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.
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 language | English |
|---|---|
| Article number | N/A |
| Pages (from-to) | 2437-2445 |
| Number of pages | 8 |
| Journal | Journal of Immunology |
| Volume | 191 |
| Issue number | 5 |
| Early online date | 29 Jul 2013 |
| DOIs | |
| Publication status | Published - Sept 2013 |
