-A12 in the brain) [ 92 ]. TCR T cells are currently under investigation against a number of antigens, including TAAs such as NY-ESO-1 (NCT0369137) and MAGE-C2 (NCT04729543), and TSAs, such as HPV E6 (NCT03578406) and KRAS G12V (NCT04146298) [ 93 ].…”

Genetically Modified T Cells for Esophageal Cancer Therapy: A Promising Clinical Application

“…It is a heterodimer consisting of an α chain and a β chain, each of which contain a variable region and a constant region. TCRs must be matched with human leukocyte antigen (HLA) alleles before they recognize and bind to specific antigens presented by peptide-MHC (pMHC) to effectively eliminate or reduce tumor cells, which is significantly distinct from the mechanism of CAR-T cells ( Table 2 ) ( 47 ). Antigens within any subcellular compartment, once processed and presented by MHC molecules, can be recognized by TCR-T cells.…”