Animal models have been developed in which adoptively transferred immune T cells can reproducibly mediate an in vivo therapeutic effect against disseminated leukemia. The prerequisites for success have been extensively investigated, since these models represent prototypes for what might be achievable with appropriately selected and amplified tumor-reactive autologous lymphocytes obtained from a tumor-bearing host. This application proposes to utilize monoclonal antibodies specific for lymphocyte subpopulations and purified cytokines to learn how the immune system might be modulated to generate an effective anti-tumor response for the purpose of treating established metastatic solid tumors and disseminated leukemias.
The specific aims are: 1) To examine the mechanism(s) by which non-cytolytic T cells promote the eradication of disseminated leukemia by examining the importance of B cell antibody production, NK activity, and tumoricidal macrophages; 2) To determine the role of secreted Gamma-interferon in the therapeutic effect of non0cytolytic T cells and to assess whether other macrophage activating factors potentially contribute to therapeutic activity; 3) To assess whether the demonstrated efficacy of purified CTL in therapy of disseminated leukemia reflects only direct cytolysis of tumor cells or is dependent on the activation and participation of tumoricidal macrophages; 4) To determine whether a major obstacle to adoptive therapy of advanced disseminated leukemia is the induction of suppressor T cells in the donor population after cell transfer; 5) To determine whether the principles for eradicating a highly antigenic disseminated leukemia can be applied to the therapy of weakly antigenic solid tumor metastases; 6) To develop models for allogeneic adoptive therapy and determine whether minor histocompatibility antigens on tumors can serve as appropriate targets for immunologic attack.
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