A comprehensive and systematic study will be undertaken to define the therapeutic utility of the hormone-like T cell growth-promoting lymphokine Interleukin-2 (IL-2) for the treatment of cancer using as a tumor model a unique mouse mammary adenocarcinoma designated as MC1. When compared to other mouse tumor models, the MC1 offers a number of advantages for defining in vivo IL 2-mediated immunomodulation of host-resistance to tumor progression. The MC1 tumor is a spontaneously arising neoplasia that is both immunogenic and immunosensitive, and undergoes complete regression after progressive growth in about 20 percent of tumor hosts by a primary lymphocyte-mediated immune rejection reaction. Moreover, host resistance of MC1-immunized mice can be adoptively transferred to untreated mice using washed lymphocytes of the spleen, lymph node or blood. The ability to cultivate the MC1 tumor as a single-cell suspension and to propagate IL 2-dependent syngeneic T cells enables further definition in vitro of this host-versus-tumor model. This study will define the effect of intratumor administration of IL-2 on MC1 tumor growth in MC1-immunized and untreated mice, and specifically the influence of IL-2 on cytolytic activity of T cells present in a large peri-tumor leukocyte population that accumulates during tumor regression. The effect of IL-2 will be defined in sequential studies that will include histopathological and morphometric analyses; phenotypic characterization of different leukocyte subsets, particularly IL-2 receptor bearing T cells as defined using [35S]-methionine radiolabelled recombinant IL-2; and functional analyses of lymphocyte-mediated anti-MC1 cytolytic activity as defined in vitro using microcytotoxicity tests and in vivo with Winn-type tumor neutralization assays. IL-2 evaluated in these studies will be derived from different sources, including: (a) human recombinant IL-2 from E. coli; (b) selected high IL-2-producing monoclones of long-term T cell lines of mice (EL-4), ape (MLA-144) and human (Jurkat J6.2); and (c) mitogen-activated normal mouse splenic leukocytes. IL-2 will be purified using anti-IL-2 monoclonal antibody affinity chromatography and reverse-phase high performance liquid chromatography.
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