TARGETING P53 FOR ADOPTIVE T-CELL IMMUNOTHERAPY

p53 gene mutations occur in most human cancers and result in an altere d protein product that accumulates within the cell. Although the obser ved endogenous human CTL response to p53 is weak, high-affinity, human p53-specific CTLs have been generated from HLA A2.1 transgenic mice i mmunized with human CTL epitope peptides, In this study, we examine th e ability of HLA A2.1-restricted and human p53-specific CTLs from HLA A2.1 transgenic mice to suppress the growth of p53-overexpressing huma n tumors in severe combined immunodeficient (SCID) mice. In vitro, mur ine p53(149-157)-specific CTLs selectively lysed the p53-overexpressin g pancreatic carcinoma cell line Panc-1 but did not recognize HLA A2.1 (-) tumor cells or HLA A2.1(+) normal human fibroblasts. Furthermore, in vivo, the growth of established human tumor xenografts in SCID mice was significantly reduced and survival was prolonged after the admini stration of p53-specific CTLs but not after the administration of cont rol CTLs or PBS alone. Following treatment with p53(149-157)-specific CTLs, regressing Panc-1 tumors were infiltrated by the CD8(+) CTLs, as demonstrated by immunohistochemistry. These findings suggest that p53 (149-157)-specific and HLA A2.1-restricted murine CTLs suppress the gr owth of established Panc-1 tumors following adoptive transfer into SCI D hosts and prolong their survival.