An IL-4/21 Inverted Cytokine Receptor Improving CAR-T Cell Potency in Immunosuppressive Solid-Tumor Microenvironment

Wang, Yi; Jiang, Hua; Luo, Hong; Sun, Yu; Shi, Bizhi; Sun, Ruixin; Li, Zonghai

doi:10.3389/fimmu.2019.01691

Cited by 78 publications

(65 citation statements)

References 30 publications

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“…For instance, our recent study demonstrated that IL12 armored GPC3redirected CAR T cells could greatly improve the antitumor activities in mouse model even with large tumor burdens (41). We also showed that introducing an IL4/21 inverted cytokine receptor into the CAR-GPC3 construct improved the CAR T-cell potency in vitro and in vivo (37). In another recent study, our group disrupted PD-1 gene expression in CAR-GPC3 T cells using the CRISPR/Cas9 gene-editing system.…”

Section: Discussionmentioning

confidence: 86%

“…Indeed, anti-GPC3 mAbs had good safety profiles in previous studies (34,35), although significant clinical benefit has yet to be established in phase II clinical trials. Recently, we demonstrated that GPC3targeted CAR T cells could eliminate GPC3 þ HCC cells in vitro and eradicate GPC3 þ HCC tumor xenografts in mice (36)(37)(38). Therefore, in the present prospective phase I studies, we explored the safety and potential efficacy of CAR-GPC3 T-cell therapy in adult Chinese patients with advanced GPC3 þ HCC.…”

Section: Introductionmentioning

confidence: 96%

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Chimeric Antigen Receptor-Glypican-3 T-Cell Therapy for Advanced Hepatocellular Carcinoma: Results of Phase I Trials

Shi

Kaseb

et al. 2020

Clinical Cancer Research

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226

156

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Purpose: Our preclinical studies demonstrated the potential of chimeric antigen receptor (CAR)-glypican-3 (GPC3) T-cell therapy for hepatocellular carcinoma (HCC). We report herein the first published results of CAR-GPC3 T-cell therapy for HCC. Patients and Methods: In two prospective phase I studies, adult patients with advanced GPC3 þ HCC (Child-Pugh A) received autologous CAR-GPC3 T-cell therapy following cyclophosphamide-and fludarabine-induced lymphodepletion. The primary objective was to assess the treatment's safety. Adverse events were graded using the Common Terminology Criteria for Adverse Events (version 4.03). Tumor responses were evaluated using the RECIST (version 1.1). Results: A total of 13 patients received a median of 19.9 Â 10 8 CAR-GPC3 T cells by a data cutoff date of July 24, 2019. We observed pyrexia, decreased lymphocyte count, and cytokine release syndrome (CRS) in 13, 12, and nine patients, respectively. CRS (grade 1/2) was reversible in eight patients. One patient experienced grade 5 CRS. No patients had grade 3/4 neurotoxicity. The overall survival rates at 3 years, 1 year, and 6 months were 10.5%, 42.0%, and 50.3%, respectively, according to the Kaplan-Meier method. We confirmed two partial responses. One patient with sustained stable disease was alive after 44.2 months. CAR T-cell expansion tended to be positively associated with tumor response. Conclusions: This report demonstrated the initial safety profile of CAR-GPC3 T-cell therapy. We observed early signs of antitumor activity of CAR-GPC3 T cells in patients with advanced HCC.

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Section: Discussionmentioning

confidence: 86%

Section: Introductionmentioning

confidence: 96%

Chimeric Antigen Receptor-Glypican-3 T-Cell Therapy for Advanced Hepatocellular Carcinoma: Results of Phase I Trials

Shi

Kaseb

et al. 2020

Clinical Cancer Research

Self Cite

226

156

View full text Add to dashboard Cite

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“…In line with this, a novel anti-CD19 CAR-T cells with constitutive activation of STAT3 showed increased proliferation and reduced terminal differentiation of CAR-T cells, and conferred superior anti-tumor effects [ 174 ]. Similarly, CAR-T cells expressing the ectodomain of the IL-4 receptor and the end domain of the IL-21 receptor activated the STAT3 pathway and enhanced Th17-like polarization, representing a potential clinical CAR-T therapy for solid tumors enriching IL-4 [ 175 ]. These studies suggest a beneficial effect of STAT3 activation in CAR-T cells.…”

Section: Integrating Stat3 In Combination Cancer Immunotherapymentioning

confidence: 99%

Targeting STAT3 in Cancer Immunotherapy

et al. 2020

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As a point of convergence for numerous oncogenic signaling pathways, signal transducer and activator of transcription 3 (STAT3) is central in regulating the anti-tumor immune response. STAT3 is broadly hyperactivated both in cancer and non-cancerous cells within the tumor ecosystem and plays important roles in inhibiting the expression of crucial immune activation regulators and promoting the production of immunosuppressive factors. Therefore, targeting the STAT3 signaling pathway has emerged as a promising therapeutic strategy for numerous cancers. In this review, we outline the importance of STAT3 signaling pathway in tumorigenesis and its immune regulation, and highlight the current status for the development of STAT3-targeting therapeutic approaches. We also summarize and discuss recent advances in STAT3-based combination immunotherapy in detail. These endeavors provide new insights into the translational application of STAT3 in cancer and may contribute to the promotion of more effective treatments toward malignancies.

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“…They showed that, upon binding of IL-4, 4/21 ICR not only activates the STAT3 pathway and polarizes engineered T cells into Th17-like cells but also promotes antitumor cytotoxicity in vitro. Moreover, 4/21 ICR CAR T cells could persist and eradicate IL-4-expressing tumors in vivo (47).…”

Section: Manipulating Car T Cells To Express Cytokines and Their Recementioning

confidence: 99%

Prolonged Persistence of Chimeric Antigen Receptor (CAR) T Cell in Adoptive Cancer Immunotherapy: Challenges and Ways Forward

et al. 2020

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CAR T cell qualities, such as persistence and functionality play important roles in determining the outcome of cancer immunotherapy. In spite of full functionality, it has been shown that poor persistence of CAR T cells can limit an effective antitumor immune response. Here, we outline specific strategies that can be employed to overcome intrinsic and extrinsic barriers to CAR T cell persistence. We also offer our viewpoint on how growing use of CAR T cells in various cancers may require modifications in the intrinsic and extrinsic survival signals of CAR T cells. We anticipate these amendments will additionally provide the rationales for generation of more persistent, and thereby, more effective CAR T cell treatments. CAR T cell qualities, such as persistence and functionality play important roles in determining the outcome of cancer immunotherapy. In spite of full functionality, it has been shown that poor persistence of CAR T cells can limit an effective antitumor immune response. Here, we outline specific strategies that can be employed to overcome intrinsic and extrinsic barriers to CAR T cell persistence. We also offer our viewpoint on how growing use of CAR T cells in various cancers may require modifications in the intrinsic and extrinsic survival signals of CAR T cells. We anticipate these amendments will additionally provide the rationales for generation of more persistent, and thereby, more effective CAR T cell treatments.

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An IL-4/21 Inverted Cytokine Receptor Improving CAR-T Cell Potency in Immunosuppressive Solid-Tumor Microenvironment

Cited by 78 publications

References 30 publications

Chimeric Antigen Receptor-Glypican-3 T-Cell Therapy for Advanced Hepatocellular Carcinoma: Results of Phase I Trials

Chimeric Antigen Receptor-Glypican-3 T-Cell Therapy for Advanced Hepatocellular Carcinoma: Results of Phase I Trials

Targeting STAT3 in Cancer Immunotherapy

Prolonged Persistence of Chimeric Antigen Receptor (CAR) T Cell in Adoptive Cancer Immunotherapy: Challenges and Ways Forward

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