Patient-specific tumor neoantigen–Major Histocompatibility Complex and neoantigen-specific T cells (Neoantigen-MHC/TCR)

Patient-specific tumor neoantigen–Major Histocompatibility Complex (MHC) complexes and neoantigen-specific T cells represent the fundamental interaction driving personalized cancer immunotherapy. Neoantigens are unique peptides derived from somatic mutations within a patient's tumor that are not present in healthy tissues, making them ideal targets for highly specific immune intervention [6, 8]. These neoantigens are processed intracellularly and presented on the tumor cell surface by MHC molecules, forming a complex that serves as a "non-self" signal to the immune system [1, 10]. Neoantigen-specific T cells, equipped with specialized T-cell receptors (TCRs), recognize these specific pMHC complexes, leading to T-cell activation, proliferation, and the targeted destruction of cancer cells [2, 5]. Therapeutic strategies leveraging this target include personalized neoantigen vaccines, such as mRNA-4157 and Autogene cevumeran, which prime the patient's immune system to generate these T cells, as well as adoptive cell therapies like lifileucel or TCR-engineered T cells [6, 7]. This approach aims to overcome tumor heterogeneity and immune evasion by focusing on the most immunogenic and tumor-restricted markers [4, 8]. Despite its promise, the efficacy of targeting these complexes can be limited by factors such as MHC downregulation, low mutational burden, and the immunosuppressive tumor microenvironment [7, 10].

Other names

Tumor-specific antigens (TSAs)NeoepitopesPersonalized cancer antigensNeoantigen-reactive T cellspMHC-TCR complexIndividualized neoantigen-specific immunotherapy (iNeST)

Recognition of tumor-specific neoantigens presented by Major Histocompatibility Complex (MHC) molecules on the surface of cancer cells by specific T-cell receptors (TCRs), leading to T-cell activation, cytokine release, and targeted lysis of the tumor cell.