title: Synergistic Chemoimmunotherapy of Epithelial Ovarian Cancer Using ErbB-Retargeted T Cells Combined with Carboplatin.
abstract: Epithelial ovarian cancer (EOC) remains the most lethal gynecologic malignancy, underscoring the need for better therapies. Adoptive immunotherapy using genetically targeted T cells represents a promising new treatment for hematologic malignancies. However, solid tumors impose additional obstacles, including the lack of suitable targets for safe systemic therapy and the need to achieve effective T cell homing to sites of disease. Because EOC undergoes transcœlomic metastasis, both of these challenges may be circumvented by T cell administration to the peritoneal cavity. In this study, we describe such an immunotherapeutic approach for EOC, in which human T cells were targeted against the extended ErbB family, using a chimeric Ag receptor named T1E28z. T1E28z was coexpressed with a chimeric cytokine receptor named 4αβ (combination termed T4), enabling the selective ex vivo expansion of engineered T cells using IL-4. Unlike control T cells, T4(+) T cells from healthy donors and patients with EOC were activated by and destroyed ErbB(+) EOC tumor cell lines and autologous tumor cultures. In vivo antitumor activity was demonstrated in mice bearing established luciferase-expressing SKOV-3 EOC xenografts. Tumor regression was accompanied by mild toxicity, manifested by weight loss. Although efficacy was transient, therapeutic response could be prolonged by repeated T cell administration. Furthermore, prior treatment with noncytotoxic doses of carboplatin sensitized SKOV-3 tumors to T4 immunotherapy, promoting enhanced disease regression using lower doses of T4(+) T cells. By combining these approaches, we demonstrate that repeated administration of carboplatin followed by T4(+) T cells achieved optimum therapeutic benefit in the absence of significant toxicity, even in mice with advanced tumor burdens.
authors.affiliation: Department of Research Oncology, King's College London, King's Health Partners Integrated Cancer Centre, Guy's Hospital Campus, London SE1 9RT, United Kingdom.
authors.forename: Ana C
authors.initials: AC
authors.lastname: Parente-Pereira
authors.forename: Lynsey M
authors.initials: LM
authors.lastname: Whilding
authors.forename: Nancy
authors.initials: N
authors.lastname: Brewig
authors.forename: Sjoukje J C
authors.initials: SJ
authors.lastname: van der Stegen
authors.forename: David M
authors.initials: DM
authors.lastname: Davies
authors.forename: Scott
authors.initials: S
authors.lastname: Wilkie
authors.forename: May C I
authors.initials: MC
authors.lastname: van Schalkwyk
authors.forename: Sadaf
authors.initials: S
authors.lastname: Ghaem-Maghami
authors.forename: John
authors.initials: J
authors.lastname: Maher
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D016190:Carboplatin / Q000008:administration & dosage*; D000077216:Carcinoma, Ovarian Epithelial; D003131:Combined Modality Therapy; D004358:Drug Therapy / Q000379:methods; D066246:ErbB Receptors / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D051379:Mice; D009375:Neoplasms, Glandular and Epithelial / Q000628:therapy*; D010051:Ovarian Neoplasms / Q000628:therapy*; D011993:Recombinant Fusion Proteins / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D014161:Transduction, Genetic; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D011993:Recombinant Fusion Proteins; D016190:Carboplatin; D066246:ErbB Receptors