NCI CLINICAL INVESTIGATOR AWARD

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The lymphokine Interleukin 2 (IL2) was first recognized for its ability to induce the proliferation of T cells activated by antigen or mitogen to express IL2 receptors. Now available in pharmacologic amounts through recombinant DNA technology, IL2 has several potential uses for the treatment of malignancies including: the induction of non-specific lymphokine activated killer (LAK) cytotoxicity; the stimulation of secretion of lymphokines with anti-neoplastic activity, e.g. lymphotoxin, tumor necrosis factor, and macrophage activating factor(s); and the augmentation of specific T cell mediated anti-tumor immunity. Using currently available methods of detection, most human tumors fail to elicit demonstrable specific host immune responses. Therefore, the generation of LAK reactivity appears to represent the most useful approach for exploiting the anti- tumor potential of IL2 at this time. When administered in high (LAK-inducing) doses, IL2 can cure mice with disseminated leukemia. Similarly, in preliminary trials the use of highdose IL2 for the treatment of advanced refractory human malignancy has resulted in tumor regression in several cases. In both mice and humans, however, the expression of the full therapeutic potential of IL2 may be limited by dose- dependent toxicity. The current proposal will explore strategies to attenuate the toxicity and/or increase the therapeutic efficacy of IL2 and thereby enhance the overall "therapeutic index", (i.e. ratio of efficacy to toxicity of IL2). The specific aims of the proposal are: 1) to determine whether the therapeutic index of high-dose IL2 can be increased by concurrent administration of in vitro activated LAK cells or LAK cell subsets; 2) to determine whether the therapeutic index of high-dose IL2 can be increased by concurrent administration of long-term cultured LAK cells or LAK cell subsets; and 3) to determine whether the therapeutic index of high-dose IL2 can be increased by in vivo elimination of potentially toxic lymphoid subsets.