Cyclophosphamide enhances anti-tubor effect of wild-type p53-specific CTL

The tumor suppressor protein p53 is overexpressed In up to 50% of all human malignancies, both in solid tumors as well as hematological malignancies, and is therefore an attractive target for immunotherapy, We have recently s hown that cytotoxic T lymphocytes (CTL), raised in p53 gene deficient (p53 -/-) mice and recognizing a murine wild-type (wt) p53 peptide, were able to eradicate a mutant p53-induced and overexpressing tumor in p53 +/+ nude mi ce. These CTL also prevented the outgrowth of a more aggressive p53-overexp ressing tumor in immunocompetent C57BL/6 mice. Importantly, this occurred i n the absence of demonstrable damage to normal tissue. Possibly due to the aggressive nature of the latter tumor, adoptive transfer of wtp53-specific CTL did not result in the eradication of established tumors, either in nude or immunocompetent mice. Therefore, we explored whether the cytotoxic drug cyclophosphamide (CY) could potentiate the therapeutic activity of wtp53-s pecific CTL, We show here that CY acts synergistically with adoptively tran sferred wtp53-specific CTL in controlling the growth of an aggressive mutan t p53-induced and overexpressing tumor. Previously described mechanisms und erlying the synergism between CY and immune T cells were evaluated, but wer e not found to be operational in this model. Int. J, Cancer 87:253-260, 200 0, (C) 2000 Wiley-Liss, Inc.