The current application is a competing renewal designed to pursue our studies on the development of novel therapies, specifically cancer vaccines, for chronic myelogenous leukemia (CML). This renewal will focus on the immunomodulatory role of the BCR-ABL tyrosine kinase inhibitor imatinib mesylate (STI-571 or GleevecTM) and its application in chemoimmunotherapy approaches for CML. This drug has become the therapy of choice for patients with CML, but the emergence of imatinib resistant leukemia remains a major challenge. This has prompted the evaluation of newer tyrosine kinase inhibitors such as dasatinib or sunitinib, and the examination of combination treatments such as chemoimmunotherapy. The field of tumor immunology has recently seen major breakthroughs, one of which is the emergence of CD4+CD25+ regulatory T cells (Treg) as critical contributors in the establishment and persistence of cancer- induced tolerance. During our current grant cycle we have reported that imatinib mesylate can be efficiently combined with a chaperone rich cell lysate vaccine (CRCL), developed in our laboratory, to treat established BCR-ABL+ leukemia. In an attempt to elucidate the mechanism of action of imatinib mesylate on immune cells, we have generated significant data indicating that this agent may negatively modulate the suppressive function of CD4+CD25+ regulatory T cells (Treg). This is a novel yet unexplored concept. Therefore, the central hypothesis to be tested in this proposal is that imatinib mesylate may not only act directly on BCR-ABL+ leukemia cells but may also sensitize immune cells to tumor vaccines by down-modulating Treg suppressive activity. To address this hypothesis, we propose the following specific aims: 1. Study the negative modulation of Treg by BCR-ABL tyrosine kinase inhibitors. We will (1) investigate how BCR-ABL tyrosine kinase inhibitors affect the immunobiology of Treg and non-Treg lymphocytes in vivo and in vitro, and (2) determine whether these drugs influence the conversion CD4+CD25- T cells into CD4+CD25+FoxP3+ Treg. 2. Determine the molecular mechanisms underlying BCR-ABL tyrosine kinase inhibitor suppression of Treg. The modulation of specific cell signalling transduction pathways and regulation of key transcription factors by BCR-ABL tyrosine kinase inhibitors in Treg and conventional T cells will be examined. 3. Optimize a chemoimmunotherapy strategy combining Treg elimination or inactivation with specific tumor vaccination. To validate the use of imatinib in chemo-immunotherapy approaches, we propose to (1) evaluate the differential efficiency of BCR-ABL tyrosine kinase inhibitors and the currently used strategies to deplete/inactivate Treg in vivo, and (2) further optimize a chemoimmunotherapy approach using BCR-ABL inhibitors and tumor specific vaccination to treat BCR-ABL+ or BCR-ABL- leukemia in mice. 4. Evaluate the effects of BCR-ABL tyrosine kinase inhibitors on Treg number, phenotype and function in CML patients. This part of the proposal is critical in order to validate the application of imatinib mesylate as a potential Treg inhibitory agent in human chemoimmunotherapy strategies. Analysis of Treg frequency, phenotype and suppressive activity will be performed in CML patients before and during imatinib mesylate therapy. These studies are based on a novel concept supported by convincing preliminary data to deplete/inactivate a major cellular component of tumor-induced tolerance using FDA approved agents. They will not only shed light on the mechanisms of action of BCR-ABL tyrosine kinase inhibitors, but may also lead to further improvement in chemo-immunotherapy of leukemia. Our proposal is therefore timely, highly relevant and significant for the development of improved treatments for CML.
This proposal is based on two clinically relevant challenges in combating chronic myelogenous leukemia: the resistance of leukemia to imatinib mesylate, and the establishment of leukemia-induced immune tolerance with regulatory T cells as the likely contributors. The proposed studies will investigate how BCR-ABL tyrosine kinase inhibitors may be used more effectively to impede the suppressive function of regulatory T lymphocytes and promote the function of anti-tumoral T cells, thereby working synergistically with leukemia- based vaccination. Results from these studies will help shed light on how to improve chemo-immunotherapic approaches not only for CML but also for other (BCR-ABL-) cancers.
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