Sustained Therapeutic Efficacy of Humanized Anti-CD19 Chimeric Antigen Receptor T Cells in Relapsed/Refractory Acute Lymphoblastic Leukemia

Heng, Gang; Jia, Jiankun; Li, Shiqi; Fu, Gang; Wang, Meiling; Qin, Dabing; Li, Yunyan; Li, Pei; Tian, Xiaobo; Zhang, Jiasi; Wu, Yi; Xiang, Shali; Wan, Jia; Zhu, Wei; Zhang, Pei; Zhang, Qianzhen; Peng, Xi; Wang, Linling; Wang, Ping; Wei, Zhihao; Zhang, Yingzi; Wang, Guiqin; Chen, Xue; Zhang, Chengcheng; Sun, Yanni; Zhao, Wenxu; Fan, Yuxia; Yang, Zhi; Chen, Jieping; Qian, Cheng

doi:10.1158/1078-0432.ccr-19-1339

Cited by 59 publications

(44 citation statements)

References 32 publications

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“…791 For instance, CD19-specific CAR-T cells (Kymriah and Yescarta) have yielded remarkable clinical trial results in the treatment of certain types of B-cell leukemia and lymphomas. [792][793][794] However, the efficacy of CAR-T cells in solid tumors is limited to date, partly due to the lack of trafficking of CAR-T cells to the tumor site, insufficient activation of the transferred T cells, and the immunosuppressive TME in solid tumors. 795 However, CAR-T-cell therapy can trigger a severe inflammatory storm, known as inflammatory cytokine release syndrome (CRS), which can lead directly to death.…”

Section: Adjusting the Inflammation In Innate Immunitymentioning

confidence: 99%

Inflammation and tumor progression: signaling pathways and targeted intervention

Zhao

Yan

et al. 2021

Sig Transduct Target Ther

1,295

682

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Cancer development and its response to therapy are regulated by inflammation, which either promotes or suppresses tumor progression, potentially displaying opposing effects on therapeutic outcomes. Chronic inflammation facilitates tumor progression and treatment resistance, whereas induction of acute inflammatory reactions often stimulates the maturation of dendritic cells (DCs) and antigen presentation, leading to anti-tumor immune responses. In addition, multiple signaling pathways, such as nuclear factor kappa B (NF-kB), Janus kinase/signal transducers and activators of transcription (JAK-STAT), toll-like receptor (TLR) pathways, cGAS/STING, and mitogen-activated protein kinase (MAPK); inflammatory factors, including cytokines (e.g., interleukin (IL), interferon (IFN), and tumor necrosis factor (TNF)-α), chemokines (e.g., C-C motif chemokine ligands (CCLs) and C-X-C motif chemokine ligands (CXCLs)), growth factors (e.g., vascular endothelial growth factor (VEGF), transforming growth factor (TGF)-β), and inflammasome; as well as inflammatory metabolites including prostaglandins, leukotrienes, thromboxane, and specialized proresolving mediators (SPM), have been identified as pivotal regulators of the initiation and resolution of inflammation. Nowadays, local irradiation, recombinant cytokines, neutralizing antibodies, small-molecule inhibitors, DC vaccines, oncolytic viruses, TLR agonists, and SPM have been developed to specifically modulate inflammation in cancer therapy, with some of these factors already undergoing clinical trials. Herein, we discuss the initiation and resolution of inflammation, the crosstalk between tumor development and inflammatory processes. We also highlight potential targets for harnessing inflammation in the treatment of cancer.

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Section: Adjusting the Inflammation In Innate Immunitymentioning

confidence: 99%

Inflammation and tumor progression: signaling pathways and targeted intervention

Zhao

Yan

et al. 2021

Sig Transduct Target Ther

1,295

682

View full text Add to dashboard Cite

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“…In a separate clinical trial (NCT02349698), Heng et al evaluated the efficacy and safety of CD19-redirected hCAR-Ts in R/R B-ALL patients. They reported enhanced long-term persistence of hCAR-Ts; exemplified by a complete remission (CR) in 60% of the treated patients (15). As persistence, correlates with enhanced durable efficacy, their study provides mechanistic insights into the beneficial attributes of hCAR-Ts; ultimately culminating in lower relapse rates as well as improved clinical impact in the treatment of R/R ALL patients.…”

Section: The Extracellular Domainmentioning

confidence: 91%

In Like a Lamb; Out Like a Lion: Marching CAR T Cells Toward Enhanced Efficacy in B-ALL

Kozani

O’Connor

2021

Molecular Cancer Therapeutics

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Combining synthetic biology with adoptive T-cell transfer has led to promising advances in the treatment of relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL), diffuse large B-cell lymphoma (DLBCL), and mantle cell lymphoma (MCL). Chimeric antigen receptors (CARs) are synthetic receptors that redirect T-cell specificity against cancer. CARs include “built-in” signaling domains that reprogram T-cell metabolism, enhance effector function, and support long-term persistence. Despite their success in blood-based malignancies, relapse can occur in CD19-redirected CAR T-cell therapies for several reasons, including poor engraftment, impaired in vivo proliferation, and T-cell senescence. Herein, we explain how subtle alterations in CAR design may overcome barriers to effective adoptive immunotherapy. We also discuss how the physiochemical properties of the single-chain variable fragment (scFv) affect differentiation and persistence. Moreover, we describe innovative advances in CAR engineering and provide insight into the development of humanized scFvs whose proposed benefits include increased persistence and improved clinical outcomes. Tumor cells can evade CAR T-cell–mediated detection and elimination due to the emergence or presence of CD19-negative leukemic cell subpopulations. We also discuss the opportunities and challenges in targeting other B-ALL–associated antigens. Identifying alternate targets is fundamentally necessary to restore the success of CAR T-cell therapies in CD19-negative patients with B-ALL.

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“…ScFv is the antigen-binding domain of CAR structure, which is composed of a single heavy and light chain of monoclonal antibody connected by a linker. A murine derived scFv has been reported to induce HLA-restricted T cellmediated cellular immune response or humoral immune response [13], while humanized scFv is expected to reduce the immunogenicity of CAR, thereby avoiding immune mediated rejection and improving the persistence and therapeutic efficacy of CAR T cells [14,15]. The different antigen-targeted scFv on the T cells membrane has different impact on CAR T cells fates.…”

Section: Extracellular Structuresmentioning

confidence: 99%

Engineering better chimeric antigen receptor T cells

2020

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CD19-targeted CAR T cells therapy has shown remarkable efficacy in treatment of B cell malignancies. However, relapse of primary disease remains a major obstacle after CAR T cells therapy, and the majority of relapses present a tumor phenotype with retention of target antigen (antigen-positive relapse), which highly correlate with poor CAR T cells persistence. Therefore, study on factors and mechanisms that limit the in vivo persistence of CAR T cells is crucial for developing strategies to overcome these limitations. In this review, we summarize the rapidly developing knowledge regarding the factors that influence CAR T cells in vivo persistence and the underlying mechanisms. The factors involve the CAR constructs (extracellular structures, transmembrane and intracellular signaling domains, as well as the accessory structures), activation signaling (CAR signaling and TCR engagement), methods for in vitro culture (T cells collection, purification, activation, gene transduction and cells expansion), epigenetic regulations, tumor environment, CD4/CD8 subsets, CAR T cells differentiation and exhaustion. Of note, among these influence factors, CAR T cells differentiation and exhaustion are identified as the central part due to the fact that almost all factors eventually alter the state of cells differentiation and exhaustion. Moreover, we review the potential coping strategies aiming at these limitations throughout this study.

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Sustained Therapeutic Efficacy of Humanized Anti-CD19 Chimeric Antigen Receptor T Cells in Relapsed/Refractory Acute Lymphoblastic Leukemia

Cited by 59 publications

References 32 publications

Inflammation and tumor progression: signaling pathways and targeted intervention

Inflammation and tumor progression: signaling pathways and targeted intervention

In Like a Lamb; Out Like a Lion: Marching CAR T Cells Toward Enhanced Efficacy in B-ALL

Engineering better chimeric antigen receptor T cells

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