Targeting NAD+ Synthesis to Potentiate CD38-Based Immunotherapy of Multiple Myeloma

Barry E Kennedy; Maryanne Sadek; Manal O Elnenaei; Anthony Reiman; Shashi A Gujar

doi:10.1016/j.trecan.2019.11.005

Targeting NAD⁺ Synthesis to Potentiate CD38-Based Immunotherapy of Multiple Myeloma

Trends Cancer. 2020 Jan;6(1):9-12. doi: 10.1016/j.trecan.2019.11.005. Epub 2019 Dec 31.

Authors

Barry E Kennedy¹, Maryanne Sadek¹, Manal O Elnenaei², Anthony Reiman³, Shashi A Gujar⁴

Affiliations

¹ Department of Pathology, Faculty of Medicine, Dalhousie University, Halifax, NS B3H 1X5, Canada.
² Department of Pathology and Laboratory Medicine, Nova Scotia Health Authority (NSHA), Halifax, NS and Canada Department of Pathology, Dalhousie University, Halifax, NS B3H 1V8, Canada.
³ Department of Oncology, Saint John Regional Hospital, Dalhousie University and University of New Brunswick, Saint John, NB E2L 4L2, Canada.
⁴ Department of Pathology, Faculty of Medicine, Dalhousie University, Halifax, NS B3H 1X5, Canada; Department of Microbiology and Immunology, Faculty of Medicine, Dalhousie University, Halifax, NS B3H 1X5, Canada; Department of Biology, Faculty of Science, Dalhousie University, Halifax, NS B3H 1X5, Canada; Beatrice Hunter Cancer Research Institute, Halifax, NS B3H 1X5, Canada. Electronic address: shashi.gujar@dal.ca.

PMID: 31952784
DOI: 10.1016/j.trecan.2019.11.005

Abstract

Antibodies targeting CD38, a NAD⁺-degrading enzyme, have emerged as a promising immunotherapy against multiple myeloma (MM). Currently, the mechanisms by which anti-CD38 antibodies establish their therapeutic effects are poorly understood. Here, we advocate for the depletion of NAD⁺ to enhance the efficacy of anti-CD38-based immunotherapies in MM.

Keywords: NAD(+); adenosine; anti-CD38 therapy; cancer metabolism; daratumumab; immunosuppression; immunotherapy; isatuximab; multiple myeloma.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

ADP-ribosyl Cyclase 1 / antagonists & inhibitors*
ADP-ribosyl Cyclase 1 / metabolism
Acrylamides / pharmacology
Acrylamides / therapeutic use
Adenosine / metabolism
Adenosine Diphosphate Ribose / metabolism
Antibodies, Monoclonal / pharmacology
Antibodies, Monoclonal / therapeutic use
Antibodies, Monoclonal, Humanized / pharmacology
Antibodies, Monoclonal, Humanized / therapeutic use
Antineoplastic Agents, Immunological / pharmacology
Antineoplastic Agents, Immunological / therapeutic use
Antineoplastic Combined Chemotherapy Protocols / pharmacology*
Antineoplastic Combined Chemotherapy Protocols / therapeutic use
Cell Line, Tumor
Cytokines / antagonists & inhibitors*
Cytokines / metabolism
Drug Synergism
Humans
Membrane Glycoproteins / antagonists & inhibitors*
Membrane Glycoproteins / metabolism
Multiple Myeloma / drug therapy*
Multiple Myeloma / immunology
Multiple Myeloma / pathology
NAD / antagonists & inhibitors*
NAD / metabolism
Niacinamide / metabolism
Nicotinamide Phosphoribosyltransferase / antagonists & inhibitors*
Nicotinamide Phosphoribosyltransferase / metabolism
Piperidines / pharmacology
Piperidines / therapeutic use
T-Lymphocytes, Cytotoxic / drug effects
T-Lymphocytes, Cytotoxic / immunology
T-Lymphocytes, Cytotoxic / metabolism
T-Lymphocytes, Regulatory / drug effects
T-Lymphocytes, Regulatory / immunology
T-Lymphocytes, Regulatory / metabolism
Tumor Escape / drug effects
Warburg Effect, Oncologic / drug effects

Substances

Acrylamides
Antibodies, Monoclonal
Antibodies, Monoclonal, Humanized
Antineoplastic Agents, Immunological
Cytokines
Membrane Glycoproteins
N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide
Piperidines
NAD
Adenosine Diphosphate Ribose
Niacinamide
daratumumab
Nicotinamide Phosphoribosyltransferase
nicotinamide phosphoribosyltransferase, human
CD38 protein, human
ADP-ribosyl Cyclase 1
Adenosine
isatuximab