With the advent of intensive combination chemotherapy programs, the great majority of patients with newly diagnosed hematologic malignancies can be induced into a complete remission status. However, despite initial sensitivity, resistance to chemotherapy with subsequent relapse is the primary cause of treatment failure in these diseases. New strategies to prevent relapse are clearly needed. In previous studies, we have examined immunologic approaches to induce or enhance anti-tumor immunity and have focused on immune modulation with exogenous lymphokines such as IL-2. In patients with solid tumors we demonstrated that relatively low doses of IL- 2 could be safely administered for prolonged periods resulting in the marked increase in the total number of circulating natural killer (NK) cells and NK activity. Similar results have also been found in patients with hematologic malignancies after either autologous or T cell depleted allogeneic BMT. In patients with AML, the use of IL-2 following completion of post-remission intensification appears able to enhance non-specific cytotoxicity against autologous AML cells without excessive systemic toxicity and thus far few relapses have been observed following immunotherapy. Studies proposed ina the next funding period will further extend our examination of the role of il-2 to enhance anti-tumor immunity. We will also begin to examine new approaches to enhance tumor immunity in patients with leukemia or lymphoma using strategies developed in other projects within this program.
The Specific Aims of this project are listed below; 1. To evaluate the systemic administration of cytokines to enhance both specific and nonspecific immunity against autologous leukemia and lymphoma. 1.1 To determine the immunologic effects of prolonged low dose IL-2 infusion and bolus IL-2 infusion when administered to patients with AML in first CR. 1.2 To define the immunologic effects of IL-2 administration following autologous BMT for B cell non-Hodgkin's lymphoma. 1.3 To evaluate the potential use of other cytokines for enhancement of non-specific immunity in vivo in patients with AML and B cell non-Hodgkin's lymphoma. 1.4 To examine the efficacy of humanized anti-CD33 monoclonal antibody in conjunction with IL-2 in patients with relapsed AML. 2. To evaluate new methods for inducing or enhancing autologous anti-tumor immunity in vivo based on the ability to enhance tumor cell expression of costimulatory molecules in vitro. 3. To develop methods for in vitro activation and expansion of autologous leukemia or lymphoma reactive T cells for use in adoptive cellular therapy.
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