Cyclophosphamide enhances anti-tumor 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 shown 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 mice. These CTL also prevented the outgrowth of a more aggressive p53-overexpressing tumor in immunocompetent C57BL/6 mice. Importantly, this occurred in 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-specific CTL. We show here that CY acts synergistically with adoptively transferred wtp53-specific CTL in controlling the growth of an aggressive mutant p53-induced and overexpressing tumor. Previously described mechanisms underlying the synergism between CY and immune T cells were evaluated, but were not found to be operational in this model.
Vierboom
M P
MP
Department of Immunohematology and Blood Bank, Leiden University Medical Center, Leiden, The Netherlands.
Bos
G M
GM
Ooms
M
M
Offringa
R
R
Melief
C J
CJ
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D019264:Adoptive Transfer; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D018906:Antineoplastic Agents, Alkylating / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D003520:Cyclophosphamide / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007150:Immunohistochemistry; D016219:Immunotherapy, Adoptive; D016898:Interferon-alpha / Q000494:pharmacology; D016899:Interferon-beta / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000235:genetics / Q000628:therapy*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000276:immunology*; D018631:ras Proteins / Q000378:metabolism
D000276:Adjuvants, Immunologic; D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D016898:Interferon-alpha; D016159:Tumor Suppressor Protein p53; D016899:Interferon-beta; D003520:Cyclophosphamide; D018631:ras Proteins; C011272:perfosfamide