Abstract
BackgroundTreatment with chimeric antigen receptor (CAR)-engineered T cells directed against the B-cell maturation antigen (BCMA) promoted transient recovery from multiple myeloma (MM). However, the absence of this antigen on immature plasma cells may limit the efficacy of this modality and facilitate relapse. The purpose of this study is to characterize a novel CAR that includes both a single-chain variable fragment (scFv)-BCMA and an scFv-CD19 in tandem orientation (tan-CAR) in an attempt to target both BCMA and CD19 expression on MM cells.MethodThe scFv sequences from the anti-CD19 antibody FMC63 and the anti-BCMA antibody C11D5.3 were ligated in tandem with transmembrane and T-cell signaling domains to generate the tan-CAR construct. Specificity and efficacy of activated tan-CAR T cells were analyzed using in vitro proliferation, cytokine release, and cytolysis assays. We also evaluated the in vivo efficacy with a xenograft mouse model that included target tumor cells that expressed CD19 or BCMA and compared the results to those obtained with conventional CAR T cells.ResultsThe in vitro studies revealed specific activation of tan-CAR T cells by K562 cells that overexpressed CD19 and/or BCMA. Cell proliferation, cytokine release, and cytolytic activity were all comparable to the responses of single scFv CAR T cells. Importantly, in vivo studies of tan-CAR T cells revealed specific inhibition of tumor growth in the mouse xenograft model that included cells expressing both CD19 and BCMA. Systemic administration of tan-CAR T cells resulted in complete tumor remission, in contrast to the reduced efficacies of BCMA-CAR T and CD19-CAR T alone in this setting.ConclusionWe report the successful design and execution of novel tan-CAR T cells that promote significant anti-tumor efficacy against both CD19 and BCMA antigen-positive tumor cells in vitro and in vivo. The data from this study reveal a novel strategy that may help to reduce the rate of relapse in the treatment with single scFv-CAR T cells.
Highlights
Multiple myeloma (MM) is a malignant neoplasm in which uncontrolled expansion and proliferation of clonal plasma cells leads to osteolytic lesions and bone marrow failure in association with end-organ damage [1]
Systemic administration of Tandem-chimeric antigen receptor (tanCAR) T cells resulted in complete tumor remission, in contrast to the reduced efficacies of B-cell maturation antigen (BCMA)-chimeric antigen receptor (CAR) T and CD19CAR T alone in this setting
The data from this study reveal a novel strategy that may help to reduce the rate of relapse in the treatment with single single-chain fragment variable (scFv)-CAR T cells
Summary
Multiple myeloma (MM) is a malignant neoplasm in which uncontrolled expansion and proliferation of clonal plasma cells leads to osteolytic lesions and bone marrow failure in association with end-organ damage [1]. Previous study proved bi-specific CAR capable of preventing antigen escape in vivo by post-mortem analysis which revealed the outgrowth of CD19− mutants in the mixed-Raji xenograft [17]. Taken together, these results suggest that we might employ CAR T cells that simultaneously recognize both CD19 and BCMA for effective treatment of MM and reduce the risk of relapse. Treatment with chimeric antigen receptor (CAR)-engineered T cells directed against the B-cell maturation antigen (BCMA) promoted transient recovery from multiple myeloma (MM). The purpose of this study is to characterize a novel CAR that includes both a single-chain variable fragment (scFv)-BCMA and an scFv-CD19 in tandem orientation (tan-CAR) in an attempt to target both BCMA and CD19 expression on MM cells
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