Chimeric Antigen Receptor T Cell with an Inducible Caspase-9 Suicide Gene Eradicates Uveal Melanoma Liver Metastases via B7-H3 Targeting.
Clin Cancer Res
; 30(15): 3243-3258, 2024 Aug 01.
Article
in En
| MEDLINE
| ID: mdl-38767611
ABSTRACT
PURPOSE:
Uveal melanoma (UM) is the most common intraocular malignant tumor. Despite successful treatment of the primary tumor, about 50% of patients will recur with systemic diseases for which there are no effective treatment strategies. Here we investigated the preclinical efficacy of a chimeric antigen receptor (CAR) T-cell-based immunotherapy targeting B7-H3. EXPERIMENTALDESIGN:
B7-H3 expression on primary and metastatic human UM samples and cell lines was assessed by RNA sequencing, flow cytometry, and immunohistochemistry. Antitumor activity of CAR T cells targeting B7-H3 was tested in vitro with UM cell lines, patient-derived organotypic tumor spheroids from patients with metastatic UM, and in immunodeficient and humanized murine models.RESULTS:
B7-H3 is expressed at high levels in >95% UM tumor cells in vitro and in vivo. We generated a B7-H3 CAR with an inducible caspase-9 (iCas9) suicide gene controlled by the chemical inducer of dimerization AP1903, which effectively kills UM cells in vitro and eradicates UM liver metastases in murine models. Delivery of iCas9.B7-H3 CAR T cells in experimental models of UM liver metastases demonstrates a durable antitumor response, even upon tumor rechallenge or in the presence of a significant metastatic disease burden. We demonstrate effective iCas9.B7-H3 CAR T-cell elimination in vitro and in vivo in response to AP1903. Our studies demonstrate more effective tumor suppression with iCas9.B7-H3 CAR T cells as compared to a B7-H3-targeted humanized monoclonal antibody.CONCLUSIONS:
These studies support a phase I clinical trial with iCas9.B7-H3 CAR T cells to treat patients with metastatic UM.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Uveal Neoplasms
/
Immunotherapy, Adoptive
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Xenograft Model Antitumor Assays
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Genes, Transgenic, Suicide
/
Caspase 9
/
B7 Antigens
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Receptors, Chimeric Antigen
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Liver Neoplasms
/
Melanoma
Limits:
Animals
/
Humans
Language:
En
Journal:
Clin Cancer Res
Journal subject:
NEOPLASIAS
Year:
2024
Document type:
Article
Country of publication:
United States