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CAR T Cells Targeting B7-H3, a Pan-Cancer Antigen, Demonstrate Potent Preclinical Activity Against Pediatric Solid Tumors and Brain Tumors.
- Source :
-
Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2019 Apr 15; Vol. 25 (8), pp. 2560-2574. Date of Electronic Publication: 2019 Jan 17. - Publication Year :
- 2019
-
Abstract
- 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.<br />Experimental Design: We 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.<br />Results: B7-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.<br />Conclusions: B7-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.<br /> (©2019 American Association for Cancer Research.)
- Subjects :
- Animals
B7 Antigens antagonists & inhibitors
Brain Neoplasms pathology
Brain Neoplasms therapy
Cell Line, Tumor
Disease Models, Animal
Humans
Immunohistochemistry
Mice
Receptors, Antigen, T-Cell genetics
Receptors, Antigen, T-Cell metabolism
Treatment Outcome
Xenograft Model Antitumor Assays
Antigens, Neoplasm immunology
B7 Antigens immunology
Brain Neoplasms etiology
Brain Neoplasms metabolism
Immunotherapy, Adoptive methods
Receptors, Chimeric Antigen metabolism
T-Lymphocytes immunology
T-Lymphocytes metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1557-3265
- Volume :
- 25
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Clinical cancer research : an official journal of the American Association for Cancer Research
- Publication Type :
- Academic Journal
- Accession number :
- 30655315
- Full Text :
- https://doi.org/10.1158/1078-0432.CCR-18-0432