A bispecific CAR-T cell therapy targeting BCMA and CD38 in relapsed or refractory multiple myeloma

Mei, Heng; Li, Chenggong; Jiang, Huanhuan; Zhao, Xinying; Huang, Zhiping; Jin, Dan; Guo, Tao; Kou, Haiming; Liu, Lin; Tang, Lu; Yin, Ping; Wang, Zhihui; Ai, Lisha; Sha, Ke; Xia, Yanfei; Deng, Jun; Chen, Lei; Cai, Li; Sun, Chaoyang; Xia, Linghui; Hua, Gaoquan; Hu, Yu

doi:10.1186/s13045-021-01170-7

Cited by 106 publications

(89 citation statements)

References 73 publications

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“…The expression of CAR-target antigens in normal organs and tissues leads to the risk of “on-target, off-tumor” targeting ( 9 ). Accordingly, we examined the expression pattern of CAR-target antigens in normal cell types at the scRNA-seq level ( Figure 1A and Table 1 ), which has not yet been characterized.…”

Section: Resultsmentioning

confidence: 99%

Single-Cell Analysis of Target Antigens of CAR-T Reveals a Potential Landscape of “On-Target, Off-Tumor Toxicity”

Zhang

Cao

et al. 2021

Front. Immunol.

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Cellular immunotherapy represented by CD19-directed chimeric antigen receptor T (CAR-T) cells has achieved great success in recent years. An increasing number of CAR-T therapies are being developed for cancer treatment, but the frequent and varied adverse events, such as “on-target, off-tumor toxicity”, limit CAR-T application. Here, we identify the target antigen expression patterns of CAR therapies in 18 tissues and organs (peripheral blood mononuclear cells, bone marrow, lymph nodes, spleen, heart, ascending aortic tissue, trachea, lung, skin, kidney, bladder, esophagus, stomach, small intestine, rectum, liver, common bile duct, and pancreas) from healthy human samples. The atlas determines target antigens expressed on some normal cell types, which facilitates elucidating the cause of “on-target, off-tumor toxicity” in special tissues and organs by targeting some antigens, but not others. Moreover, we describe the target antigen expression patterns of B-lineage-derived malignant cells, acute myeloid leukemia (AML), and solid tumors. Overall, the present study indicates the pathogenesis of “on-target, off-tumor toxicity” during CAR therapies and provides guidance on taking preventive measures during CAR treatment.

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Section: Resultsmentioning

confidence: 99%

Single-Cell Analysis of Target Antigens of CAR-T Reveals a Potential Landscape of “On-Target, Off-Tumor Toxicity”

Zhang

Cao

et al. 2021

Front. Immunol.

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“…These transduction efficiencies were from cell products generated from apheresis in clinics and were lower than those reported (>50%) in most preclinical studies. The transduction rate for BCMA/CD38 Tandem Bi-CAR T cells from patients in the clinical study can drop to 12%, even though 59.4% was reported in the same Tandem Bi-CAR T cells from PBMC of healthy donors used in the preclinical models [38], indicating that transduction efficiency in preclinical models may not be able to predict outcomes in the clinical setting.…”

Section: Complex Construct Optimizationmentioning

confidence: 87%

Current Status and Perspectives of Dual-Targeting Chimeric Antigen Receptor T-Cell Therapy for the Treatment of Hematological Malignancies

Xie¹,

Zhou

et al. 2022

Cancers

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Single-targeted chimeric antigen receptor (CAR) T cells tremendously improve outcomes for patients with relapsed/refractory hematological malignancies and are considered a breakthrough therapy. However, over half of treated patients experience relapse or refractory disease, with antigen escape being one of the main contributing mechanisms. Dual-targeting CAR T-cell therapy is being developed to minimize the risk of relapse or refractory disease. Preclinical and clinical data on five categories of dual-targeting CAR T-cell therapies and approximately fifty studies were summarized to offer insights and support the development of dual-targeting CAR T-cell therapy for hematological malignancies. The clinical efficacy (durability and survival) is validated and the safety profiles of dual-targeting CAR T-cell therapy are acceptable, although there is still room for improvement in the bispecific CAR structure. It is one of the best approaches to optimize the bispecific CAR structure by boosting T-cell transduction efficiency and leveraging evidence from preclinical activity and clinical efficacy.

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“…Similarly, for MM, combinatorial approaches with BCMA and other plasma cell surface antigens such as CD38 are under development [ 45 , 50 – 54 ]. In vivo models investigating these dual CAR strategies consistently showed superior tumor clearance and prevention of antigen escape, offering the prospect for deeper and more durable clinical responses [ 44 , 48 , 53 , 55 ].…”

Section: Discussionmentioning

confidence: 99%

Two for one: targeting BCMA and CD19 in B-cell malignancies with off-the-shelf dual-CAR NK-92 cells

et al. 2022

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Background Chimeric antigen receptor (CAR) T-cell therapy has proven to be a valuable new treatment option for patients with B-cell malignancies. However, by applying selective pressure, outgrowth of antigen-negative tumor cells can occur, eventually resulting in relapse. Subsequent rescue by administration of CAR-T cells with different antigen-specificity indicates that those tumor cells are still sensitive to CAR-T treatment and points towards a multi-target strategy. Due to their natural tumor sensitivity and highly cytotoxic nature, natural killer (NK) cells are a compelling alternative to T cells, especially considering the availability of an off-the-shelf unlimited supply in the form of the clinically validated NK-92 cell line. Methods Given our goal to develop a flexible system whereby the CAR expression repertoire of the effector cells can be rapidly adapted to the changing antigen expression profile of the target cells, electrotransfection with CD19-/BCMA-CAR mRNA was chosen as CAR loading method in this study. We evaluated the functionality of mRNA-engineered dual-CAR NK-92 against tumor B-cell lines and primary patient samples. In order to test the clinical applicability of the proposed cell therapy product, the effect of irradiation on the proliferative rate and functionality of dual-CAR NK-92 cells was investigated. Results Co-electroporation of CD19 and BMCA CAR mRNA was highly efficient, resulting in 88.1% dual-CAR NK-92 cells. In terms of CD107a degranulation, and secretion of interferon (IFN)-γ and granzyme B, dual-CAR NK-92 significantly outperformed single-CAR NK-92. More importantly, the killing capacity of dual-CAR NK-92 exceeded 60% of single and dual antigen-expressing cell lines, as well as primary tumor cells, in a 4h co-culture assay at low effector to target ratios, matching that of single-CAR counterparts. Furthermore, our results confirm that dual-CAR NK-92 irradiated with 10 Gy cease to proliferate and are gradually cleared while maintaining their killing capacity. Conclusions Here, using the clinically validated NK-92 cell line as a therapeutic cell source, we established a readily accessible and flexible platform for the generation of highly functional dual-targeted CAR-NK cells.

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A bispecific CAR-T cell therapy targeting BCMA and CD38 in relapsed or refractory multiple myeloma

Cited by 106 publications

References 73 publications

Single-Cell Analysis of Target Antigens of CAR-T Reveals a Potential Landscape of “On-Target, Off-Tumor Toxicity”

Single-Cell Analysis of Target Antigens of CAR-T Reveals a Potential Landscape of “On-Target, Off-Tumor Toxicity”

Current Status and Perspectives of Dual-Targeting Chimeric Antigen Receptor T-Cell Therapy for the Treatment of Hematological Malignancies

Two for one: targeting BCMA and CD19 in B-cell malignancies with off-the-shelf dual-CAR NK-92 cells

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