Adoptive Immunotherapy for Epithelial Ovarian Cancer Using T Cells Simultaneously Targeted to Tumor and Tumor-Associated Macrophages
Abstract
Adoptive T-cell immunotherapy represents an exciting advance, pioneered for hematologic malignancies and metastatic melanoma. To translate this technology to epithelial ovarian carcinoma (EOC), chimeric antigen receptors (CAR) may be used to re-target T-cell specificity against native tumor antigens. The hypothesis underlying this synergistic partnership award is that CAR-based immunotherapy of EOC will be more effective if simultaneous targeting of tumor cells and tumor-associated macrophages (TAM) is achieved. Initially, we set out to test this hypothesis using T-cells that express CARs with specificity for MUC1 (expressed by tumor cells) and CSF-1R (expressed both by tumor cells and TAM). In-vitro experiments demonstrated some efficacy of this therapeutic strategy. We then used a previously established (EOC-like) tumor model based upon MDA-MB-435 cells, engineered to co-express MUC1 and CSF-1 allowing us test therapeutic efficacy in-vivo. However, no significant therapeutic activity was observed in this model, prompting us to propose a revised statement of work which has been approved. As per revised statement of work, we embarked upon a parallel approach in which tumor-associated ErbB receptors were targeted. To achieve this, a CAR named T1E28z was constructed. T1E28z targets T-cells against several ErbB dimer species that are upregulated in EOC. Liposomal clodronate was used to achieve depletion of TAM. To test efficacy, we developed in-vitro culture models using patient-derived tumor material. We have shown effective tumor cell killing by autologous T1E28z-transduced T-cells of both patient-derived tumor and EOC cell lines (IGROV-1 and SKOV-3). Next, xenograft EOC models were established using SKOV-3 and IGROV-1 tumor cell lines. Using bioluminescence imaging, we have also shown efficacy of T1E28z+ T-cells in controlling established SKOV-3 tumors in SCID Beige mice. Highly efficient depletion of TAM has been achieved using liposomal clodronate but did not infl
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2011
- Accession Number
- ADA549851
Entities
People
- John Maher
Organizations
- King's College London