NOVEL TARGETS FOR THE TREATMENT OF AML

Dana-Farber Cancer Institute, Boston MA

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): Advances in molecular genetics have led to improved understanding of the pathogenesis of acute myelogenous leukemia (AML) and the mechanisms underlying the generation of a host anti-tumor immune response in these patients. While a large number of tumor antigens that elicit humoral and/or cellular reactions in cancer patients have been defined through innovative cloning strategies and biochemical approaches, relatively little is known about the antigenic targets in AML. To learn more about antileukemia immune responses, we propose to determine the immunogenicity of a novel leukemia antigen and to identify additional promising targets for vaccination studies. First, we will conduct a Phase I clinical trial evaluating the biologic activity and toxicity of vaccination with the novel antigen MAIAP. This gene product is a new member of the inhibitor of apoptosis protein (IAP) family. The expression in AML cells of two other members of this family, survivin and XIAP, has been correlated with poor prognosis, likely reflecting the ability of IAPs to antagonize caspase activity and thereby promote cell survival. Although we initially identified MAIAP as a tumor antigen in a melanoma patient responding to vaccination with irradiated, autologous GM-CSF secreting tumor cells, MAIAP is frequently expressed in primary AML and is thus an attractive vaccine target for this disease. In the second part of this project, we will identify additional novel AML antigens by studying in detail the anti-leukemia immune response elicited in patients by vaccination with irradiated, autologous AML cells engineered to secrete GM-CSF or the infusion of donor lymphocytes following allogeneic bone marrow transplantation. Lastly, to complement these immunologic approaches, we will conduct a Phase I clinical trial to determine the safety and biologic activity of novel flt3 inhibitors. The frequent occurrence of flt3 mutations in AML cells together with the striking clinical activity of the STI571 bcr-abl kinase inhibitor in CML suggest that targeted pharmacologic therapy for AML may be possible. If the immunotherapeutic and pharmacologic approaches demonstrate biologic activity and safety, we plan to evaluate them in combination as well. The specific aims of this project are: 1. To determine the safety and biologic activity of vaccination with MAIAP in patients with AML. 2. To identify novel AML antigens through antibody-based expression cloning strategies. 3. To determine the toxicity and biologic activity of novel flt3 inhibitors in patients with AML.