DEVELOPMENT OF A SAFE AND EFFECTIVE ADRIAMYCIN PLUS INTERLEUKIN-2 THERAPY AGAINST BOTH ADRIAMYCIN-SENSITIVE AND ADRIAMYCIN-RESISTANT LYMPHOMAS

This laboratory has extensively studied Adriamycin (doxorubicin)-induc ed immunomodulation. Despite demonstration of favorable effects, littl e therapeutic advantage was seen, and it was decided to test Adriamyci n in combination with interleukin 2 (IL2). Considerable toxicity was s een with either high-dose IL2 or high-dose Adriamycin alone, using the syngeneic C57B1/6-EL4 T cell lymphoma model. When the doses of either agent were reduced to decrease toxicity, little therapeutic effect wa s seen. In contrast, an effective protocol without apparent toxicity w as developed by combining a moderate dose of Adriamycin (4 mg/kg, IV D ays 1 and 8 or only Day 8) with prolonged administration of a moderate dose of IL2 (2 mu g, b.i.d., i.p., Days 9 to 40). This protocol resul ted in up to 80% long-term survivors among mice inoculated on Day 0 wi th EL4 lymphoma (5 x 10(4) cells). It should be noted that under these conditions, neither agent, when administered singly, induced long ter m survivors, and that following the inoculation of only 10-100 EL4 tum or cells all animals died in the absence of treatment. The survivors d eveloped protective immunity as demonstrated by their ability to resis t reimplantation with EL4 tumor. Furthermore, this resistance to tumor reimplantation could be transferred into naive hosts with spleen cell s from tumor-bearing mice receiving the combination protocol; exposure of mice to sublethal whole body irradiation prior to tumor implantati on completely abrogated the efficacy of this combination treatment. Fi nally, it was shown that this combination protocol was equally effecti ve against an Adriamycin-resistant subline of EL4 that expresses the m ultidrug resistance phenotype.