IMMUNOLOGICAL RESPONSES CRITICAL TO THE THERAPEUTIC EFFECTS OF ADRIAMYCIN PLUS INTERLEUKIN-2 IN C57BL 6 MICE BEARING SYNGENEIC EL4 LYMPHOMA/

A safe and effective therapeutic combination of moderate doses of Adri amycin (doxorubicin, 4 mg/kg, IV, Days 1 and 8 or only Day 8) plus pro longed administration of moderate doses of interleukin 2 (2 mu g, b.i. d., Days 9-40) was developed in the syngeneic EL4 (5 x 10(4) cells, IP , Day 0) lymphoma - C57B1/6 mouse model and has been reported in the c ompanion paper. The studies described herein demonstrate that the effe ctiveness of this combination treatment against EL4 lymphoma growing i ntraperitoneally in C57B1/6 mice was dependent upon the presence of CD 8(+) cells. Thus, the induction of long-term survivors (60-80%) by Adr iamycin plus interleukin 2 was completely ablated by pretreatment of m ice with anti-CD8 monoclonal antibody (MAb), whereas pretreatment with anti-CD4 MAb only partially inhibited the therapeutic effects and ant i-NK1.1 MAb had no effect. A close association between survival, an in crease in phenotypically identified CD8(+) cells, and an increase in s pecific anti-EL4 cytolytic activity was demonstrated with cells from t he tumor site (peritoneum) but not consistently with cells from the sp leen. No association was observed between survival and modulations in natural killer (NK), lymphokine-activated killer (LAK), or tumoricidal macrophage activity of spleen or peritoneal cells. Taken together the results indicate that, in this model, the most relevant correlate of a therapeutically effective host antitumor response is the level of sp ecific EL4 tumor killing by cells present at the tumor site. Based on the findings reported herein, it can be predicted that weakly immunoge nic tumors may be eradicated by immunologic mechanisms elicited in con junction with properly designed therapeutic regimens.