A safe and potent anti-CD19 CAR T cell therapy

Ying, Zhitao; Huang, Xue F.; Xiang, Xiaoyu; Liu, Yanling; Xi, Kang; Song, Yuqin; Guo, Xiaojing; Liu, Hanzhi; Ding, Ning; Zhang, Tingting; Duan, Peng; Lin, Yi; Zheng, Wen; Wang, Xiaopei; Lin, Ningjing; Tu, Meifeng; Xie, Yun; Zhang, Chen; Liu, Weiping; Deng, Lijuan; Gao, Shaopeng; Ping, Lingyan; Wang, Xuejuan; Zhou, Nina; Zhang, Junqing; Wang, Yulong; Lin, Songfeng; Mamuti, Mierzhati; Yu, Xueyun; Fang, Lizhu; Wang, Shuai; Song, Haifeng; Wang, Guan; Jones, Lindsey; Zhu, Jun; Chen, Si-Yi

doi:10.1038/s41591-019-0421-7

Cited by 359 publications

(275 citation statements)

References 39 publications

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“…7,9 Zhitao Ying et al found that altering the structure of CAR T-cells can result in lower levels of cytokines and thus enhance safety while retaining potent cytolytic activity. 10 We observed that the levels of cytokines in serum did not increase significantly after CAR T-cell infusion, which also contributed to controlling CRS. The observed efficacy and safety in our study revealed the potential feasibility of this shortened ex vitro culture combining with the improved clinical treatment strategies.…”

mentioning

confidence: 71%

“…These include enterocyte injury, 7 altered microbial composition, 9 increased permeability 7 and bacterial overgrowth. 10 We have previously proposed that increased translocation of intestinal bacteria/bacterial products into the systemic circulation is responsible for the increased number of activated neutrophils in SCD. 11 Others have found intestinal microbiota to regulate CANs in SCD mice.…”

Section: Rifaximin For Sickle Cell Diseasementioning

confidence: 99%

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Shortening the ex vivo culture of CD19‐specific CAR T‐cells retains potent efficacy against acute lymphoblastic leukemia without CAR T‐cell‐related encephalopathy syndrome or severe cytokine release syndrome

Huang

Guo

et al. 2019

American J Hematol

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S.T. and R.H. managed the patients and wrote the manuscript. Z.G. collected the data. LD revised the manuscript. C.S., X.Z. and C.Y. contributed to patient management. L.Z. produced the figures and Table. Y.H. participated in the registration of the clinical research. J.Y. and Z.L. were responsible for clinical trial recruitment and data revision. J.D. performed flow cytometry detection and bone marrow cell morphology detection. P.C. was responsible for the statistical analysis. Y.S.L. produced CAR T-cells. L.C. designed the study and guided CAR T-cell production. Y.H.L. contributed to the study design and manuscript writing.

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mentioning

confidence: 71%

Section: Rifaximin For Sickle Cell Diseasementioning

confidence: 99%

Shortening the ex vivo culture of CD19‐specific CAR T‐cells retains potent efficacy against acute lymphoblastic leukemia without CAR T‐cell‐related encephalopathy syndrome or severe cytokine release syndrome

Huang

Guo

et al. 2019

American J Hematol

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“…Hinge sequences have been derived from membrane proximal regions of multiple immune molecules, including CD28, CD8α, and the constant regions of immunoglobulins . In addition to determining whether the antigen recognition domain can physically access its target ligand on an opposing cell, the hinge region may also influence T cell persistence and the likelihood of causing cytokine release syndrome . The TM domain anchors the CAR to the plasma membrane, bridging the extracellular hinge and antigen recognition domains with the intracellular signaling region.…”

Section: Cars and Tcrs Are Structurally And Biophysically Distinct Anmentioning

confidence: 99%

“…[50][51][52] In addition to determining whether the antigen recognition domain can physically access its target ligand on an opposing cell, the hinge region may also influence T cell persistence 51,53 and the likelihood of causing cytokine release syndrome. 54 The TM domain anchors the CAR to the plasma membrane, bridging the extracellular hinge and antigen recognition domains with the intracellular signaling region. The TM region promotes the stable surface expression of a CAR 55 and can also influence whether the receptor aggregates with itself or endogenous CD3ζ molecules.…”

Section: Car Structurementioning

confidence: 99%

T cell receptor‐based cancer immunotherapy: Emerging efficacy and pathways of resistance

Chandran

Klebanoff

2019

Immunological Reviews

237

185

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Adoptive cell transfer (ACT) using chimeric antigen receptor (CAR)‐modified T cells can induce durable remissions in patients with refractory B‐lymphoid cancers. By contrast, results applying CAR‐modified T cells to solid malignancies have been comparatively modest. Alternative strategies to redirect T cell specificity and cytolytic function are therefore necessary if ACT is to serve a greater role in human cancer treatments. T cell receptors (TCRs) are antigen recognition structures physiologically expressed by all T cells that have complementary, and in some cases superior, properties to CARs. Unlike CARs, TCRs confer recognition to epitopes derived from proteins residing within any subcellular compartment, including the membrane, cytoplasm and nucleus. This enables TCRs to detect a broad universe of targets, such as neoantigens, cancer germline antigens, and viral oncoproteins. Moreover, because TCRs have evolved to efficiently detect and amplify antigenic signals, these receptors respond to epitope densities many fold smaller than required for CAR‐signaling. Herein, we summarize recent clinical data demonstrating that TCR‐based immunotherapies can mediate regression of solid malignancies, including immune‐checkpoint inhibitor refractory cancers. These trials simultaneously highlight emerging mechanisms of TCR resistance. We conclude by discussing how TCR‐based immunotherapies can achieve broader dissemination through innovations in cell manufacturing and non‐viral genome integration techniques.

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“…However, despite the constant increase in our understanding of T cell responses, all consequences of T cell genetic manipulation cannot be predicted. CAR T cell therapy has been associated with life-threatening adverse effects, such as cytokine release syndrome resulting from massive CAR T cell activation [16].…”

Section: Car-structure and Signallingmentioning

confidence: 99%

Adoptive Cell Therapy—Harnessing Antigen-Specific T Cells to Target Solid Tumours

Chruściel

Urban-Wójciuk

Arcimowicz

et al. 2020

Cancers

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In recent years, much research has been focused on the field of adoptive cell therapies (ACT) that use native or genetically modified T cells as therapeutic tools. Immunotherapy with T cells expressing chimeric antigen receptors (CARs) demonstrated great success in the treatment of haematologic malignancies, whereas adoptive transfer of autologous tumour infiltrating lymphocytes (TILs) proved to be highly effective in metastatic melanoma. These encouraging results initiated many studies where ACT was tested as a treatment for various solid tumours. In this review, we provide an overview of the challenges of T cell-based immunotherapies of solid tumours. We describe alternative approaches for choosing the most efficient T cells for cancer treatment in terms of their tumour-specificity and phenotype. Finally, we present strategies for improvement of anti-tumour potential of T cells, including combination therapies.

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A safe and potent anti-CD19 CAR T cell therapy

Cited by 359 publications

References 39 publications

Shortening the ex vivo culture of CD19‐specific CAR T‐cells retains potent efficacy against acute lymphoblastic leukemia without CAR T‐cell‐related encephalopathy syndrome or severe cytokine release syndrome

Shortening the ex vivo culture of CD19‐specific CAR T‐cells retains potent efficacy against acute lymphoblastic leukemia without CAR T‐cell‐related encephalopathy syndrome or severe cytokine release syndrome

T cell receptor‐based cancer immunotherapy: Emerging efficacy and pathways of resistance

Adoptive Cell Therapy—Harnessing Antigen-Specific T Cells to Target Solid Tumours

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