TGF-β inhibition via CRISPR promotes the long-term efficacy of CAR T cells against solid tumors

Tang, Na; Cheng, Chen; Zhang, Xingying; Qiao, Miaomiao; Li, Na; Mu, Wei; Wei, Xiaofei; Han, Weidong; Wang, Haoyi

doi:10.1172/jci.insight.133977

Cited by 261 publications

(192 citation statements)

References 43 publications

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“…Immunosuppressive TME of solid tumors is one of the main causes. Attempts to overcome this limitation, including expressing heparinase to degrade the extracellular matrix (ECM), 29 knocking out transforming growth factor-β (TGFβ) receptors, 22 or expressing dominant-negative TGFβ receptors 30 to resist TGFβ-rich environment, using CAR-Target fibroblast activation protein (FAP) antigen to deplete fibroblast cells, 31 or engineering CAR-T cells lacking immune checkpoint genes, [32][33][34][35] have shown promise in animal models.…”

Section: Discussionmentioning

confidence: 99%

“…To generate CAR-T cells recognizing mesothelin antigens, we constructed a CAR composed of a fully human scFv (P4) recognizing mesothelin along with CD28 and CD3ζ signaling domain (P4 CAR). 21,22 To confirm the specificity of P4 CAR-T cells, we examined the ability of P4 CAR-T cells to lyse CRL5826 (human lung cancer expressing mesothelin) [ . These results confirmed that CADO could inhibit the tumor cell killing capacity and the cytokine release of CAR-T cells.…”

Section: Adenosine Suppressed the Cytolysis Ability And Cytokine Prodmentioning

confidence: 99%

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Improving the anti-solid tumor efficacy of CAR-T cells by inhibiting adenosine signaling pathway

Tang

Cheng

et al. 2020

OncoImmunology

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Chimeric antigen receptor T (CAR-T) cell therapy has been applied successfully in treating hematologic malignancies; however, it shows very limited efficacy in treating solid tumors. Adenosine is one of the key immunosuppressive metabolites in tumor microenvironment (TME) of solid tumors. Although the effect of adenosine has been well studied using mouse CART cells, its effect on human CART cells has not been fully elucidated. In particular, there was no evaluation of the CART cells with blocked adenosine signaling in tumor xenograft animal model, which is essential for determining the feasibility of future clinical trials. In this study, we found the expression of A2a receptor (A2AR) and A2b receptor (A2BR) both upregulated in human-derived CART cells, and only A2AR was responsible for adenosine-induced impairment of CART cell function. Disrupting A2AR gene in human CART cells with CRISPR-Cas9 increased the anti-tumor function and prevented the exhaustion of CART cells in vitro. Furthermore, CRL5826-CDX model and two patient-derived xenograft solid tumor models were applied to evaluate the efficacy of A2AR knockout CART cells, which showed superior capability of inhibiting tumor growth. Taken together, these results demonstrate that A2AR knockout CART cells have the potential of being an improved CART cell therapy in treating solid tumors.

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Section: Discussionmentioning

confidence: 99%

Section: Adenosine Suppressed the Cytolysis Ability And Cytokine Prodmentioning

confidence: 99%

Improving the anti-solid tumor efficacy of CAR-T cells by inhibiting adenosine signaling pathway

Tang

Cheng

et al. 2020

OncoImmunology

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“…The receptor most commonly upregulated in tumor cells is TGF-β1, which negatively regulates CAR T-cell cytotoxic function via TGF-β receptors. With an attempt to enhance CAR T cells using CRISPR/Cas9, Tang et al managed to knock down TGFBR2 and to improve the in vivo CAR T cells in an animal model (65).…”

Section: (Iv) Transformation Of Growth Factor Beta Receptor 2 (Tgfbr2mentioning

confidence: 99%

“…TGF-β favors the conversion of CD4 + effector T cells into CD4 + Tregs and blocks the secretion of cytotoxic molecules and cytokines in CD8 + T cells. In CAR T cells, the presence of TGF-β1 accelerates the exhaustion of CAR T cells by upregulating the PD1-and FOXP3-dependent Treg-like phenotype of CAR T cells (65). TGFBR2 knockout enhances the antitumor efficacy of CAR T cells in vivo in cell line-derived xenograft and patient tumor-derived xenograft (PDX) mesothelin pancreatic carcinoma.…”

Section: Expansion Persistence and Potency Of Car T Cellsmentioning

confidence: 99%

“…TGFBR2 knockout enhances the antitumor efficacy of CAR T cells in vivo in cell line-derived xenograft and patient tumor-derived xenograft (PDX) mesothelin pancreatic carcinoma. After the PDX tumor was eliminated by TGFBR2-KO CAR T cells, the treated mice were re-challenged with novel contralaterally reinoculated patient-derived tumor cells, showing a persistence and antitumor properties (65). The adenosine A2A receptor, also known as ADORA2A, plays a regulatory role in the adaptive immune system.…”

Section: Expansion Persistence and Potency Of Car T Cellsmentioning

confidence: 99%

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Using Gene Editing Approaches to Fine-Tune the Immune System

et al. 2020

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Genome editing technologies not only provide unprecedented opportunities to study basic cellular system functionality but also improve the outcomes of several clinical applications. In this review, we analyze various gene editing techniques used to finetune immune systems from a basic research and clinical perspective. We discuss recent advances in the development of programmable nucleases, such as zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and clustered regularly interspaced short palindromic repeat (CRISPR)-Cas-associated nucleases. We also discuss the use of programmable nucleases and their derivative reagents such as base editing tools to engineer immune cells via gene disruption, insertion, and rewriting of T cells and other immune components, such natural killers (NKs) and hematopoietic stem and progenitor cells (HSPCs). In addition, with regard to chimeric antigen receptors (CARs), we describe how different gene editing tools enable healthy donor cells to be used in CAR T therapy instead of autologous cells without risking graft-versus-host disease or rejection, leading to reduced adoptive cell therapy costs and instant treatment availability for patients. We pay particular attention to the delivery of therapeutic transgenes, such as CARs, to endogenous loci which prevents collateral damage and increases therapeutic effectiveness. Finally, we review creative innovations, including immune system repurposing, that facilitate safe and efficient genome surgery within the framework of clinical cancer immunotherapies.

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Strengthening the CAR‐T cell therapeutic application using CRISPR/Cas9 technology

Nezhad

Yazdanifar

Abdollahpour‐Alitappeh

et al. 2021

Biotech & Bioengineering

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Adoptive cell immunotherapy with chimeric antigen receptor T (CAR‐T) cell has brought a revolutionary means of treatment for aggressive diseases such as hematologic malignancies and solid tumors. Over the last decade, the United States Food and Drug Administration (FDA) approved five types of CAR‐T cell therapies for hematologic malignancies, including Idecabtagene vicleucel (Abecma), Lisocabtagene maraleucel (Breyanzi), Brexucabtagene autoleucel (Tecartus), Tisagenlecleucel (Kymriah), and Axicabtagene ciloleucel (Yescarta). Despite outstanding results gained from different clinical trials, CAR‐T cell therapy is not free from side effects and toxicities, and needs careful investigations and improvements. Gene‐editing technology, clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR‐associated protein 9 (Cas9) system, has emerged as a promising tool to address some of the CAR‐T therapy hurdles. Using CRISPR/Cas9 technology, CAR expression as well as other cellular pathways can be modified in various ways to enhance CAR‐T cells antitumor function and persistence in immunosuppressive tumor microenvironment. CRISPR/Cas9 technology can also be used to decrease CAR‐T cell toxicities and side effects. Hereby, we discussed the practical challenges and hurdles related to the accuracy, efficiency, efficacy, safety, and delivery of CRISPR/Cas9 technology to the genetically engineered‐T cells. Combining of these two state‐of‐the‐art technologies, CRISPR/Cas9 and CAR‐T cells, the field of oncology has an extraordinary opportunity to enter a new era of immunotherapy, which offers novel therapeutic options for different types of tumors.

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TGF-β inhibition via CRISPR promotes the long-term efficacy of CAR T cells against solid tumors

Cited by 261 publications

References 43 publications

Improving the anti-solid tumor efficacy of CAR-T cells by inhibiting adenosine signaling pathway

Improving the anti-solid tumor efficacy of CAR-T cells by inhibiting adenosine signaling pathway

Using Gene Editing Approaches to Fine-Tune the Immune System

Strengthening the CAR‐T cell therapeutic application using CRISPR/Cas9 technology

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