Tumor peptide-Human Leukocyte Antigen complex (pHLA)

The Tumor peptide-Human Leukocyte Antigen (HLA) complex is a molecular assembly presented on the surface of cancer cells, consisting of a degraded protein fragment (peptide) bound within the groove of an HLA molecule. This complex serves as the fundamental unit recognized by the T-cell receptor (TCR), allowing the adaptive immune system to identify and eliminate cells expressing mutated, neonatal, or overexpressed intracellular proteins [1]. Unlike traditional monoclonal antibodies or CAR-T cells that are restricted to surface-bound antigens, pHLA complexes enable the therapeutic targeting of the intracellular proteome, which contains the vast majority of potential tumor-specific targets [2]. Current therapeutic modalities targeting these complexes include TCR-engineered T-cell (TCR-T) therapies and bispecific TCR-redirection molecules, such as Immune Mobilizing Monoclonal TCRs Against Cancer (ImmTACs) [3]. These treatments are highly specific to both the peptide sequence and the patient's specific HLA allele, with HLA-A*02:01 being the most common restricted allele in clinical development [4]. Notable clinical successes include the approval of tebentafusp for metastatic uveal melanoma and afamitresgene autoleucel for synovial sarcoma [5, 6]. However, significant challenges persist, including the risk of lethal cross-reactivity if the targeted peptide sequence mimics those found in vital healthy tissues and the ability of tumors to evade detection by downregulating HLA expression [7]. Sources: [1] Murphy, K., & Weaver, C. (2016). Janeway's Immunobiology. [2] Walseng, E., et al. (2017). "A TCR-based chimeric antigen receptor." Scientific Reports. [3] Damato, B. E., et al. (2019). "Tebentafusp: A First-in-Class Low-Affinity TCR-Based Bispecific T-Cell Engager." Expert Opinion on Investigational Drugs. [4] Barker, D. J., et al. (2023). "HLA-A*02:01-restricted T cell receptors in cancer immunotherapy." [5] Nathan, P., et al. (2021). "Overall Survival with Tebentafusp in Metastatic Uveal Melanoma." New England Journal of Medicine. [6] U.S. Food and Drug Administration (2024). "FDA approves gene therapy for metastatic synovial sarcoma." [7] Garrido, F., et al. (2016). "The HLA class I phenotype of tumors." Cancer Immunology, Immunotherapy.

Other names

Peptide-MHC complexpMHCTumor-associated antigen-HLA complexNeoantigen-HLA complexpMHC class I complexAntigen-HLA complex

T-cell receptor (TCR) mediated recognition, T-cell redirection, Adoptive cell transfer, Cytotoxic T-lymphocyte activation