Successful immunotherapy of mouse melanoma and sarcoma with recombinant interleukin-2 and cyclophosphamide

Abstract

Recombinant human interleukin-2 (rIL-2, courtesy of Cetus Corporation, Emeryville, CA, U.S.A.) is highly effective in eradicating syngeneic tumor when administered to C57BL/6 mice implanted with a nonimmunogenic, rapidly growing clone of B16 melanoma, or an immunogenic methylcholanthrene-induced sarcoma, 1-3 days, before beginning treatment at 5 X 10(4) U/injection daily for 5 days, and then on alternate days for 4 weeks. Low-dose cyclophosphamide (CY, 50 mg/kg), injected intraperitoneally (i.p.) 4 times at weekly intervals, greatly facilitated tumor eradication in rIL-2-treated mice. Most early subcutaneous (s.c.) tumors were cured by combining CY i.p. with repeated perilesional s.c. injections of rIL-2, i.e, 100% cure for 1-day and 87-91% for 3-day melanomas. When rIL-2 was administered without CY, the cure rate was 64% for 1-day and 67% for 3-day melanomas. This cure rate indicated a synergism between rIL-2 and CY, since CY alone did not affect tumor incidence. CY was therefore administered in all subsequent experiments. Treatment with rIL-2, localized to the site of the melanoma or sarcoma, was most effective, although systemic (i.p.) administration achieved results regardless of tumor site. When either tumor was implanted s.c. and rIL-2 treatment was also given s.c. locally, beginning 1-3 days later, 87-100% of the mice were cured, compared with 35-50% cured when rIL-2 was administered i.p., and 0% cured in excipient buffer-injected controls. Conversely, with i.p. treatment of i.p. tumors, 60-83% of the mice were tumor-free on day 50, as compared with only 17% tumor-free if treatment was s.c. These in vivo model systems should prove useful in helping establish protocols for human therapy.