期刊
MOLECULAR THERAPY-ONCOLYTICS
卷 11, 期 -, 页码 20-38出版社
CELL PRESS
DOI: 10.1016/j.omto.2018.08.002
关键词
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资金
- NIH [DP2CA174502]
- Heilongjiang Province Program for Application Technology Research and Development [GA15C108]
- Ministry of Science and Technology of the People's Republic of China [2014DFA31630]
- National Natural Science Foundation of China [8177101833, 81571646]
- Maria and Gabriele Troiano Brain Cancer Immunotherapy Fund
- Templeton Family Initiative in Neuro-Oncology
- Penn Center for Precision Medicine Accelerator Fund
- Graduate Innovative Research Program of Harbin Medical University [YJSCX2015-20HYD]
- Parker Institute for Cancer Immunotherapy
- Tmunity Therapeutics
- University of Pennsylvania Cancer Immunotherapy Program
We generated two humanized interleukin-13 receptor alpha 2 (IL-13R alpha 2) chimeric antigen receptors (CARs), Hu07BBz and Hu08BBz, that recognized human IL-13R alpha 2, but not IL-13R alpha 1. Hu08BBz also recognized canine IL-13R alpha 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 alpha 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 alpha 2 CAR T cells also demonstrated benefit from a self-secreted antiCTLA-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 alpha 2 and were recognized by Hu08BBz. Canine IL-13R alpha 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 alpha 2 CAR T cells in dog with spontaneous IL-13R alpha 2-positive glioma, which will help to inform a human clinical trial design for glioblastoma using humanized scFv-based IL-13R alpha 2 targeting CAR T cells.
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