TP53 R175H (presented via HLA-A*02:01)

Class

Autologous TCR-engineered T-cell therapy

Pathway

Engineered TCR recognizes the mutant TP53 R175H neoantigen in an HLA-A*02:01 context, directing cytotoxic T-cell killing of tumor cells

TP53 is the most commonly mutated gene across human cancers, encoding a tumor suppressor protein that normally halts cell division or triggers cell death in response to DNA damage. The R175H mutation is one of several recurrent "hotspot" substitutions that disable this protective function and, in many tumors, confer additional cancer-promoting properties. Because R175H arises at a fixed position, cells harboring it can process and display a short mutant peptide fragment on their surface bound to a specific human leukocyte antigen (HLA) molecule, HLA-A*02:01, forming a neoantigen: a marker unique to the tumor and effectively absent from healthy tissue. This therapeutic approach isolates a patient's own T cells, equips them with an engineered T-cell receptor (TCR) that recognizes this precise peptide-HLA combination, and reinfuses them so they can seek out and destroy tumor cells presenting the mutant peptide. Unlike antibody-based therapies, which target proteins located on the cell surface, TCR-engineered T cells can reach intracellular oncoproteins such as mutant p53 because the antigen-presentation pathway displays fragments of internal proteins to the immune system. This strategy is relevant broadly to solid tumors carrying the TP53 R175H mutation together with the required HLA allele, offering a route to attack an otherwise difficult-to-drug intracellular target shared across cancer types.