Targeting CD38 enhances the antileukemic activity of ibrutinib in chronic lymphocytic leukemia

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 Nunes Chini, Asher A Chanan Khan, Sikander Ailawadhi, Aneel Paulus

Research output: Contribution to journalArticle

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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 immuneeffector 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.

Original languageEnglish (US)
Pages (from-to)3974-3985
Number of pages12
JournalClinical Cancer Research
Volume25
Issue number13
DOIs
StatePublished - Jan 1 2019

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B-Cell Chronic Lymphocytic Leukemia
Heterografts
B-Lymphocytes
Antibody-Dependent Cell Cytotoxicity
PCI 32765
Multiple Myeloma
Phagocytosis
Immunoblotting
daratumumab
Research Design
Therapeutics
Down-Regulation
Apoptosis
Survival
Antibodies
Growth

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Targeting CD38 enhances the antileukemic activity of ibrutinib in chronic lymphocytic leukemia. / Manna, Alak; Aulakh, Sonikpreet; Jani, Prachi; Ahmed, Salman; Akhtar, Sharoon; Coignet, Marie; Heckman, Michael; Meghji, Zahara; Bhatia, Kirtipal; Sharma, Aarushi; Sher, Taimur; Alegria, Victoria; Malavasi, Fabio; Chini, Eduardo Nunes; Chanan Khan, Asher A; Ailawadhi, Sikander; Paulus, Aneel.

In: Clinical Cancer Research, Vol. 25, No. 13, 01.01.2019, p. 3974-3985.

Research output: Contribution to journalArticle

Manna, A, Aulakh, S, Jani, P, Ahmed, S, Akhtar, S, Coignet, M, Heckman, M, Meghji, Z, Bhatia, K, Sharma, A, Sher, T, Alegria, V, Malavasi, F, Chini, EN, Chanan Khan, AA, Ailawadhi, S & Paulus, A 2019, 'Targeting CD38 enhances the antileukemic activity of ibrutinib in chronic lymphocytic leukemia', Clinical Cancer Research, vol. 25, no. 13, pp. 3974-3985. https://doi.org/10.1158/1078-0432.CCR-18-3412
Manna, Alak ; Aulakh, Sonikpreet ; Jani, Prachi ; Ahmed, Salman ; Akhtar, Sharoon ; Coignet, Marie ; Heckman, Michael ; Meghji, Zahara ; Bhatia, Kirtipal ; Sharma, Aarushi ; Sher, Taimur ; Alegria, Victoria ; Malavasi, Fabio ; Chini, Eduardo Nunes ; Chanan Khan, Asher A ; Ailawadhi, Sikander ; Paulus, Aneel. / Targeting CD38 enhances the antileukemic activity of ibrutinib in chronic lymphocytic leukemia. In: Clinical Cancer Research. 2019 ; Vol. 25, No. 13. pp. 3974-3985.
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T1 - Targeting CD38 enhances the antileukemic activity of ibrutinib in chronic lymphocytic leukemia

AU - Manna, Alak

AU - Aulakh, Sonikpreet

AU - Jani, Prachi

AU - Ahmed, Salman

AU - Akhtar, Sharoon

AU - Coignet, Marie

AU - Heckman, Michael

AU - Meghji, Zahara

AU - Bhatia, Kirtipal

AU - Sharma, Aarushi

AU - Sher, Taimur

AU - Alegria, Victoria

AU - Malavasi, Fabio

AU - Chini, Eduardo Nunes

AU - Chanan Khan, Asher A

AU - Ailawadhi, Sikander

AU - Paulus, Aneel

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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 immuneeffector 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.

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