Adoptive Immunotherapy for Epithelial Ovarian Cancer Using T Cells Simultaneously Targeted to Tumor and Tumor-Associated Macrophages
Abstract
The hypothesis underlying this synergistic partnership award was that immunotherapy of epithelial ovarian carcinoma (EOC) with chimeric antigen receptor (CAR)-expressing T-cells would be potentiated if simultaneous targeting of tumor cells and tumor-associated macrophages (TAM) was achieved. To test this hypothesis, we initially engineered T-cells to 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. To test efficacy in-vivo, we used a previously established (EOC-like) tumor model based upon MDA-MB-435 cells, engineered to co-express MUC1 and CSF- 1R. However, no significant therapeutic activity was observed in this model. As per an agreed revised statement of work, a CAR termed T1E28z was constructed which targets T-cells against several ErbB receptor dimers that are upregulated in EOC. Liposomal clodronate was used to achieve depletion of TAM. We showed that T1E28z-transduced T-cells were effective in mediating the killing of both autologus patient-derived tumor cell cultures and EOC cell lines (IGROV-1 and SKOV-3). Next, xenograft EOC models were established using luciferase-expressing SKOV-3 tumor cells. Using bioluminescence imaging (BLI), we demonstrated that T1E28z+ T-cells mediated the regression of established SKOV-3 tumors in SCID Beige mice. Whilst highly efficient depletion of TAM has been achieved using liposomal clodronate, this did not influence anti-tumor activity in this model. However, potency of immunotherapy was enhanced by repeated administration of T1E28z-engineered T-cells. T-cell activity was imaged in this study by co-expression of renilla luciferase in these cells. This analysis revealed that T-cells undergo progressive decline in tumor-bearing mice, providing a strong rationale for repeated administration to achieve maximum efficacy.
Document Details
- Document Type
- Technical Report
- Publication Date
- Nov 01, 2012
- Accession Number
- ADA569673
Entities
People
- John Maher
Organizations
- King's College London