Combined local hyperthermia and immunotherapy treatment of an experimental subcutaneous murine melanoma

Immunotherapy (IT) has become an accepted therapeutic modality for a limited number of tumor types. One of the limiting factors in the use of interleukin-2 (IL-2) has been dose-related toxicity. We undertook these studies to study the effects of combined therapy on a murine melanoma. The B16 melanoma was implanted in the right hindlimb of C57BL/6 mice and therapy begun on day 3 (microscopic tumor model) or day 10 (macroscopic tumor model). Animals were divided into four groups: No therapy, local hyperthermia (HT) alone (45 degrees C x 15 minutes on days 3 and 6 or days 10 and 13), HT+IL-2 at 300,000 IU ip tid, and HT+IL-2 at 600,000 IU ip tid. We have shown in multiple previous experiments that IL-2 alone at these doses has no effect on tumor growth; these groups were omitted. In the microscopic model, tumors in the no treatment group were an average of 400 mm2. Animals treated with HT alone had a mean tumor size of 300 mm2. However, tumors in animals receiving both therapeutic modalities measured a mean of 100 mm2 (300,000 IU IL-2 ip tid) and 80 mm2 (600,000 IU IL-2 ip tid). In the macroscopic tumor model, tumors in animals receiving no treatment were an average of 7.5 times larger than on day 10, in animals receiving HT alone were an average of 5 times larger, animals receiving IL-2 were 2.95 times larger (both dose levels). These results show that combined IT+HT therapy resulted in significantly (P < .05) reduced growth with both microscopic and macroscopic tumors compared to HT alone or no therapy in a murine subcutaneous melanoma model using doses significantly lower than those usually needed to observe a therapeutic response with IL-2 used alone. This study further supports the use of this combined modality approach in patients with advanced malignancies.