Targeting p53 for adoptive T-cell immunotherapy.
p53 gene mutations occur in most human cancers and result in an altered protein product that accumulates within the cell. Although the observed endogenous human CTL response to p53 is weak, high-affinity, human p53-specific CTLs have been generated from HLA A2.1 transgenic mice immunized with human CTL epitope peptides. In this study, we examine the ability of HLA A2.1-restricted and human p53-specific CTLs from HLA A2.1 transgenic mice to suppress the growth of p53-overexpressing human tumors in severe combined immunodeficient (SCID) mice. In vitro, murine p53(149-157)-specific CTLs selectively lysed the p53-overexpressing 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 administration of p53-specific CTLs but not after the administration of control 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 growth of established Panc-1 tumors following adoptive transfer into SCID hosts and prolong their survival.
McCarty
T M
TM
Department of Surgery, City of Hope National Medical Center, Duarte, California 91010, USA.
Liu
X
X
Sun
J Y
JY
Peralta
E A
EA
Diamond
D J
DJ
Ellenhorn
J D
JD
D000818:Animals; D016158:Genes, p53 / Q000235:genetics*; D006801:Humans; D016219:Immunotherapy, Adoptive; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D013370:Subrenal Capsule Assay; D016019:Survival Analysis; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured