THERAPY OF MURINE TUMORS WITH P53 WILD-TYPE AND MUTANT SEQUENCE PEPTIDE-BASED VACCINES

The BALB/c Meth A sarcoma carries a p53 missense mutation at codon 234 , which occurs in a peptide, termed 234CM, capable of being presented to cytotoxic T lymphocytes (CTL) by H-2K(d) molecules (Noguchi, Y., E. C. Richards, Y.-T. Chen, and L.J. Old. 1994. Proc. Natl. Acad. Sci. US A. 91:3171-3175). Immunization of BALB/c mice with bone marrow-derived dendritic cells (DC), generated in the presence of granulocyte macrop hage colony-stimulating factor and interleukin 4, and prepulsed with t he Meth A p53 mutant peptide, induced CTL that specifically recognized peptide-pulsed P815 cells, as well as Meth A cells naturally expressi ng this epitope. Immunization with this vaccine also protected naive m ice from a subsequent tumor challenge, and it inhibited tumor growth i n mice bearing day 7 subcutaneous Meth A tumors. We additionally deter mined that immunization of BALB/c mice with DC pulsed with the p53 pep tide containing the wild-type residue at position 234, 234CW, induced peptide-specific CTL that reacted against several methylcholanthrene-i nduced BALB/c sarcomas, including CMS4 sarcoma, and rejection of CMS4 sarcoma in vaccination and therapy (day 7) protocols. These results su pport the efficacy of DC-based, p53-derived peptide vaccines for the i mmunotherapy of cancer. The translational potential of this strategy i s enhanced by previous reports showing that DC can readily be generate d from human peripheral blood lymphocytes.