TCR-T immunotherapy is one-of-a-kind!

The TCR molecule is part of a superfamily of immunoglobulins that consists of two antigen-specific covalently bonded polymorphic subunits that are linked to at least four different types of signal transduction chains. The TCR and the major histocompatibility complex (MHC) must interact in order for T cells to be activated.

The intensity of TCR-pMHC (peptide-MHC) interactions controls the destiny of immature thymocytes and is critical for naive T cell survival. TCR-T immunotherapy boosts the host immune system by interacting effectively with MHC molecules, particularly class II molecules, which are uniquely recognized by TCR-T cells and CAR-T cells. CAR-T cells primarily detect tumor surface antigens, whereas TCR-T cells recognize intracellular tumor-specific antigens. TCR-T cells become more successful in tumor therapy as a result of this.

Adoptive Cell Transfer Therapy (ACT)

1. CAR-T vs. TCR-T

Among ACT therapies, both TCR-T and CAR-T cells have been successfully used in the clinical treatment of solid tumors.

CARs are composed of single-chain antibodies that target tumor antigens, transmembrane structural domains, and the CD3 intracellular activation structural domain. Engineered CARs can recognize specific tumor-associated antigens and bind untreated tumor surface antigens without the need for MHC treatment.

TCRs, on the other hand, are homodimers that attach to MHC antigen complexes. CARs identify tumor antigens but have several drawbacks, such as extratumor toxicity, as compared to TCRs. In T cell-based therapeutics, TCRs offer some structural benefits over CARs, such as more subunits in their receptor structure, more immune receptor tyrosine-based activation motifs (ITAMs), reduced antigen dependence, and more co-stimulatory receptors (CD3, CD4, CD28, etc.). TCRs with a low MHC affinity range can activate T cells effectively, whereas CARs need a higher affinity range.

2. Recombinant TCRs

The TCR is one of the body’s most complicated receptors, with six distinct receptor subunits that have a wide range of functions in T cells. TCR changes in tumor-infiltrating lymphocytes (TILs) have a big impact on tumor-specific T cells. TCR variety is linked to antitumor effects, and alterations in TCRs lead to T cell proliferation.

TCR engineering of TILs is one of the best therapeutic approaches for tumors. TCR consists of α and β chains bound to peptide-MHC ligands, signaling subunits of the CD3 complex (ϵ, γ, and δ), and CD3ζ homodimers. All subunits, except CD3ζ, have extracellular immunoglobulin (Ig) structural domains. Based on these structures, new technologies that utilize engineered TCRs are ImmTAC, TRuCs, and TAC.

2.1. Immune-mobilising monoclonal TCRs (T cell receptors) against cancer (ImmTAC)

Engineered, soluble, and affinity-enhanced monoclonal TCRs (mTCRs) were used to create ImmTACs that are fusion proteins that combine a designed TCR targeting system with the effector function of a single-chain antibody fragment (scFv). The TCR identifies peptides produced from intracellular targets of human leukocyte antigen (HLA) presentation in the formation of ImmTACs.

2.2 T cell receptor fusion constructs (TRuCs)

The T cell receptor fusion construct is an antibody binding domain fused to T cell receptor subunit designed to effectively recognize tumor surface antigens.TRuCs consist of specific antibodies targeting tumor-associated antigens fused to the extracellular N-termini of five TCR subunits (TCRα, TCRβ, CD3ϵ, CD3γ, and CD3δ), providing engineered T cells with novel target specificity and HLA non-dependent target cell clearance capacity that can be activated by the corresponding target cells.

2.3 T-cell antigen coupler (TAC)

Another modified TCR cell that promotes more robust antitumor responses and decreases toxicity in a non-MHC-dependent manner is the T cell coupler. By attaching to the CD3 structural domain of tac chimeric protein, a TCR/CD3 complex is formed, resulting in a stronger T cell response. TAC genetically modified T cells, compared to second-generation CARs, allow for increased infiltration in solid tumors after passaging while simultaneously reducing T cell proliferation and extratumor toxicity in healthy tissues expressing antigens.

Engineered T cells have demonstrated to be particularly effective in the therapy of hematological cancers in recent years. TCR modulation is important for T cell reactivation, immunological response, and clinical consequences on antigens from other countries. TCR-T cells, on the other hand, have benefits that CAR-T cells lack, and have shown considerable promise in both preclinical and clinical studies. TCR-T will undoubtedly demonstrate its distinctive attractiveness in the future, bringing hope to cancer patients seeking relief from their disease discomfort.