A combination of humanised anti-CD19 and anti-BCMA CAR T cells in patients with relapsed or refractory multiple myeloma: a single-arm, phase 2 trial

Zhang, Yan; Cao, Jiang; Cheng, Hai; Qiao, Jianlin; Zhang, Huanxin; Wang, Ying; Shi, Ming; Lan, Jianping; Fei, Xiao-Ming; Jin, Lai; Jing, Guangjun; Sang, Wei; Zhu, Feng; Chen, Wei; Wu, Qingyun; Yao, Yao; Wang, Gang; Zhao, Jing; Zheng, Junnian; Li, Zhenyu; Xu, Kailin

doi:10.1016/s2352-3026(19)30115-2

Cited by 240 publications

(233 citation statements)

References 28 publications

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“…The FDA has approved two second-generation CAR T cell therapies targeting CD19 (Yescarta and Kymriah) for treatment against non-Hodgkin lymphomas and acute lymphoblastic leukemia [135] . Efforts to expand the CAR T cell repertoire have led to trials featuring CARs directed toward B-cell mature antigen enriched on multiple myeloma cells [136] and several other tumor antigens related to solid tumors [137] . Dual-signaling CARs contain two distinct CAR molecules with different scFv domains.…”

Section: Car T Cellsmentioning

confidence: 99%

Cell-mediated immune resistance in cancer

Wang¹,

Hays²,

Rama³

et al. 2019

CDR

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The genetic and epigenetic aberrations that underlie immune resistance lead to tumors that are refractory to clinically established and experimental immunotherapies, including monoclonal antibodies and T cell-based therapies. From various forms of cytotoxic T cells to small molecule inhibitors that revamp the tumor microenvironment, these therapies have demonstrated notable responses in cancer models and a resistant subset of cancer patients, used both alone and in combination. However, even current approaches, such as those targeting checkpoint molecules, tumor ligands, and involving gene-related therapies, present a challenge in non-responding patients. In this perspective, we discuss the most common mechanisms of immune resistance, including tumor heterogeneity, tumor ligand and major histocompatibility complex modulation, anti-apoptotic pathways, checkpoint inhibitory ligands, immunosuppressive cells and factors in the tumor microenvironment, and activation-induced cell death. In addition, we discuss the strategies designed to circumvent these resistance pathways to showcase the potential of emerging technologies in battling the rise of resistance.

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Section: Car T Cellsmentioning

confidence: 99%

Cell-mediated immune resistance in cancer

Wang¹,

Hays²,

Rama³

et al. 2019

CDR

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“…[23,24] This may be related to the absence of the target antigen from the tumor cell surface that has been observed in response to single scFV-CAR T-cell therapy [12]; Previous data showed CD19 expression on plasma cells with characterized cancer stem cell-like properties is a poor prognostic indicator [25]. Clinical data [15] showed BCMA-CAR combined CD19-CAR T cells resulted in MRD negative completely remission leading us to develop tandem CAR-T targeting both CD19 and BCMA, reducing the cost of manufacturing two kind of CAR-T products, while achieving maintaining the long-term remission of patients.…”

Section: Discussionmentioning

confidence: 99%

Characterization of novel dual tandem CD19/BCMA chimeric antigen receptor T cells to potentially treat multiple myeloma

Kang

Zhang

et al. 2020

Preprint

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Background: Treatment 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. Method: The 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. Results: The 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. Conclusion: We 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.

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“…In this regards, targeting a combination of antigens expression on myeloma cells may be more effective. A single-arm study evaluating the combination of humanized anti-CD19 and anti-BCMA CAR-T cells in patients with relapsed or refractory MM in 21 patients in China showed that the approach of targeting different antigens separately is feasible [217]. The ORR was 95% with 9 (43%) sCRs and 3 (14%) CRs.…”

Section: Durability Of Response With Car-t Cell Therapiesmentioning

confidence: 99%