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.

Fig. 1.. Choice of target antigen in TCR-T cell therapy.

(A) Tumor-associated antigens (TAAs) are overexpressed in tumor versus normal tissues, whereas tumor-specific antigens (TSAs) are expressed exclusively in the tumor. Pros and cons of each antigen type are displayed in the last column. IHC, immunohistochemistry. (B) After identifying the antigen, epitopes need to be predicted on the basis of data-driven bioinformatic tools (examples: NetMHC and MHC Flurry) and their presence in tumor cells confirmed by peptidomics/immunopeptidomics. These steps are followed by the identification of epitope-specific TCRs. Int, intensity; m/z, mass/charge ratio.

Fig. 2.. TCR identification, optimization, and validation.

(A) T cells from healthy donor’s peripheral blood mononuclear cells (PBMCs) or patient’s TILs can be primed by antigen-presenting cells (APCs) loaded with one or several epitopes or antigens to stimulate the activation and expansion of specific T cells. TCRs from these specific T cells can be identified by sequencing T cell bulk or single cells. RACE-PCR, rapid amplification of cDNA ends–polymerase chain reaction; IFN-γ, interferon-γ. (B) TCR optimization can be performed by modifying the constant regions of both TCRα and TCRβ chains to prevent mispairing and increase TCR expression and stability. More recently, mutations in the variable regions but outside CDR regions have been shown to improve TCR expression and stability. TCR affinity maturation aims at increasing TCR affinity. (C) Once the TCR has been identified, in vitro and in vivo functional assays validate the specificity and the efficacy of the engineered T cells.

Fig. 3.. Methods to assess the potential toxicities of TCR-T cell therapies.

(A) Methods to anticipate on-target off-tumor toxicities (presence of the targeted epitope in normal tissues). (B) Methods to anticipate off-target off-tumor toxicities (presence of a cross-reactive epitope in normal tissues).