Anticancer drugs plus cytokines: immunodulation based therapies of mouse tumors.

As demonstrated in this laboratory, several cytotoxic anticancer agents have immunomodulating effects at relatively low doses and, in combination with non-toxic doses of certain cytokines, can exert immunity-dependent curative effects in mouse tumor models. Thus, adriamycin (Dox) has been shown to enhance the activation of macrophages with associated increases of IL1 and TNF production, to stimulate the production of IL2 and the development and action of CTLs. In the EL4 lymphoma C57BL/6 mouse model, combinations of appropriate regimens of Dox plus IL2 or TNF induce cures and the long-term survivors exhibit life-long immunological memory. Combinations of cyclophosphamide plus TNF have analogous effects. In the E0771 breast tumor C57BL/6 mouse model, Dox plus TNF at doses which are without antitumor activity when given alone, cause complete cures of established tumors with concomitant stimulation of CTL and NK cells responses. The mechanisms involved in these therapeutic responses are discussed. In conclusion, the results obtained substantiate the possibility of establishing antitumor curative combination regimens based on the utilization of low non-toxic immunomodulating doses of certain anticancer drugs and specific cytokines.