Expanding Anti-CD38 Immunotherapy for Lymphoid Malignancies

Authors

Xu Wang
Xinfang Yu
Wei Li
Praveen Neeli
Ming Liu
Ling Li
Mingzhi Zhang
Xiaosheng Fang
Ken H Young
Yong Li

Publication Date

6-28-2022

Journal

Journal of Experimental & Clinical Cancer Research

DOI

10.1186/s13046-022-02421-2

PMID

35765110

PMCID

PMC9237984

PubMedCentral® Posted Date

6-28-2022

PubMedCentral® Full Text Version

Post-Print

Published Open-Access

no

Keywords

ADP-ribosyl Cyclase 1, Adult, Animals, Humans, Immunotherapy, Lymphoma, Lymphoma, B-Cell, Mice, Multiple Myeloma, Xenograft Model Antitumor Assays, Multiple myeloma, Non-Hodgkin lymphoma, CD38, CAR T, Daratumumab, All-trans retinoic acid

Abstract

BACKGROUND: Lymphoid neoplasms, including multiple myeloma (MM), non-Hodgkin lymphoma (NHL), and NK/T cell neoplasms, are a major cause of blood cancer morbidity and mortality. CD38 (cyclic ADP ribose hydrolase) is a transmembrane glycoprotein expressed on the surface of plasma cells and MM cells. The high expression of CD38 across MM and other lymphoid malignancies and its restricted expression in normal tissues make CD38 an attractive target for immunotherapy. CD38-targeting antibodies, like daratumumab, have been approved for the treatment of MM and tested against lymphoma and leukemia in multiple clinical trials.

METHODS: We generated chimeric antigen receptor (CAR) T cells targeting CD38 and tested its cytotoxicity against multiple CD38high and CD38low lymphoid cancer cells. We evaluated the synergistic effects of all-trans retinoic acid (ATRA) and CAR T cells or daratumumab against cancer cells and xenograft tumors.

RESULTS: CD38-CAR T cells dramatically inhibited the growth of CD38high MM, mantle cell lymphoma (MCL), Waldenstrom’s macroglobulinemia (WM), T-cell acute lymphoblastic leukemia (T-ALL), and NK/T-cell lymphoma (NKTCL) in vitro and in mouse xenografts. ATRA elevated CD38 expression in multiple CD38low cancer cells and enhanced the anti-tumor activity of daratumumab and CD38-CAR T cells in xenograft tumors.

CONCLUSIONS: These findings may expand anti-CD38 immunotherapy to a broad spectrum of lymphoid malignancies and call for the incorporation of ATRA into daratumumab or other anti-CD38 immunological agents for cancer therapy.

Comments

Associated Data