Although the majority of patients with acute lymphoblastic leukemia (ALL) can be cured with aggressive multimodality therapy, a considerable number still relapse and succumb to their disease. Moreover, even patients who are cured can be severely and permanently compromised by the morbidity and potential late mortality that accompanies these aggressive treatment regimens. Therefore, new strategies are needed to reduce the number of relapses as well as to decrease the intensity and duration of treatment. The goal of PROJECT 1 is to attempt to harness the effector arms of the immune system to induce or enhance anti-ALL immunity. For the first time, basic science and preclinical immunologic studies provide a rationale and strong foundation upon which to undertake these studies. Specifically, the discovery of costimulatory molecules and their importance in the induction of specific T cell mediated tumor immunity provide not only new concepts but, more importantly, the reagents necessary to undertake preclinical and clinical trials. Both in vitro studies and animal models have demonstrated that induction of the B7 family of costimulatory molecules is both necessary and sufficient to induce T cell specific anti- tumor immunity. This immunity is not only protective on rechallenge but can also eradicate minimal residual tumor cells in the host. Methods to induce or introduce B7 into ALL exist or are currently being developed. Moreover, with the advent of cloning technologies and the availability of new recombinant lymphokines, it is also now possible to modulate both non- specific and specific immune effectors in the host. Previous studies have shown that high numbers of natural killer cells can be generated and selectively activated in vivo with prolonged administration of low doses of IL-2. More importantly, this treatment appears to correlate with clinical outcome. These experiments suggest that induction of natural killer cells may eradicate minimal residual disease in the patient. The recent discoveries of IL-12 and IL-15, both of which can also modulate both non-specific and specific immunity, provide additional methods to manipulate the immune response in the patient. To test these new therapeutic approaches we will focus our immunologic studies on both relapsed and newly diagnosed patients with minimal residual disease. To achieve these ends, we propose two specific aims. FIRST: We will attempt to alter the ALL cell to induce or augment specific T-cell mediated anti- tumor immunity in vitro and then in clinical trials. SECOND: We plan to treat patients with ALL with cytokines in order to induce or augment T cell or NK mediated anti-leukemia immunity. Ultimately, it is our objective to utilize both of these strategies to induce or enhance non- specific and/or specific anti-ALL immunity to either treat minimal residual disease following conventional induction therapy and/or to reduce the intensity of conventional therapy and concomitant toxicities while preserving the high cure rate seen in this disease.
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