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CAR T Cells Targeting B7-H3, a Pan-Cancer Antigen, Demonstrate Potent Preclinical Activity Against Pediatric Solid
Robbie G Majzner1, Johanna L Theruvath1, Anandani Nellan2
1Department of Pediatrics, Stanford University School of Medicine, Palo Alto, California.
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 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.
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.
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.
Insights
Chimeric antigen receptor (CAR) T-cell therapy targeting B7-H3 shows promise for pediatric solid tumors. This approach demonstrated significant tumor regression in preclinical models, offering a potential new treatment for difficult-to-treat childhood cancers.
Area of Science:
- Oncology
- Immunotherapy
- Pediatric Cancer Research
Background:
- Relapsed pediatric solid tumors and CNS malignancies have limited treatment options.
- Chimeric antigen receptor (CAR) T-cell therapy is successful in pediatric acute lymphoblastic leukemia but not yet solid tumors.
- Targeting solid tumors is challenging due to a lack of suitable cell surface molecules.
Purpose of the Study:
- To identify and evaluate B7-H3 (CD276) as a potential target for CAR T-cell therapy in pediatric solid tumors.
- To develop and test novel B7-H3 CAR T cells in preclinical pediatric cancer models.
Main Methods:
- Developed a novel B7-H3 CAR using a binder from a mAb with prior human safety data.
- Tested B7-H3 CAR T cells in various pediatric cancer xenograft models.
- Assessed CAR T-cell efficacy based on B7-H3 surface antigen expression levels.
Main Results:
- B7-H3 CAR T cells demonstrated significant in vivo antitumor activity.
- Established solid tumors, including osteosarcoma, medulloblastoma, and Ewing sarcoma, showed regression in xenograft models.
- Efficacy correlated with high B7-H3 surface antigen density, suggesting a therapeutic window despite low-level normal tissue expression.
Conclusions:
- B7-H3 CAR T cells represent a promising therapeutic strategy for specific relapsed or refractory pediatric malignancies.
- Further investigation in carefully designed clinical trials is warranted.
- This approach could offer a new option for children with lethal solid tumors.
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