Characterization of the Therapeutic Effects of Novel Chimeric Antigen Receptor T Cells Targeting CD38 on Multiple Myeloma.

Xiaorui Li,Bingjie Shi,Ping Wang,Yaru Feng,Zhuoying Yu,Fengqin Shang,Tieshan Wang,Zhiru Song,Jing Zhang,Jianxun Wang

doi:10.3389/fonc.2021.703087

Abstract

Multiple myeloma (MM) is a tumor type characterized by the unregulated proliferation of clonal plasma cells in the bone marrow. Immunotherapy based on chimeric antigen receptor T cell (CAR-T) therapy has achieved exciting success in the treatment of hematological malignant tumors. CD38 is highly and evenly expressed in MM and is an attractive target for MM treatment. Here, we successfully constructed two novel second-generation CAR-T cells targeting CD38 by retroviral vector transduction. CD38 CAR-T cells could be activated effectively after stimulation with CD38-positive tumor cells and secrete cytokines such as IFN-γ and TNF-α to promote tumor cell apoptosis in in vitro experiments. Real-time fluorescence monitoring experiments, luciferase detection experiments and flow cytometry experiments revealed the efficient and specific killing abilities of CD38 CAR-T cells against CD38-positive tumor cells. The proliferation ability of CD38 CAR-T cells in vitro was higher than that of untransduced T cells. Further antitumor experiments in vivo showed that CD38 CAR-T cells could be quickly activated to secrete IFN-γ and eliminate tumors. Thus, novel CD38-targeted second-generation CAR-T cells have efficient and specific antitumor activity and may become a novel therapy for the clinical treatment of MM.

Highlights

Multiple myeloma (MM) is a hematologic malignancy characterized by the uncontrolled expansion of plasma cells in bone marrow [1]
The results showed that high titers of CD38 CAR retroviral particles were generated (Figure 1C)
We found that compared with Pan-T cells, CD38 CAR-T cells showed a stronger cytolytic effect on RPMI-gfp-luc and Raji-luc cells, and this cytolytic ability was positively correlated with the E:T ratio (Figure 2A)

Summary

Introduction

Multiple myeloma (MM) is a hematologic malignancy characterized by the uncontrolled expansion of plasma cells in bone marrow [1]. It is estimated that in 2021, a total of 34,920 new cases of the disease will be diagnosed and that 15,600 MM-related deaths will occur in the US [6]. MM is still incurable to a large extent and has a high recurrence rate [10, 11]. In this regard, new immunotherapies have been developed to combat MM

Methods

Results

Conclusion