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Author Notes:

Flavia Pichiorri

Department of Hematologic Malignancies Translational Science, City of Hope, 1500 E. Duarte Rd., Duarte, CA 91010.

Phone: 626-218-4908

fpichiorri@coh.org

Amrita Krishnan

Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA 91010.

Phone: 626-218-2405

akrishnan@coh.org

Author contributions: DV, AD, SJF, PJY, JJK, JS, STR, CCH, GM, AK, and FP designed research; DV, AD, MM, EGG, ET, EC, FB, X Wu, JK, TM, ST, CK, MH, MR, DS, RRM, TE performed research; DV, AV, LG, JFS, X Wang analyzed data; AD, JFS, AK and FP wrote the manuscript; all authors reviewed the manuscript.

We thank Dori Triplet, Evelyn Flores, Elizabeth Hartman and Debbie Flood for administrative support. We also thank Suzan King and Steve Allen for their support.

Competing interests: AK is a consultant for Celgene and Janssen, serves on the speakers’ bureau for SutroBioPharma, zPredicta, Celgene, Amgen, and Takeda, and has stock ownership in Celgene. CCH has received research grants from Takeda & Oncolytics Biotech; research and personal grants from Janssen, BMS, Sanofi, Nektar, and Karyopharm; and personal grants from Imbrium Pharmaceuticals and Oncopeptides, all outside the submitted work.

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Research Funding:

Research was in part supported by the National Institute of Health under grant number NIH-2-R01-CA201382(FP, CCH) and in part under the NIH-2-R01-CA238429-01 (FP, JS, XW) and in part by the Steven Gordon and Briskin Family Innovation Grant. Research reported in this publication included work performed at the Liquid Tissue Bank, Analytical Cytometry, and Integrative Genomics and Bioinformatics shared resource cores supported by the National Institutes of Health under award number P30CA033572. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Oncology
  • Hematology
  • UP-REGULATION
  • IFN-GAMMA
  • MULTIPLE
  • DEXAMETHASONE
  • LENALIDOMIDE
  • MONOTHERAPY
  • BORTEZOMIB

Daratumumab induces mechanisms of immune activation through CD38+NK cell targeting

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Journal Title:

LEUKEMIA

Volume:

Volume 35, Number 1

Publisher:

, Pages 189-200

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Daratumumab (Dara), a multiple myeloma (MM) therapy, is an antibody against the surface receptor CD38, which is expressed not only on plasma cells but also on NK cells and monocytes. Correlative data have highlighted the immune-modulatory role of Dara, despite the paradoxical observation that Dara regimens decrease the frequency of total NK cells. Here we show that, despite this reduction, NK cells play a pivotal role in Dara anti-MM activity. CD38 on NK cells is essential for Dara-induced immune modulation, and its expression is restricted to NK cells with effector function. We also show that Dara induces rapid CD38 protein degradation associated with NK cell activation, leaving an activated CD38-negative NK cell population. CD38+ NK cell targeting by Dara also promotes monocyte activation, inducing an increase in T-cell costimulatory molecules (CD86/80) and enhancing anti-MM phagocytosis activity ex vivo and in vivo. In support of Dara’s immunomodulating role, we show that MM patients that discontinued Dara therapy because of progression maintain targetable unmutated surface CD38 expression on their MM cells, but retain effector cells with impaired cellular immune function. In summary, we report that CD38+ NK cells may be an unexplored therapeutic target for priming the immune system of MM patients.

Copyright information:

2020

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