IMMUNOMODULATORY PROPERTIES OF ANTINEOPLASTIC DRUGS ADMINISTERED IN CONJUNCTION WITH GM-CSF-SECRETING CANCER CELL VACCINES

Cancer cells genetically modified to secrete immunoregulatory cytokine s offer great promise for human cancer treatment as tumor vaccines. Ho wever, in preclinical animal studies, large established cancer burdens have appeared difficult to eradicate with such vaccines. For example, lethally-irradiated GM-CSF-secreting CT26 colon carcinoma cell vaccin e therapy tends to cure only animals bearing 1x10(5) wild-type CT26 ce lls or less. For many human cancers, antineoplastic chemotherapy can o ften significantly reduce systemic cancer burdens. Unfortunately, for most advanced metastatic solid organ cancers, such as cancers of the b reast, colon, and prostate, antineoplastic drug treatments generally f ail to effect cancer cures. Treatment regimens combining genetically-m odified cancer cell vaccine therapy and antineoplastic chemotherapy ha ve the potential to increase advanced cancer cure rates if antineoplas tic drugs and drug combinations that do not inhibit vaccine-induced im mune responses can be identified. To assess the potential immunomodula tory properties of commonly-used antineoplastic drugs that might be us ed in combination with cancer vaccine treatments, we studied the effec ts of the drugs on antitumor immune responses manifest by animals rece iving lethally-irradiated GM-CSF-secreting CT26 cell vaccines. Immunom odulatory properties of the antineoplastic drugs were evaluated i) by monitoring drug effects on the generation of tumor-specific CD8+ cytot oxic T-lymphocytes (CTLs) in response to GM-CSF-secreting CT26 vaccine administration, ii) by determining drug effects on the resistance of vaccinated animals to subsequent challenge with lethal inoculae of CT2 6 cells, and iii) by evaluating combination drug and vaccine treatment efficacy against established CT26 tumors. Using this approach, doxoru bicin was found to possess apparent immunostimulatory activities, depe nding on the dose and schedule of administration, while cyclophosphami de appeared immunosuppressive. The different immunomodulatory properti es of doxorubicin and cyclophosphamide may be clinically relevant: com bination doxorubicin and vaccine treatment of established CT26 cancers increased cure rates over that achieved with either agent alone, whil e combination cyclophosphamide and vaccine treatment of animals carryi ng CT26 tumors was no better in curing the animals than drug treatment alone.