Systematically optimized BCMA/CS1 bispecific CAR-T cells robustly control heterogeneous multiple myeloma

Eugenia Zah,Christine E Brown,Yvonne Y Chen,Vinya Bhuvan,Stanley B Gosliner,Eunwoo Nam,Uyen Tran,Xiuli Wang,Brenda Y Ji

doi:10.1038/s41467-020-16160-5

Abstract

Chimeric antigen receptor (CAR)-T cell therapy has shown remarkable clinical efficacy against B-cell malignancies, yet marked vulnerability to antigen escape and tumor relapse exists. Here we report the rational design and optimization of bispecific CAR-T cells with robust activity against heterogeneous multiple myeloma (MM) that is resistant to conventional CAR-T cell therapy targeting B-cell maturation antigen (BCMA). We demonstrate that BCMA/CS1 bispecific CAR-T cells exhibit superior CAR expression and function compared to T cells that co-express individual BCMA and CS1 CARs. Combination therapy with anti–PD-1 antibody further accelerates the rate of initial tumor clearance in vivo, while CAR-T cell treatment alone achieves durable tumor-free survival even upon tumor re-challenge. Taken together, the BCMA/CS1 bispecific CAR presents a promising treatment approach to prevent antigen escape in CAR-T cell therapy against MM, and the vertically integrated optimization process can be used to develop robust cell-based therapy against novel disease targets.

Highlights

Chimeric antigen receptor (CAR)-T cell therapy has shown remarkable clinical efficacy against B-cell malignancies, yet marked vulnerability to antigen escape and tumor relapse exists
Outcomes from recent clinical trials indicate that B-cell maturation antigen (BCMA)-targeted CAR-T-cell therapy is vulnerable to antigen escape[4,5,7]
CS1 is expressed on natural killer (NK) cells, natural killer T (NKT) cells, CD8+ T cells, activated monocytes, and dendritic cells, albeit at much lower levels than on plasma cells[17,25]

Summary

Introduction

Chimeric antigen receptor (CAR)-T cell therapy has shown remarkable clinical efficacy against B-cell malignancies, yet marked vulnerability to antigen escape and tumor relapse exists. We report the rational design and optimization of bispecific CAR-T cells with robust activity against heterogeneous multiple myeloma (MM) that is resistant to conventional CAR-T cell therapy targeting B-cell maturation antigen (BCMA). The BCMA/CS1 bispecific CAR presents a promising treatment approach to prevent antigen escape in CAR-T cell therapy against MM, and the vertically integrated optimization process can be used to develop robust cell-based therapy against novel disease targets. A substantial fraction of patients treated with BCMA CAR-T cells eventually relapse even when BCMA expression is retained[4,5,7], suggesting a lack of durable effector function by the engineered T cells To address these challenges, we set out to develop a new CAR-T cell treatment for MM exhibiting greater resistance to antigen escape and improved long-term effector function. We reason that simultaneous targeting of BCMA and CS1 would leverage the therapeutic efficacy of BCMA targeting while providing a safeguard against tumor escape due to BCMA loss

Methods

Results

Conclusion