Targeting CD38 Enhances the Antileukemic Activity of Ibrutinib in Chronic Lymphocytic Leukemia.

Abstract

PURPOSE:

CD38 has emerged as a high-impact therapeutic target in multiple myeloma, with the approval of daratumumab (anti-CD38 mAb). The clinical importance of CD38 in patients with chronic lymphocytic leukemia (CLL) has been known for over 2 decades, although it's relevance as a therapeutic target in CLL remains understudied.

EXPERIMENTAL DESIGN:

We investigated the biological effects and antitumor mechanisms engaged by daratumumab in primary CLL cells. Besides its known immune-effector mechanisms (antibody-dependent cell-mediated cytotoxicity, complement-dependent death, and antibody-dependent cellular phagocytosis), we also measured direct apoptotic effects of daratumumab alone or in combination with ibrutinib. In vivo antileukemic activity was assessed in a partially humanized xenograft model. The influence of CD38 on B-cell receptor (BCR) signaling was measured via immunoblotting of Lyn, Syk, BTK, PLCγ2, ERK1/2, and AKT.

RESULTS:

In addition to immune-effector mechanisms; daratumumab also induced direct apoptosis of primary CLL cells, which was partially dependent on FcγR cross-linking. For the first time, we demonstrated the influence of CD38 on BCR signaling where interference of CD38 downregulated Syk, BTK, PLCγ2, ERK1/2, and AKT; effects that were further enhanced by addition of ibrutinib. In comparison to single-agent treatment, the combination of ibrutinib and daratumumab resulted in significantly enhanced anti-CLL activity in vitro and significantly decreased tumor growth and prolonged survival in the in vivo CLL xenograft model.

CONCLUSIONS:

Overall, our data demonstrate the antitumor mechanisms of daratumumab in CLL; furthermore, we show how cotargeting BTK and CD38 lead to a robust anti-CLL effect, which has clinical implications.

• Authors: Alak Manna, Sonikpreet Aulakh, Prachi Jani, Salman Ahmed, Sharoon Akhtar, Marie Coignet, Michael Heckman, Zahara Meghji, Kirtipal Bhatia, Aarushi Sharma, Taimur Sher, Victoria Alegria, Fabio Malavasi, Eduardo N Chini, Asher Chanan-Khan, Sikander Ailawadhi, Aneel Paulus
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 25 Issue 13 Pg. 3974-3985 (07 01 2019) ISSN: 1557-3265 [Electronic] United States
• PMID: 30940652 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2019 American Association for Cancer Research.

Chemical References

• Antibodies, Monoclonal
• Antineoplastic Agents
• Antineoplastic Agents, Immunological
• Membrane Glycoproteins
• Piperidines
• Protein Kinase Inhibitors
• Pyrazoles
• Pyrimidines
• Receptors, Antigen, B-Cell
• ibrutinib
• daratumumab
• CD38 protein, human
• ADP-ribosyl Cyclase 1
• Adenine

Topics

• ADP-ribosyl Cyclase 1 (antagonists & inhibitors, metabolism)
• Adenine (analogs & derivatives)
• Animals
• Antibodies, Monoclonal (pharmacology)
• Antineoplastic Agents (pharmacology)
• Antineoplastic Agents, Immunological (pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Disease Models, Animal
• Drug Synergism
• Humans
• Leukemia, Lymphocytic, Chronic, B-Cell (drug therapy, metabolism, mortality, pathology)
• Membrane Glycoproteins (antagonists & inhibitors, metabolism)
• Mice
• Piperidines
• Protein Kinase Inhibitors (pharmacology)
• Pyrazoles (pharmacology)
• Pyrimidines (pharmacology)
• Receptors, Antigen, B-Cell (metabolism)
• Xenograft Model Antitumor Assays