Antitumor Protection from the Murine T-Cell Leukemia/Lymphoma EL4 by the Continuous Subcutaneous Coadministration of Recombinant Macrophage-Colony Stimulating Factor and Interleukin-21

Combined continuous s.c. Coadministration of macrophage-colony stimulating factor (M-CSF) plus interleukin-2 (IL-2) by osmotic pump protected mice given i.v. injections of a lethal dose ulT.1.4 T-cell leukemia/ lymphoma. Antitumor protection was significantly greater than that af forded by treatment with either cytokine alone. Since neither IL-2 recep tors nor M-CSF receptors were expressed on EIA the antitumor effect was likely attributed to murine effector cells. To determine how M-CSF + IL-2 provided this effect, we performed immunophenotypic and func tional analyses as well as in vivo depletion studies of putative antitumor effector cells. Splenic phenntyping experiments revealed that the highest levels of macrophages and natural killer cells were observed in mice given the cytokine combination rather than either M-CSF or IL-2 alone. In vivo depletion of natural killer cells ablated the antitumor protective effect of M-CSF and IL-2. T-cells were also important for M-CSF + IL-2 efficacy, since adult thymcctomy/T-cell depletion significantly inhibited the ability of cytokine Coadministration to protect against EL4. Coadministration of the 2 cytokines significantly elevated in vivo levels of CD3*CD4*, CD3*CD8*, CD.VNK1.1* T-cells, and CD3MTD25* (activated) T-cells, and elevated anti-1 I 4 cytotoxic T-cell activity measured in vitro. Although WBC counts and fluorescence-activated cell sorter studies showed that M-CSF t IL-2 treatment significantly elevated neutrophils, s.c. delivery of granulocyte-colony stimulating factor at doses sufficient to induce neutrophilia was unable to confer anti-EL4 protection. These studies indicate that macrophages, T-cells, and natural killer cells are all important in the M-CSF + IL-2 ¡iiiii-l'.l.4 response. The superior antitumor effect of this cytokine combination along with the ability of M-CSF to diminish the toxicity of IL-2 in this model suggests that further investigations into the clinical potential of this combination treatment are warranted.