In our prior studies supported by NIH funding we identified the role of the bone marrow (BM) microenvironment in conferring growth, survival, and drug resistance in multiple myeloma (MM) cells. Importantly, we have successfully translated multiple novels agents (bortezomib, carfilzomib, lenalidomide, and pomalidomide) targeting these interactions from the bench to the bedside and FDA approval for treatment of MM. However, MM remains incurable in many cases despite novel therapies, suggesting the need for further identification of factors in the host-MM BM microenvironment that mediate tumorigenesis and drug resistance. Our studies provided the first evidence that plasmacytoid dendritic cells (pDCs) in the BM microenvironment both mediate characteristic immune deficiency in MM; as well as promote tumor cell growth, survival, and drug resistance. Specifically, we showed increased numbers and more frequent localization of pDCs in MM patient BM than normal BM. The functional significance of increased numbers of pDCs in MM BM is evident from our observations that pDCs: are relatively resistant to novel and conventional therapies; protect tumor cells from therapy-induced cytotoxicity; as well as promote tumor growth and survival. Aberrant pDC function is evidenced in their interactions not only with MM cells, but also with other immune effector T cells and NK cells, thereby suppressing immune responses in MM. Based on these findings, we hypothesize that directly targeting pDCs and/or pDCs interactions with MM and immune effector cells in the MM BM milieu will enhance both anti- tumor immunity and cytotoxicity. The current proposal aims to target pDCs and pDC-MM-T-NK cell interactions in novel therapeutic strategies for MM with the goal of restoring anti-MM immunity, enhancing MM cytotoxicity, overcoming drug-resistance, and improving patient outcome. We propose to utilize two distinct, yet interconnected and complementary, approaches: 1) Depletion of pDCs in the MM BM milieu (Aim 1) using a novel therapeutic strategy directed specifically against dysfunctional pDCs; and 2) Restoration of pDC immune function by triggering pDC maturation and/or blocking the immune checkpoints mediating pDC-T cell, pDC-NK cell, and pDC-MM cell interactions (Aim 2). To accomplish these goals, we will pursue the following Specific Aims:
Specific Aim 1 : To investigate pDCs-depletion as a novel therapy in MM. (1a) To conduct a Phase I/II clinical trial of novel agent SL-401 to deplete dysfunctional pDCs. (1b) To pre-clinically examine efficacy of anti-MM therapies with pDCs depletion.
Specific Aim 2 : To restore pDCs immune function by inducing pDC maturation and/or blocking the immune checkpoints mediating pDC-T cell, pDC-NK cell, or pDC-MM cell interactions. The current proposal is therefore innovative, since it will for the first time translate our research targeting MM-pDCs to the bedside and clinical trials, as well as provide the pre-clinical basis for future combination novel immune-based therapies.

Public Health Relevance

This new paradigm to target tumor cell interactions with immune effector (pDCs, T cells, NK cells) in MM offers great promise not only to change the natural history of MM, but also serve as a model for targeted immunotherapeutics in other cancers.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Merritt, William D
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Dana-Farber Cancer Institute
United States
Zip Code
Ray, A; Das, D S; Song, Y et al. (2018) Combination of a novel HDAC6 inhibitor ACY-241 and anti-PD-L1 antibody enhances anti-tumor immunity and cytotoxicity in multiple myeloma. Leukemia 32:843-846
Anderson, Kenneth C (2018) Promise of Immune Therapies in Multiple Myeloma. J Oncol Pract 14:411-413
Bae, J; Hideshima, T; Zhang, G L et al. (2018) Identification and characterization of HLA-A24-specific XBP1, CD138 (Syndecan-1) and CS1 (SLAMF7) peptides inducing antigens-specific memory cytotoxic T lymphocytes targeting multiple myeloma. Leukemia 32:752-764
Lamberto, Ilaria; Liu, Xiaoxi; Seo, Hyuk-Soo et al. (2017) Structure-Guided Development of a Potent and Selective Non-covalent Active-Site Inhibitor of USP7. Cell Chem Biol 24:1490-1500.e11
Song, Y; Li, S; Ray, A et al. (2017) Blockade of deubiquitylating enzyme Rpn11 triggers apoptosis in multiple myeloma cells and overcomes bortezomib resistance. Oncogene 36:5631-5638
Zhang, Li; Tai, Yu-Tzu; Ho, Matthew Zhi Guang et al. (2017) Interferon-alpha-based immunotherapies in the treatment of B cell-derived hematologic neoplasms in today's treat-to-target era. Exp Hematol Oncol 6:20
Cleynen, A; Szalat, R; Kemal Samur, M et al. (2017) Expressed fusion gene landscape and its impact in multiple myeloma. Nat Commun 8:1893
Anderson, Kenneth C (2017) Should minimal residual disease negativity be the end point of myeloma therapy? Blood Adv 1:517-521
Das, Deepika Sharma; Das, Abhishek; Ray, Arghya et al. (2017) Blockade of Deubiquitylating Enzyme USP1 Inhibits DNA Repair and Triggers Apoptosis in Multiple Myeloma Cells. Clin Cancer Res 23:4280-4289
Zhang, L; Tai, Y-T; Ho, M et al. (2017) Regulatory B cell-myeloma cell interaction confers immunosuppression and promotes their survival in the bone marrow milieu. Blood Cancer J 7:e547

Showing the most recent 10 out of 13 publications