Synergistic chemo-immunotherapy of epithelial ovarian cancer using ErbB re-targeted T-cells combined with carboplatin.

Ana Parente Pereira, Lynsey Whilding, Nancy Brewig, Sjoukje Van Der Stegen, David M. Davies, Scott Wilkie, May van Schalkwyk, John Maher, Sadaf Ghaem-Maghami

Research output: Contribution to journalArticlepeer-review

46 Citations (Scopus)

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 transcoelomic 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 4ab (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.
Original languageEnglish
Article numberN/A
Pages (from-to)2437-2445
Number of pages8
JournalJournal of Immunology
Volume191
Issue number5
Early online date29 Jul 2013
DOIs
Publication statusPublished - Sept 2013

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