CD19-CAR-T Cells Bearing a KIR/PD-1-Based Inhibitory CAR Eradicate CD19+HLA-C1− Malignant B Cells While Sparing CD19+HLA-C1+ Healthy B Cells

Tao, Ling; Farooq, Muhammad Asad; Gao, Yao-Xin; Zhang, Li; Niu, Congyi; Ajmal, Iqra; Ying, Zhe; He, Cong; Zhao, Guixia; Yao, Jie; Liu, Mingyao; Jiang, Wenzheng

doi:10.3390/cancers12092612

Cited by 26 publications

(22 citation statements)

References 51 publications

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“…The implementation of the inhibitory approach for producing a NOT gate was pioneered by Fedorov at al ( 77 )., who recruited the signaling domains of the T cell inhibitory receptors CTLA-4 and PD-1 to create inhibitory CARs (iCARs) ( Figure 1 ). Since then a number of studies exploring NOT gates have examined iCARs incorporating inhibitory signaling elements that are derived from T or NK cell-associated inhibitory receptors, including PD-1 ( 40 , 78 ), BTLA ( 79 ) and LIR1 ( 39 ).…”

Section: Selected Strategiesmentioning

confidence: 99%

Implementing Logic Gates for Safer Immunotherapy of Cancer

2021

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Targeting solid tumors with absolute precision is a long-standing challenge in cancer immunotherapy. The identification of antigens, which are expressed by a large fraction of tumors of a given type and, preferably, across various types, but not by normal cells, holds the key to developing safe, off-the-shelf immunotherapies. Although the quest for widely shared, strictly tumor-specific antigens has been the focus of tremendous effort, only few such candidates have been implicated. Almost all antigens that are currently explored as targets for chimeric antigen receptor (CAR) or T cell receptor (TCR)-T cell therapy are also expressed by healthy cells and the risk of on-target off-tumor toxicity has remained a major concern. Recent studies suggest that this risk could be obviated by targeting instead combinations of two or more antigens, which are co-expressed by tumor but not normal cells and, as such, are tumor-specific. Moreover, the expression of a shared tumor antigen along with the lack of a second antigen that is expressed by normal tissues can also be exploited for precise recognition. Additional cues, antigenic or non-antigenic ones, which characterize the tumor microenvironment, could be harnessed to further increase precision. This review focuses on attempts to define the targetable signatures of tumors and assesses different strategies employing advanced synthetic biology for translating such information into safer modes of immunotherapy, implementing the principles of Boolean logic gates.

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Section: Selected Strategiesmentioning

confidence: 99%

Implementing Logic Gates for Safer Immunotherapy of Cancer

2021

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“…When KIR is engaged to human leukocyte antigen C1 (HLA-C1) on normal B-cells, it will deliver an inhibitory signaling via the intracellular PD-1 domain to avoid the destruction of normal B-cells caused by CAR-T cells (Fig. 3) [81].…”

Section: Cd37-targeted Car-t Cell Therapymentioning

confidence: 99%

Advances in chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma

2021

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B-cell non-Hodgkin lymphoma (B-NHL) is a group of heterogeneous disease which remains incurable despite developments of standard chemotherapy regimens and new therapeutic agents in decades. Some individuals could have promising response to standard therapy while others are unresponsive to standard chemotherapy or relapse after autologous hematopoietic stem-cell transplantation (ASCT), which indicates the necessity to develop novel therapies for refractory or relapsed B-NHLs. In recent years, a novel cell therapy, chimeric antigen receptor T-cell therapy (CAR-T), was invented to overcome the limitation of traditional treatments. Patients with aggressive B-NHL are considered for CAR-T cell therapy when they have progressive lymphoma after second-line chemotherapy, relapse after ASCT, or require a third-line therapy. Clinical trials of anti-CD19 CAR-T cell therapy have manifested encouraging efficacy in refractory or relapsed B-NHL. However, adverse effects of this cellular therapy including cytokine release syndrome, neurotoxicity, tumor lysis syndrome and on-target, off-tumor toxicities should attract our enough attention despite the great anti-tumor effects of CAR-T cell therapy. Although CAR-T cell therapy has shown remarkable results in patients with B-NHL, the outcomes of patients with B-NHL were inferior to patients with acute lymphoblastic leukemia. The inferior response rate may be associated with physical barrier of lymphoma, tumor microenvironment and low quality of CAR-T cells manufactured from B-NHL patients. Besides, some patients relapsed after anti-CD19 CAR-T cell therapy, which possibly were due to limited CAR-T cells persistence, CD19 antigen escape or antigen down-regulation. Quite a few new antigen-targeted CAR-T products and new-generation CAR-T, for example, CD20-targeted CAR-T, CD79b-targeted CAR-T, CD37-targeted CAR-T, multi-antigen-targeted CAR-T, armored CAR-T and four-generation CAR-T are developing rapidly to figure out these deficiencies.

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“…Other suicide switches include inducible caspase-9, which could be dimerized to activate the downstream intracellular apoptotic signaling, thereby eliminating the CAR-T cells ( 74 ). The inhibitory chimeric antigen receptors contain a PD-1 or CTLA-4 based inhibitory domain, which could shield the normal cells from being killed by specific CAR-T cells, to overcome the on target, off tumor toxicities ( 75 ). We believe that the immunosuppression of TME could be overcome with gene editing tools and combined therapies that could protect the CAR-T (CAR-NK or TCR-T) cells from inhibition of TME ( 76 ).…”

Section: Concluding Remarks and Outlookmentioning

confidence: 99%

Genetically Modified T Cells for Esophageal Cancer Therapy: A Promising Clinical Application

et al. 2021

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Esophageal cancer is an exceedingly aggressive and malignant cancer that imposes a substantial burden on patients and their families. It is usually treated with surgery, chemotherapy, radiotherapy, and molecular-targeted therapy. Immunotherapy is a novel treatment modality for esophageal cancer wherein genetically engineered adoptive cell therapy is utilized, which modifies immune cells to attack cancer cells. Using chimeric antigen receptor (CAR) or T cell receptor (TCR) modified T cells yielded demonstrably encouraging efficacy in patients. CAR-T cell therapy has shown robust clinical results for malignant hematological diseases, particularly in B cell-derived malignancies. Natural killer (NK) cells could serve as another reliable and safe CAR engineering platform, and CAR-NK cell therapy could be a more generalized approach for cancer immunotherapy because NK cells are histocompatibility-independent. TCR-T cells can detect a broad range of targeted antigens within subcellular compartments and hold great potential for use in cancer therapy. Numerous studies have been conducted to evaluate the efficacy and feasibility of CAR and TCR based adoptive cell therapies (ACT). A comprehensive understanding of genetically-modified T cell technologies can facilitate the clinical translation of these adoptive cell-based immunotherapies. Here, we systematically review the state-of-the-art knowledge on genetically-modified T-cell therapy and provide a summary of preclinical and clinical trials of CAR and TCR-transgenic ACT.

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CD19-CAR-T Cells Bearing a KIR/PD-1-Based Inhibitory CAR Eradicate CD19+HLA-C1− Malignant B Cells While Sparing CD19+HLA-C1+ Healthy B Cells

Cited by 26 publications

References 51 publications

Implementing Logic Gates for Safer Immunotherapy of Cancer

Implementing Logic Gates for Safer Immunotherapy of Cancer

Advances in chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma

Genetically Modified T Cells for Esophageal Cancer Therapy: A Promising Clinical Application

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