p53-specific T cell receptor (p53-TCR)

The p53-specific T cell receptor (TCR) is a specialized immune receptor engineered or isolated to recognize fragments of the p53 tumor suppressor protein presented by MHC Class I molecules on the surface of cancer cells. p53 is the most frequently mutated gene in human cancers, and these mutations often result in the presentation of unique "neoantigens" that are not found in healthy tissues. By targeting these p53-derived peptide-MHC complexes, therapeutic modalities such as TCR-engineered T-cell (TCR-T) therapy and TCR-like antibodies can selectively direct the immune system's cytotoxic power against malignant cells. This approach is particularly valuable for targeting "undruggable" intracellular proteins like p53, which cannot be reached by conventional monoclonal antibodies. However, the development of these therapies requires high specificity to avoid "on-target, off-tumor" toxicity against low levels of wild-type p53 in normal tissues, as well as "off-target" cross-reactivity with unrelated self-peptides. Clinical trials are currently evaluating several p53-specific TCR-based therapies, focusing on common hotspot mutations like R175H in the context of prevalent HLA alleles such as HLA-A*02:01.

Other names

MHC class I–restricted T cell receptor recognizing p53-derived peptide–MHC I complexesp53-reactive T cell receptorTP53-specific T cell receptorp53-targeted TCRp53-specific TCR

Engineered T cells or bispecific molecules utilize the TCR's specificity to bind p53-derived neoantigens presented by MHC Class I, triggering T cell activation and the release of cytotoxic granules (perforin/granzyme) and cytokines (IFN-gamma) to induce tumor cell apoptosis.