Your browser doesn't support javascript.
loading
Chimeric Antigen Receptor T Cell with an Inducible Caspase-9 Suicide Gene Eradicates Uveal Melanoma Liver Metastases via B7-H3 Targeting.
Ventin, Marco; Cattaneo, Giulia; Arya, Shahrzad; Jia, Jingyu; Gelmi, Maria C; Sun, Yi; Maggs, Luke; Ksander, Bruce R; Verdijk, Robert M; Boland, Genevieve M; Jenkins, Russell W; Haq, Rizwan; Jager, Martine J; Wang, Xinhui; Ryeom, Sandra; Ferrone, Cristina R.
Afiliación
  • Ventin M; Department of Surgery, Division of Gastrointestinal and Surgical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
  • Cattaneo G; Department of Surgery, Division of Gastrointestinal and Surgical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
  • Arya S; Department of Surgery, Division of Gastrointestinal and Surgical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
  • Jia J; Department of Surgery, Division of Gastrointestinal and Surgical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
  • Gelmi MC; Department of Ophthalmology, Leiden University Medical Center, Leiden, the Netherlands.
  • Sun Y; Department of Medicine, Mass General Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
  • Maggs L; Department of Surgery, Division of Gastrointestinal and Surgical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
  • Ksander BR; Department of Ophthalmology, Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, Massachusetts.
  • Verdijk RM; Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands.
  • Boland GM; Department of Pathology, Section Ophtalmic Pathology, Erasmus Medical Center, Rotterdam, the Netherlands.
  • Jenkins RW; Department of Surgery, Division of Gastrointestinal and Surgical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
  • Haq R; Department of Medicine, Mass General Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
  • Jager MJ; Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
  • Wang X; Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
  • Ryeom S; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
  • Ferrone CR; Department of Ophthalmology, Leiden University Medical Center, Leiden, the Netherlands.
Clin Cancer Res ; 30(15): 3243-3258, 2024 Aug 01.
Article en 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. EXPERIMENTAL

DESIGN:

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.
Asunto(s)
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias de la Úvea / Inmunoterapia Adoptiva / Ensayos Antitumor por Modelo de Xenoinjerto / Genes Transgénicos Suicidas / Caspasa 9 / Antígenos B7 / Receptores Quiméricos de Antígenos / Neoplasias Hepáticas / Melanoma Límite: Animals / Humans Idioma: En Revista: Clin Cancer Res Asunto de la revista: NEOPLASIAS Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias de la Úvea / Inmunoterapia Adoptiva / Ensayos Antitumor por Modelo de Xenoinjerto / Genes Transgénicos Suicidas / Caspasa 9 / Antígenos B7 / Receptores Quiméricos de Antígenos / Neoplasias Hepáticas / Melanoma Límite: Animals / Humans Idioma: En Revista: Clin Cancer Res Asunto de la revista: NEOPLASIAS Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos