Requirements for successful immunotherapy and chemoimmunotherapy of a murine model of ovarian cancer.

A comprehensive study of nonspecific immunotherapy has been conducted in an established murine model of ovarian cancer in order to determine the relative effectiveness of commonly used bacterial immunostimulants, the importance of the route and schedule of administration of these agents, and their effects in combination with chemotherapy. Implants of 10(5) or 10(6) ovarian tumor cells i.p. kill all syngeneic C3HeB/FeJ mice within 25 days. Corynebacterium parvum (700 microgram/mouse i.p. 24 hr after a 10(5) tumor cell inoculum) cures 75% of the mice; in contrast, neither i.v. nor s.c. administration improves survival rates. After the same tumor challenge, Bacillus Calmette-Guérin was minimally effective at extremely high doses only, while the methanol extraction residue of B. Calmette-Guérin was ineffective. Two days after an implant of 10(6) tumor cells, neither cyclophosphamide, nor cis-diamminedichloroplastinum(II) (cisplatin), nor C. parvum increased survival. Combination of C. parvum with cyclophosphamide or cisplatin resulted in a synergism shown by the 40 and 60% cure rates, respectively. However, combination of C. parvum with an active agent, doxorubicin, resulted in toxicity even in untumored animals. This study demonstrates that therapeutic efficacy of immunotherapy depends critically on the choice of an appropriate agent and route of administration and, to a lesser extent, on the dose and schedule used. The observation provides a rationale for carefully conducted Phase I and Phase II studies of treatment with bacterial immunostimulants, alone or in combination with chemotherapy, in human ovarian cancer.