As shown in this laboratory, combinations of doxorubicin plus interleukin 2 (DOX + IL2) exert curative effects in C57BL/6 mice implanted with 10-5 EL4 lymphoma cells, a relatively nonimmunogenic syngeneic tumor/mouse model where 10 EL4 cells kill all the control hosts. The same curative effects are seen in mice inoculated with DOX-resistant EL4. The cured mice have long lasting immunological memory against EL4. The curative effects are T cell dependent as they are reduced by antibody deletion of CD8+ and less so CD4+ T cells. The role of DOX-induced stimulation of macrophages in determining the curative effects is not yet clear. The present proposal is to verify the generality of the phenomena seen in the EL4 model in C57BL/6 mice implanted with E0771 mammary carcinoma or Lewis Lung carcinoma and in BALB/c mice implanted with colon carcinoma 26: both the curative effects of DOX + lL2 and causative immunomodulation (T cells, macrophages, NK and LAK cells) will be characterized. The role of immunomodulation will be further defined by testing the effects of l) deleting selected T cell subsets with specific antibodies, 2) effector function in responding vs non- responding mice and 3) adoptive transfer of relevant effector cells. Using TNF knockout C57BL/6 mice, the possible role of TNF in the curative effects of DOX + lL2 will be ascertained. The curative effects of combinations in which DOX is replaced by daunorubicin or epirubicin will be examined in the EL4 model to evaluate the possible specificity of the DQX effects. The modification of the curative effects of DOX + lL2 in the EL4 model by therapeutic vaccination with x-ray or DOX killed EL4 cells will be assessed as a curative combined modality and also to verify the essentiality of the role of EL4 associated antigens in the curative effects of DOX + lL2. Standard tumor transplantation, treatment and evaluation procedures, immune effector assays, immune memory tests, adoptive cell transfers and vaccination procedures are to be used which are all procedures that have been employed in this laboratory.
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