P53 immunotherapy of cancer

Abstract

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.