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 B 16 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°C ± 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.