• Robbie G Majzner, Johanna L Theruvath, Anandani Nellan, Sabine Heitzeneder, Yongzhi Cui, Christopher W Mount, Skyler P Rietberg, Miles H Linde, Peng Xu, Christopher Rota, Elena Sotillo, Louai Labanieh, Daniel W Lee, Rimas J Orentas, Dimiter S Dimitrov, Zhongyu Zhu, Brad St Croix, Alberto Delaidelli, Alla Sekunova, Ezio Bonvini, Siddhartha S Mitra, Martha M Quezado, Ravindra Majeti, Michelle Monje, SorensenPoul H BPHBDepartment of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.Department of Molecular Oncology, British Columbia Cancer Agency, Vancouver, British Columbia, Canada., John M Maris, and Crystal L Mackall.
• Department of Pediatrics, Stanford University School of Medicine, Palo Alto, California.
• Clin Cancer Res. 2019 Apr 15; 25 (8): 2560-2574.

PurposePatients with relapsed pediatric solid tumors and CNS malignancies have few therapeutic options and frequently die of their disease. Chimeric antigen receptor (CAR) T cells have shown tremendous success in treating relapsed pediatric acute lymphoblastic leukemia, but this has not yet translated to treating solid tumors. This is partially due to a paucity of differentially expressed cell surface molecules on solid tumors that can be safely targeted. Here, we present B7-H3 (CD276) as a putative target for CAR T-cell therapy of pediatric solid tumors, including those arising in the central nervous system.Experimental DesignWe developed a novel B7-H3 CAR whose binder is derived from a mAb that has been shown to preferentially bind tumor tissues and has been safely used in humans in early-phase clinical trials. We tested B7-H3 CAR T cells in a variety of pediatric cancer models.ResultsB7-H3 CAR T cells mediate significant antitumor activity in vivo, causing regression of established solid tumors in xenograft models including osteosarcoma, medulloblastoma, and Ewing sarcoma. We demonstrate that B7-H3 CAR T-cell efficacy is largely dependent upon high surface target antigen density on tumor tissues and that activity is greatly diminished against target cells that express low levels of antigen, thus providing a possible therapeutic window despite low-level normal tissue expression of B7-H3.ConclusionsB7-H3 CAR T cells could represent an exciting therapeutic option for patients with certain lethal relapsed or refractory pediatric malignancies, and should be tested in carefully designed clinical trials.©2019 American Association for Cancer Research.

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