CD38: targeted therapy in multiple myeloma and therapeutic potential for solid cancers

ABSTRACT

Introduction

CD38 is expressed by some cells of hematological malignancies and tumor-related immunosuppressive cells, including regulatory T cells, regulatory B cells, and myeloid-derived suppressor cells. CD38 is an effective target in some hematological malignancies such as multiple myeloma (MM). Daratumumab (Dara), a CD38-targeting antibody, can eliminate CD38^high immune suppressor cells and is regarded as a standard therapy for MM because of its outstanding clinical efficacy. Other CD38 monospecific antibodies, such as isatuximab, MOR202, and TAK079, showed promising effects in clinical trials.

Area covered

This review examines the expression, function, and targeting of CD38 in MM and its potential to deplete immunosuppressive cells in solid cancers. We summarize the distribution and biological function of CD38 and discuss the application of anti-CD38 drugs in hematological malignancies. We also analyz the role of CD38⁺ immune cells in the tumor microenvironment to encourage additional investigations that target CD38 in solid cancers. PubMed and ClinicalTrials were searched to identify relevant literature from the database inception to 30 April 2020.

Expert opinion

There is convincing evidence that CD38-targeted immunotherapeutics reduce CD38⁺ immune suppressor cells. This result suggests that CD38 can be exploited to treat solid tumors by regulating the immunosuppressive microenvironment.

KEYWORDS:

• CD38
• multiple myeloma
• cancer immunotherapy
• bispecific antibody
• chimeric antigen receptor T cell
• mdsc

Article highlights

• CD38 has enzyme activity, adhesion effects, and crosses with CXCL12-CXCR4 and CD49d/CD29-VCAM1 signals. Through these multiple functions, CD38 plays a vital role in normal cell functions and tumor growth.

• Daratumumab eliminates cancer cells that utilize classic Fc-dependent immune mechanisms. It also induces direct apoptotic action, inhibits CD38 ectoenzyme activity, and exerts immunomodulatory effects via the elimination of CD38+ immune-suppressor cells.

• Daratumumab is regarded as a standard therapy for MM due to its outstanding clinical efficacy. Other CD38 monospecific antibodies, such as isatuximab, MOR202, and TAK079, showed promising effects in clinical trials.

• The CD38 bispecific antibodies, AMG424 and GBR1342, in phase I clinical trials, trigger T cell activation, proliferation, and cytokine release to eliminate CD38+ relapsed/refractory multiple myeloma (RRMM) cells.

• Targeting CD38 could enhance antitumor immune responses in solid cancers due to the immunosuppressive role of some CD38+ cells in the tumor microenvironment.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

One reviewer has engaged in consultancy work for Janssen and Sanofi, makers of antiCD38 drugs for use in myeloma. Peer reviewers on this manuscript have no other relevant financial or other relationships to disclose

Additional information

Funding

This work was funded by the National Natural Science Foundation of China (No. 81874120) and Wuhan Science and Technology Bureau (No. 2017060201010170).