Checkpoint Blockade Reverses Anergy in IL-13Ra2 Humanized scFv-Based CAR T Cells to Treat Murine and Canine Gliomas.
This type of treatment worked miracles in other types of cancer. The first attempt in human glioblastoma wasn't spectacular but these researchers may have found a way to make it work at least in dogs and rats. Lets hope it translates to people!
Posted on: 10/12/2018
Mol Ther Oncolytics. 2018 Aug 28;11:20-38. doi: 10.1016/j.omto.2018.08.002. eCollection 2018 Dec 21.
Checkpoint Blockade Reverses Anergy in IL-13Rα2 Humanized scFv-Based CAR T Cells to Treat Murine and Canine Gliomas.
Yin Y1,2,3, Boesteanu AC2, Binder ZA3, Xu C2,4, Reid RA2, Rodriguez JL2, Cook DR2, Thokala R2,3, Blouch K2, McGettigan-Croce B2, Zhang L3, Konradt C5, Cogdill AP2, Panjwani MK6,4, Jiang S2, Migliorini D2,4, Dahmane N7, Posey AD Jr2,4, June CH2,8,4, Mason NJ6,5,4, Lin Z1, O'Rourke DM3, Johnson LA2,8.
1. The Fourth Section of Department of Neurosurgery, The First Affiliated Hospital, Harbin Medical University, Harbin 150001, China.
2. Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
3. Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
4. Parker Institute for Cancer Immunotherapy, Philadelphia, PA 19104, USA.
5. Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
6. Department of Clinical Sciences and Advanced Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
7. Department of Neurological Surgery, Weill Cornell Medicine, New York, NY 10065, USA.
8. Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
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.
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