Shared tumor-associated antigen peptide–major histocompatibility complex (pMHC) (Shared TAA-pMHC)

Shared tumor-associated antigen (TAA) peptide–major histocompatibility complex (pMHC) targets represent a sophisticated class of therapeutic targets in oncology, formed by the presentation of intracellularly derived peptides on Major Histocompatibility Complex (MHC) molecules. These antigens are "shared" because they are found across various patients and tumor types, typically originating from cancer-testis antigens, differentiation antigens, or overexpressed proteins [1, 5]. This presentation allows the immune system to recognize and eliminate cells expressing abnormal or overexpressed internal proteins that would otherwise be invisible to traditional antibody-based therapies [5]. Therapeutic interventions targeting these complexes primarily include engineered T-cell receptor (TCR) therapies, such as TCR-T cells and bispecific T-cell engagers known as ImmTACs [1, 2]. Notable examples of drugs targeting these complexes include tebentafusp, which targets a gp100 peptide presented by HLA-A*02:01, and afamitresgene autoleucel, which targets a MAGE-A4 peptide [3, 4]. Because these targets are HLA-restricted, patient selection requires specific genetic testing for the appropriate HLA allele, most commonly HLA-A*02:01 [1, 3]. Clinical challenges associated with these targets include the risk of on-target off-tumor toxicity if the antigen is expressed in healthy tissues, as well as systemic inflammatory responses like cytokine release syndrome [2, 4]. Despite these challenges, targeting shared TAA-pMHC complexes offers a promising "off-the-shelf" approach for treating various solid tumors that lack traditional surface markers [5].

Other names

Tumor-associated antigen peptide-MHC complexesTAA-pMHCCancer-testis antigen-MHC complexesDifferentiation antigen-MHC complexesShared pMHC targets

T-cell receptor (TCR) mediated recognition of peptide-MHC complexes, leading to T-cell activation and tumor cell lysis. This is achieved through engineered TCR-T cells or bispecific T-cell engagers (ImmTACs) that bridge T cells to the pMHC target.