3 OVERALL PROGRAM CRITIQUE 3 PROGRESS DURING THE CURRENT FUNDING PERIOD 4 PROGRAM LEADERSHIP 4 PROGRAM AS AN INTEGRATED EFFORT 4 PROJECT AND CORE SUMMARIES OF DISCUSSION 4 COLLABORATING INSTITUTIONS 6 HUMAN SUBJECTS (Resume) 6 VERTEBRATE ANIMALS (Resume) 7 BUDGETARY OVERLAP 7 INDIVIDUAL PROJECTS AND CORES 8 PROJECT 1: Targeting Myeloma Cell-Host Bone Marrow Interactions 8 PROJECT 2: Innate and Adaptive Anti-Myeloma Immunity 15 PROJECT 3: Adoptive Immunotherapy for Multiple Myeloma Using Educated T Cells 23 CORE A: Administrative and Clinical Support 31 CORE B: Biostatistics and Bioinformatics 33 CORE C: Cell Processing and Immune Assessment 36 COMMITTEE BUDGET RECOMMENDATIONS 39 SPECIAL EMPHASIS PANEL ROSTER DESCRIPTION (provided by applicant): Multiple myeloma (MM) affected 19,900 new individuals in the United States in 2007, with 10,800 related deaths, and remains incurable despite conventional and high dose therapies. The major goal of the current proposal, """"""""Host-Tumor Cell Interactions in Myeloma: Therapeutic Applications,"""""""" is to characterize and down regulate host tumor promoting mechanisms and enhance anti-MM host immune responses in order to develop novel targeted therapeutics which achieve long-term disease free survival and potential cure of MM. This Program builds upon and extends progress during the prior funding period and now has three major goals. We utilized our in vitro and in vivo models to demonstrate a central role of bone marrow stromal cells (BMSCs) promoting growth and conferring drug resistance in MM cells. We then showed that bortezomib and lenalidomide mediate MM cell cytotoxicity in the BM milieu, and rapidly translated these findings from the bench to the bedside and FDA approval. We are now focusing our studies on characterizing the role of an immune accessory cell, the plasmacytoid dendritic cell (pDC), in MM pathogenesis. Our theme for Project 1 is to identify the mechanisms of pDC-induced MM cell growth in order to develop novel therapeutics targeting this interaction within the BM milieu. During the prior granting period, we have identified MM antigens based upon the induction of immune responses in both the autologous and allogeneic setting. Conversely, we have begun to characterize mechanisms underlying immune dysfunction (NKG2D and Th17 pathways) in MM. Our theme for Project 2 is to identify and target cellular and soluble factors modulating autologous anti-MM responses to develop effective strategies targeting these pathways to improve immune responses and inhibit myeloma cell growth. Finally, we have carried out in vitro and in vivo preclinical studies demonstrating that MM-DC fusions can induce anti-MM immune responses. We went on to show that MM-DC fusion vaccination was well tolerated, and can induce immune responses and stabilization of disease in MM patients. Our theme for Project 3 is to couple vaccination with adoptive therapy to overcome host immunosuppressive mechanisms and thereby further enhance anti-MM immunity. Administrative (A) and Biostatistics/Bioinfomatics (B) Cores will assist in design, conduct, analysis, and reporting of laboratory and clinical studies. Immune Assessment and Cell Manufacturing Core (C) will provide immunological monitoring and produce cells for adoptive transfer. This Program therefore represents an integrated and interrelated series of three Projects and three Cores that interact on both a scientific and clinical level to characterize and therapeutically exploit anti-MM immunity. Both within and between projects, laboratory based mechanistic studies will translate to clinical studies;and conversely, observations from clinical protocols will suggest new basic investigations. Ultimately, our goal is to validate MM-host cell interactions as a target for novel therapeutics to improve patient outcome in MM.
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