Funding
National Cancer Institute (NCI)
United States Department of Health and Human Services
Find out more...U.S. Department of Defense (DOD)
Bontius Stichting (Bontius Foundation)
Oogfonds (Eye fund)
Expect Miracles Foundation (EMF)
Universiteit Leiden (Leiden University)
P.A. Jager-van Gelder Fund
Stichting Blinden-Penning (Blind-Penning Foundation)
Dawn K. Neher Fund for Ocular Melanoma Research
Pan-Massachusetts Challenge (PMC)
Massachusetts Life Sciences Center (MLSC)
ARTICLE ABSTRACT
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.
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.
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.
These studies support a phase I clinical trial with iCas9.B7-H3 CAR T cells to treat patients with metastatic UM.
