Majzner et al. showed that the immune checkpoint B7-H3 is highly and homogeneously expressed on many pediatric solid tumors (including sarcomas and brain tumors) and generated a CAR construct based on the humanized anti-B7-H3 antibody enoblituzumab. B7-H3 CAR T cells completely eradicated or significantly controlled established tumors in osteosarcoma, Ewing sarcoma, and medulloblastoma xenograft models, including metastases. In vitro and in vivo, CAR T cells killed tumor cells with high, but not low, expression of B7-H3, indicating a therapeutic window of tumor reactivity that might potentially limit toxicity.
PURPOSE: Patients 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 DESIGN: We developed a novel B7-H3 CAR whose binder is derived from a monoclonal antibody 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. RESULTS: B7-H3 CAR T cells mediate significant anti-tumor 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. CONCLUSIONS: B7-H3 CAR T cells could represent an exciting therapeutic option for patients with certain lethal relapsed or refractory pediatric malignancies which should be tested in carefully designed clinical trials.
Author Info: (1) Stanford University School of Medicine. (2) Department of Pediatrics, Stanford University. (3) Pediatrics, University of Colorado Denver. (4) Department of Pediatrics, Stanford
Author Info: (1) Stanford University School of Medicine. (2) Department of Pediatrics, Stanford University. (3) Pediatrics, University of Colorado Denver. (4) Department of Pediatrics, Stanford University School of Medicine. (5) Pediatric Oncology Branch, National Cancer Institute. (6) Department of Neurology, Stanford University School of Medicine. (7) Department of Pediatrics, Stanford University School of Medicine. (8) Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine. (9) Department of Pediatrics, Stanford University School of Medicine. (10) Harvard University. (11) Department of Pediatrics, Stanford University School of Medicine. (12) Department of Bioengineering, Stanford University School of Medicine. (13) Pediatric Hematology/Oncology, University of Virginia. (14) Immunotherapy Integration Hub, Seattle Children's Research Institute. (15) Center for Antibody Therapeutics, University of Pittsburgh. (16) Cancer and Inflammation Program, National Cancer Institute. (17) Center for Cancer Research, National Cancer Institute. (18) Department of Molecular Oncology, British Columbia Cancer Research Centre. (19) Department of Pathology and Laboratory Medicine, British Columbia Cancer Agency. (20) Research, MacroGenics, Inc. (21) Pediatrics, University of Colorado Anschutz Medical Campus. (22) Laboratory of Pathology, National Cancer Institute. (23) Medicine, Stanford University School of Medicine. (24) Stanford University. (25) Department of Molecular Oncology, British Columbia Cancer Research Centre. (26) Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia. (27) Stanford Cancer Institute and Departments of Pediatrics and Medicine, Stanford University cmackall@stanford.edu.
