Protective specific immunity induced by doxorubicin plus TNF-alpha combination treatment of EL4 lymphoma-bearing C57BL/6 mice

The therapeutic efficacy of a single (day 8), moderate dose (4 mg/kg, i.v.) of doxorubicin (DOX, Adriamycin) combined with recombinant human TNF-alpha (3 different doses and 5 different schedules, i.v.) was evaluated in C57BL /6 mice bearing an implant (s.c.) of the DOX-sensitive, TNF-alpha-resistant EL4 lymphoma. In parallel to monitoring survival, the levels of several ho st anti-tumor cytolytic effector functions of splenocytes and thymocytes we re evaluated throughout the treatment period and in long-term survivors (LT S). DOX treatment alone resulted in a moderate (approx, 20%) increase in li fe span but no cures, TNF-alpha alone, at any tested dose or schedule, had little or no positive effect: on survival. The combinations of DOX and TNF- alpha were only slightly better than DOX alone with respect to the time to death of mice that died (approx. 29% increase); however, each of the combin ations involving 1,000 U TNF-alpha/injection produced a fraction (20% to 80 %) of LTS. The host defense activities examined included those of splenic a nd thymic cytolytic T lymphocytes (CTL) and lymphokine-activated killer cel ls as well as splenic tumoricidal macrophages. Although most activities wer e modulated by tumor growth and/or treatment, only CTL responsiveness appea red to correlate with survival. CTL activity in the treated groups with LTS was significantly higher than in control groups late in the treatment peri od. Finally, ex vivo analyses of splenocytes and thymocytes together with t he rejection of implanted tumor at 17 months established that LTS displayed specific long-term immune memory. Int. J. Cancer 87:101-109, 2000. (C) 200 0 Wiley-Liss, Inc.