Directed Purinergic Signaling as Immunotherapy in Leukemia

Beth Israel Deaconess Medical Center, Boston MA

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Abstract

SUMMARY Acute Myeloid Leukemia (AML) is a lethal hematological malignancy, for which chemotherapy is rarely curative. Tumor heterogeneity results in significant plasticity and the emergence of chemotherapy resistant clones that also escape immune clearance. Dendritic cells may be fused with patient derived AML or other tumor cells to generate experimental vaccines. These have demonstrable efficacy in murine models of syngeneic TIB-49 murine AML leukemic engraftment; as well as in early clinical studies. Our goal is to further enhance fusion vaccine efficacy to create durable clinical responses. This proposal is directed at correction of the immunosuppressive milieu characteristic of the tumor microenvironment. Extracellular adenosine generated by the ectonucleotidase CD39 is a newly recognized ?immune checkpoint? that interferes with immune responses to hematological malignancy. We will test whether anti-CD39 and re-directing purinergic signaling alters immunometabolism in models of AML, without predisposing to autoimmune reactions and other toxicity. We will then study how modifications of current reagents might deplete Tregs, via antibody-directed cellular cytotoxicity (ADCC), thereby further eliciting rejection of AML cells in vivo. Hypothesis: Antibodies to CD39 act as immune checkpoint inhibitors, deplete T regulatory cells and boost effects of DC/AML immunization in AML. SPECIFIC AIM 1: Determine whether anti-CD39 monoclonal antibodies boost immune responses in concert with DC immunization. We will direct purinergic elements of immune responses by infusions of anti- CD39 and study direct impacts on leukemia cells as well as immune responses to TIB-49 H-2b plus CRL-1838 and TIB-68 H-2d cells in syngeneic mouse models of AML. We will also define immunostimulatory and autoimmune effects in current DC/AML vaccination strategies. SPECIFIC AIM 2: Develop derivatives of anti-CD39 5F2-mIgG1 and mIgG2c to neutralize ectonucleotidase activity and deplete T regulatory cells in AML in vivo. We will modify and refine the available anti-CD39 mAb by isotype switch and generation of afucosyl derivatives, to impede ATP scavenging, potentially target leukemia cells, deplete Tregs, and prevent adenosine production in the proposed models of AML. The derived data will help in identifying optimal therapeutic purinergic-based regimens for immunotherapeutics of leukemia. Our studies have the potential for immediate translation. The biological reagents we are developing and testing could guide therapeutic trials in humans.