Patient-specific tumor neoantigen-specific T-cell receptor (NeoTCR) (NeoTCR)

Patient-specific tumor neoantigen-specific T-cell receptors (NeoTCRs) are specialized proteins engineered to recognize unique mutations, or neoantigens, present only in an individual patient's tumor cells [1]. These neoantigens result from somatic mutations that create novel protein sequences not found in the normal human genome, providing a highly specific target for the immune system [2]. In clinical applications, NeoTCRs are typically used in adoptive cell transfer (ACT) therapies, where a patient's T-cells are genetically modified to express a TCR that has been identified and validated to bind a specific neoepitope presented by the patient's Major Histocompatibility Complex (MHC) [3]. Upon re-infusion, these engineered T-cells circulate and infiltrate tumor sites, where the NeoTCR binds to its cognate antigen, triggering T-cell activation, proliferation, and the release of cytotoxic molecules like granzymes and perforins to kill the cancer cells [5]. This personalized approach is designed to minimize "off-target" damage to healthy tissues, as the target antigens are absent outside the tumor [1]. However, challenges remain, including the complex process of neoantigen identification, the potential for tumor escape through HLA downregulation, and the risk of cytokine-related toxicities [5]. Current research focuses on optimizing the identification of high-affinity TCRs and improving the persistence of the engineered cells within the immunosuppressive tumor microenvironment [2].

Other names

Neoantigen-specific T-cell receptorPersonalized TCRTumor-specific TCRNeo-TCRNeoantigen-reactive T-cell receptor

NeoTCRs function by binding to specific neoepitopes (mutated peptides) presented by the patient's HLA molecules on the tumor cell surface, which triggers the formation of an immunological synapse, T-cell signaling via the CD3 complex, and subsequent release of cytotoxic effectors like perforin and granzymes to induce apoptosis in the target cell [1, 5].