The ins and outs of TCR-T cell therapy

Adoptive cell transfer (ACT) therapy is one of the most effective therapeutic options for tumor immunotherapy that is currently emerging in clusters. Chimeric antigen receptors (CARs) and engineered T cell receptors (TCRs) are the main adoptive immunotherapies in recent years. TCR-engineered T cells express tumor antigen-specific receptors with alpha and beta chains generated from high-quality, high-affinity clones of antigen-specific T cells.

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. This makes TCR-T cells more effective in tumor therapy.

Recombinant TCRs

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

TCR engineering of TILs is one of the best therapeutic approaches for tumors. TCR consists of? and? chains bound to peptide-MHC ligands, signaling subunits of the CD3 complex (?,?, and?), and CD3? homodimers. All subunits, except CD3?, have extracellular immunoglobulin (Ig) structural domains. ImmTAC, TRuCs, and TAC are novel technologies that use tailored TCRs and are based on these structures.

ImmTAC

ImmTACs were designed using engineered, soluble, and affinity-enhanced monoclonal TCRs (mTCRs). ImmTACs are essentially fusion proteins that combine an engineered TCR targeting system with single-chain antibody fragment (scFv) effector function. In the construction of ImmTACs, the TCR recognizes peptides derived from intracellular targets of human leukocyte antigen (HLA) presentation.

ImmTAC promotes T cell-mediated effector function by specifically targeting HLA-peptide complexes on the tumor cell surface and interacting with CD3 via scFv antibody fragments. ImmTAC also activates CD8+ T cells and efficiently redirects and activates effector and memory CD8+ and CD4+ cells in a dose-dependent manner. ImmTAC promotes T cell-mediated effector function by secreting multiple cytokines exhibiting multifunctional responses, such as TNF-?, IFN-?, IL-6, MIP1?-?, and IFN-?-inducible protein10.

TRuCs

T cell receptor fusion constructs (TRuCs), an antibody binding domain fused to T cell receptor subunits, are designed to efficiently recognize tumor surface antigens. TRuCs consist of specific antibodies targeting tumor-associated antigens fused to the extracellular N-termini of five TCR subunits (TCR?, TCR?, CD3?, CD3?, and CD3?), providing engineered T cells with novel target specificity and HLA non-dependent target cell clearance, which can be activated by the corresponding target cells.

TAC

T cell antigen connector (TAC) is another engineered TCR cell that induces more potent antitumor responses and reduces toxicity in a non-MHC-dependent manner. TAC chimeric proteins form TCR/CD3 complexes and obtain more T cell responses by binding to the CD3 structural domain.

TAC receptor activity is closely related to the selection of the CD3 binding domain. For example, single-chain antibodies from OKT3 (muromonab-CD3) have lower cytokine production and cytotoxicity compared to UCHT1, which may lead to substantially different functional outcomes. Compared to second-generation CARs, TAC genetically engineered T cells not only facilitate greater infiltration in solid tumors after passaging, but also reduce T cell expansion and extratumor toxicity in healthy tissues expressing antigens.