6533b821fe1ef96bd127ac5c

RESEARCH PRODUCT

p53 Immunotherapy of Cancer

subject

description

Mutation and overexpression of the p53 tumor suppressor protein are the most common genetic alterations in human cancers. Peptides derived from non-mutated (wild type, wt) and mutated p53-molecules, processed and presented in the context of major histocompatibility complex (MHC) molecules by tumor cells for T-cell recognition, could serve as broad targets for cancer immunotherapy. Isolating p53-reactive T lymphocytes in healthy donors or patients has been hampered by the fact that most individuals display a peripheral p53-reactive T-cell repertoire that is devoid of high-avidity MHC class I-restricted cytotoxic T lymphocytes (CTL). Only low-avidity T lymphocytes are left due to self-tolerance to this ubiquitously expressed molecule. The transfer into T cells of T-cell antigen receptor (TCR) genes encoding high-affinity TCRs and recognizing defined tumor-associated antigens can circumvent these hurdles. Delivery of a high-affinity CD8-independent, p53-specific TCR into human T cells offers an exciting strategy to redirect CD8+ T lymphocytes with broad tumor-specific CTL activity and turn CD4+ T cells into potent tumor-reactive, p53-specific T helper (Th) cells. Adoptive transfer of p53 TCR-engineered human lymphocytes offers a novel approach for a broad-spectrum immunotherapy of malignant disease.