Safety, Tolerability and Efficacy of Enhanced IL-13Rα2 Targeted Chimeric Antigen Receptor T Cell Immunotherapy Against Recurrent/Refractory Grade 4 Glioma

This is a dose exploration clinical trial to assess the safety and feasibility of the IL13Ra2-targeted CAR-T in glioma.

开始日期2024-03-21

申办/合作机构

北京天坛医院

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100 项与 IL13Rα2 CAR-T(TCR CURE Biopharma) 相关的临床结果

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100 项与 IL13Rα2 CAR-T(TCR CURE Biopharma) 相关的转化医学

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100 项与 IL13Rα2 CAR-T(TCR CURE Biopharma) 相关的专利（医药）

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项与 IL13Rα2 CAR-T(TCR CURE Biopharma) 相关的文献（医药）

2024-10-03·Neuro-Oncology

IL-13Rα2/TGF-β bispecific CAR-T cells counter TGF-β-mediated immune suppression and potentiate anti-tumor responses in glioblastoma

Article

作者: Guemes, Miriam ; Phyu, Su ; Shih, Ryan M ; Chang, ZeNan L ; Chen, Yvonne Y ; Okada, Hideho ; Breunig, Joshua J ; Uy, Benjamin R ; Prins, Robert M ; Comin-Anduix, Begonya ; Brown, Christine E ; Nathanson, David A ; Shafer, Amanda ; Galic, Zoran ; Grausam, Katie B ; Hou, Andrew J

AbstractBackgroundChimeric antigen receptor (CAR)-T cell therapies targeting glioblastoma (GBM)-associated antigens such as interleukin-13 receptor subunit alpha-2 (IL-13Rα2) have achieved limited clinical efficacy to date, in part due to an immunosuppressive tumor microenvironment (TME) characterized by inhibitory molecules such as transforming growth factor-beta (TGF-β). The aim of this study was to engineer more potent GBM-targeting CAR-T cells by countering TGF-β-mediated immune suppression in the TME.MethodsWe engineered a single-chain, bispecific CAR targeting IL-13Rα2 and TGF-β, which programs tumor-specific T cells to convert TGF-β from an immunosuppressant to an immunostimulant. Bispecific IL-13Rα2/TGF-β CAR-T cells were evaluated for efficacy and safety against both patient-derived GBM xenografts and syngeneic models of murine glioma.ResultsTreatment with IL-13Rα2/TGF-β CAR-T cells leads to greater T-cell infiltration and reduced suppressive myeloid cell presence in the tumor-bearing brain compared to treatment with conventional IL-13Rα2 CAR-T cells, resulting in improved survival in both patient-derived GBM xenografts and syngeneic models of murine glioma.ConclusionsOur findings demonstrate that by reprogramming tumor-specific T-cell responses to TGF-β, bispecific IL-13Rα2/TGF-β CAR-T cells resist and remodel the immunosuppressive TME to drive potent anti-tumor responses in GBM.

2018-12-01·Molecular Therapy - Oncolytics2区 · 医学

Checkpoint Blockade Reverses Anergy in IL-13Rα2 Humanized scFv-Based CAR T Cells to Treat Murine and Canine Gliomas

2区 · 医学

ArticleOA

作者: Zhang, Logan ; Reid, Reiss A ; O'Rourke, Donald M ; Panjwani, M Kazim ; Konradt, Christoph ; Rodriguez, Jesse L ; Posey, Avery D ; Mason, Nicola J ; June, Carl H ; Xu, Chong ; Jiang, Shuguang ; Blouch, Kristin ; Johnson, Laura A ; Thokala, Radhika ; Migliorini, Denis ; Cook, Danielle R ; Dahmane, Nadia ; Binder, Zev A ; McGettigan-Croce, Bevin ; Boesteanu, Alina C ; Yin, Yibo ; Lin, Zhiguo ; Cogdill, Alexandria P

We generated two humanized interleukin-13 receptor α2 (IL-13Rα2) chimeric antigen receptors (CARs), Hu07BBz and Hu08BBz, that recognized human IL-13Rα2, but not IL-13Rα1. Hu08BBz also recognized canine IL-13Rα2. Both of these CAR T cell constructs demonstrated superior tumor inhibitory effects in a subcutaneous xenograft model of human glioma compared with a humanized EGFRvIII CAR T construct used in a recent phase 1 clinical trial (ClinicalTrials.gov: NCT02209376). The Hu08BBz demonstrated a 75% reduction in orthotopic tumor growth using low-dose CAR T cell infusion. Using combination therapy with immune checkpoint blockade, humanized IL-13Rα2 CAR T cells performed significantly better when combined with CTLA-4 blockade, and humanized EGFRvIII CAR T cells' efficacy was improved by PD-1 and TIM-3 blockade in the same mouse model, which was correlated with the levels of checkpoint molecule expression in co-cultures with the same tumor in vitro. Humanized IL-13Rα2 CAR T cells also demonstrated benefit from a self-secreted anti-CTLA-4 minibody in the same mouse model. In addition to a canine glioma cell line (J3T), canine osteosarcoma lung cancer and leukemia cell lines also express IL-13Rα2 and were recognized by Hu08BBz. Canine IL-13Rα2 CAR T cell was also generated and tested in vitro by co-culture with canine tumor cells and in vivo in an orthotopic model of canine glioma. Based on these results, we are designing a pre-clinical trial to evaluate the safety of canine IL-13Rα2 CAR T cells in dog with spontaneous IL-13Rα2-positive glioma, which will help to inform a human clinical trial design for glioblastoma using humanized scFv-based IL-13Rα2 targeting CAR T cells.

100 项与 IL13Rα2 CAR-T(TCR CURE Biopharma) 相关的药物交易

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