Project Grant R41AI179340

DENDRITIC CELL THERAPY FOR GVHD - ABSTRACT. HEMATOLOGIC MALIGNANCIES ARE OFTEN TREATED WITH ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION (HSCT). HOWEVER, HSCT IS COMPLICATED BY GRAFT-VS-HOST DISEASE (GVHD), A SEVERE, POTENTIALLY LETHAL COMPLICATION INITIATED WHEN DONOR ALLOREACTIVE T CELLS ATTACK HOST CELLS AND ORGANS. DESPITE THE ADMINISTRATION OF PROPHYLACTIC REGIMENS FOR AGVHD AS STANDARD PRE- TRANSPLANTATION THERAPY, UP TO 60% OF THESE PATIENTS DEVELOP AGVHD OF GRADE II OR HIGHER, AND REQUIRE ADDITIONAL IMMUNOSUPPRESSIVE INTERVENTION. THUS, THERE IS AN URGENT NEED TO IMPROVE PRE-TRANSPLANTATION THERAPIES TO PREVENT AGVHD. WE IDENTIFIED A PROBIOTIC EXOPOLYSACCHARIDE (EPS) THAT INDUCES TOLEROGENIC DENDRITIC CELLS (DCS) THAT INHIBIT T CELL PROLIFERATION, AND WE FOUND THAT EPS-TREATED HUMAN DCS (EPS-DCS) BOTH INHIBITED T CELL PROLIFERATION IN MIXED LYMPHOCYTE REACTIONS, AND SIGNIFICANTLY INCREASED SURVIVAL OF HUMANIZED NSG-HLA-A2 MICE AFTER TRANSPLANTATION WITH HUMAN PERIPHERAL BLOOD MONONUCLEAR CELLS (HPBMC). THE DATA INDICATE THAT A CELL-BASED THERAPY USING EPS-DCS CAN MITIGATE AGVHD, AND THE GOAL OF THIS PHASE I R41 GRANT IS TO DETERMINE THE IN VIVO FATE OF EPS-DCS AND OPTIMIZE PROTECTION FROM GVHD BY THESE EPS-DCS; OPTIMIZE TREATMENT TO MAXIMIZE THE GRAFT VS LEUKEMIA RESPONSE; AND ESTABLISH DC AND T CELL BIOMARKERS OF EPS-MEDIATED SUPPRESSION OF GVHD. THESE STUDIES WILL PROVIDE A NOVEL CELL-BASED THERAPY FOR PREVENTING GVHD IN PATIENTS RECEIVING HSCT. THIS CELL THERAPY WILL BE TRANSLATABLE TO HUMANS BECAUSE LARGE NUMBERS OF EPS-DCS CAN BE GENERATED AND FROZEN IN BULK AND USED AS "OFF THE SHELF" TREATMENT, FOR ALL PATIENTS, INDEPENDENT OF MHC TYPES.