Dataset Information

Checkpoint Blockade Reverses Anergy in IL-13R?2 Humanized scFv-Based CAR T Cells to Treat Murine and Canine Gliomas.

ABSTRACT: We generated two humanized interleukin-13 receptor ?2 (IL-13R?2) chimeric antigen receptors (CARs), Hu07BBz and Hu08BBz, that recognized human IL-13R?2, but not IL-13R?1. Hu08BBz also recognized canine IL-13R?2. 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-13R?2 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-13R?2 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-13R?2 and were recognized by Hu08BBz. Canine IL-13R?2 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-13R?2 CAR T cells in dog with spontaneous IL-13R?2-positive glioma, which will help to inform a human clinical trial design for glioblastoma using humanized scFv-based IL-13R?2 targeting CAR T cells.

SUBMITTER: Yin Y

PROVIDER: S-EPMC6174845 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Publications

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

Yin Yibo Y Boesteanu Alina C AC Binder Zev A ZA Xu Chong C Reid Reiss A RA Rodriguez Jesse L JL Cook Danielle R DR Thokala Radhika R Blouch Kristin K McGettigan-Croce Bevin B Zhang Logan L Konradt Christoph C Cogdill Alexandria P AP Panjwani M Kazim MK Jiang Shuguang S Migliorini Denis D Dahmane Nadia N Posey Avery D AD June Carl H CH Mason Nicola J NJ Lin Zhiguo Z O'Rourke Donald M DM Johnson Laura A LA

Molecular therapy oncolytics 20180828

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 ...[more]

PMID: 30306125

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Project description:BackgroundOncolytic viruses constitute a growing field of interest, both in human and veterinary oncology, given that they are particularly helpful for treating non-surgical tumors and disseminated cancer, such as high-grade gliomas. Companion dogs present malignant gliomas with biological, genetic, phenotypic, immunological, and clinical similarities to human gliomas. These features favor comparative approaches, leading to the treatment of canine oncological patients to achieve translational applications to the human clinic. The systemic administration of oncolytic viruses presents a challenge due to their limitations in effectively targeting tumors and metastases. Therefore, the aim of this study is to evaluate the safety and antitumor activity of a virotherapy used in spontaneous canine tumors.MethodsTen dogs with high-grade rostrotentorial gliomas underwent weekly systemic endovenous cellular virotherapy with dCelyvir (canine mesenchymal stem cells infected with the canine oncolytic adenovirus ICOCAV17) for 8 weeks. Efficacy was determined in seven dogs according to the Response Assessment in Veterinary Neuro-Oncology criteria considering clinical status and MRI measurements. Medical history, physical and neurological examinations, and vaccination status were evaluated prior to and during follow-up. Safety was evaluated by physical examinations and hematological and biochemical changes in peripheral blood. Immune populations were analyzed by flow cytometry in peripheral blood and by gene expression and immunohistochemistry in the tumor microenvironment.ResultsThe treatment was well tolerated and major adverse effects were not observed. Two dogs had partial responses (76% and 86% reduction in tumor size), and 3/7 showed stable disease. ICOCAV17 was detected in peripheral blood in nine dogs, and a correlation between the ICOCAV17 particles and anti-canine adenovirus (CAV) antibodies was observed. ICOCAV17 was detected in 3/9 tumor tissues after necropsies. Regarding tumor-infiltrating lymphocytes, the dogs with disease stabilization and partial response tended to have reduced memory B-cell infiltration and increased monocyte/macrophage lineage cells.ConclusionsThese findings indicate that dCelyvir is safe and presents efficacy in canine rostrotentorial high-grade gliomas. These data are relevant to the ongoing phase Ib regulated human clinical trial that is administering this virotherapy to children, adolescents, and young adults with diffuse pontine glioma. Celyvir should be further explored as a treatment in veterinary and human neuro-oncology.

Dataset Information

Checkpoint Blockade Reverses Anergy in IL-13R?2 Humanized scFv-Based CAR T Cells to Treat Murine and Canine Gliomas.

Publications

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

Similar Datasets

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