TCR-engineered T cell therapy in solid tumors: State of the art and perspectives

Abstract

T cell engineering has changed the landscape of cancer immunotherapy. Chimeric antigen receptor T cells have demonstrated a remarkable efficacy in the treatment of B cell malignancies in hematology. However, their clinical impact on solid tumors has been modest so far. T cells expressing an engineered T cell receptor (TCR-T cells) represent a promising therapeutic alternative. The target repertoire is not limited to membrane proteins, and intrinsic features of TCRs such as high antigen sensitivity and near-to-physiological signaling may improve tumor cell detection and killing while improving T cell persistence. In this review, we present the clinical results obtained with TCR-T cells targeting different tumor antigen families. We detail the different methods that have been developed to identify and optimize a TCR candidate. We also discuss the challenges of TCR-T cell therapies, including toxicity assessment and resistance mechanisms. Last, we share some perspectives and highlight future directions in the field.

Deletions of DNA in cancer and their possible uses for therapy

“…[2] Recent advances, including the use of inhibitors of specific kinases and other enzymes, the use of retinoic acid/arsenoxide, the strategy of synthetic lethality, and new approaches to immunotherapy often decelerate the growth of tumors and can be, with some patients and some cancers, either completely or nearly curative. [9][10][11][12][13][14][15][16][17][18][19][20] Nevertheless, a majority of human cancers are still incurable once they have metastasized.…”

Multimodal single-cell profiling of T cell specificity and reactivity in lung cancer

“…In addition to the identification of a tumor-reactive signature, the scMultiomic approach may also support the preferential enrichment of tumor-reactive T cells through a gene network of exhaustion markers, likely caused by repeated antigen stimulation. The identification of TCRs could be used or engineered for molecular or cell therapies [86][87][88] . Recent findings demonstrate that single TCRs could be harnessed as therapeutics for multiple cancer types by exploiting their cross-reactivity against multiple tumor antigens 89 ; this underlines the importance of identifying tumor-reactive TCRs, potentially through methods such as gene signature enrichment.…”

The cell stress and immunity cycle in cancer: Toward next generation of cancer immunotherapy

“…141 Most CAR-T cells are designed with specificity for immune cell lineage antigens, for example, CD19, a cell surface molecule, expressed on all B cells making them very successful in the treatment of B-cell malignancies. 141,154 However, the success rates of CAR-T cells in solid tumors are less rewarding, due to multiple bottlenecks such as scarcity of available antigens, tumor heterogeneity, and tumor immunosuppression. 155 A potential strategy to overcome this issue is via T-cell receptor-engineered T (TCR-T)-cell therapy.…”

“…Each TCR-T cell can also detect and eliminate multiple antigen presenting cancer cells due to their lower affinity for their target compared to CARs. 154,157 Therefore, isolating various TCRs, that recognize mutated peptides presented by HLA classes in a patient, and back engineering them into autologous T cells for ACT therapy creates new potential ways to treat several cancers. 156 Various clinical studies using TCR-T cell therapy (e.g., NCT05194735, NCT05438667) are currently ongoing.…”

“…The targetable antigen repertoire for TCR‐T cells is much larger than for CAR‐T cells. TCRs are able to recognize epitopes derived from membrane and intracellular proteins, whereas CAR‐T cells are limited to cell surface targets 154–156 . Antigen recognition for TCR‐T cells is confined to the HLA allele presenting the epitope, thereby limiting the amount of patients that can benefit from a certain TCR‐T‐cell therapy 154,157 .…”