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.

Public Health Relevance

The overall goal of this program is to characterize MM-host cell interactions and to validate and down regulate tumor promoting mechanisms and enhance anti-MM host immune responses in order to develop novel targeted therapeutics which can achieve long-term disease free survival and potential cure of MM.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA078378-13
Application #
8249898
Study Section
Special Emphasis Panel (ZCA1-RPRB-J (O1))
Program Officer
Merritt, William D
Project Start
1998-08-01
Project End
2015-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
13
Fiscal Year
2012
Total Cost
$1,974,463
Indirect Cost
$743,553
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
Das, D Sharma; Ray, A; Das, A et al. (2016) A novel hypoxia-selective epigenetic agent RRx-001 triggers apoptosis and overcomes drug resistance in multiple myeloma cells. Leukemia 30:2187-2197
Ray, Arghya; Ravillah, Durgadevi; Das, Deepika S et al. (2016) A novel alkylating agent Melflufen induces irreversible DNA damage and cytotoxicity in multiple myeloma cells. Br J Haematol 174:397-409
An, Gang; Acharya, Chirag; Feng, Xiaoyan et al. (2016) Osteoclasts promote immune suppressive microenvironment in multiple myeloma: therapeutic implication. Blood 128:1590-603
Tagde, Ashujit; Rajabi, Hasan; Bouillez, Audrey et al. (2016) MUC1-C drives MYC in multiple myeloma. Blood 127:2587-97
Jiang, H; Acharya, C; An, G et al. (2016) SAR650984 directly induces multiple myeloma cell death via lysosomal-associated and apoptotic pathways, which is further enhanced by pomalidomide. Leukemia 30:399-408
Gullà, Annamaria; Di Martino, Maria Teresa; Gallo Cantafio, Maria Eugenia et al. (2016) A 13 mer LNA-i-miR-221 Inhibitor Restores Drug Sensitivity in Melphalan-Refractory Multiple Myeloma Cells. Clin Cancer Res 22:1222-33
Tai, Yu-Tzu; Acharya, Chirag; An, Gang et al. (2016) APRIL and BCMA promote human multiple myeloma growth and immunosuppression in the bone marrow microenvironment. Blood 127:3225-36
Bommarito, Davide; Martin, Allison; Forcade, Edouard et al. (2016) Enhancement of tumor cell susceptibility to natural killer cell activity through inhibition of the PI3K signaling pathway. Cancer Immunol Immunother 65:355-66
Ohguchi, Hiroto; Hideshima, Teru; Bhasin, Manoj K et al. (2016) The KDM3A-KLF2-IRF4 axis maintains myeloma cell survival. Nat Commun 7:10258
Bae, J; Prabhala, R; Voskertchian, A et al. (2015) A multiepitope of XBP1, CD138 and CS1 peptides induces myeloma-specific cytotoxic T lymphocytes in T cells of smoldering myeloma patients. Leukemia 29:218-29

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