Breast Cancer Immunotherapy With Intra-Tumoral Injection of Genetically Modified Dendritic Cells
Abstract
We have hypothesized that intra-tumoral injection of immature DCs should result in acquisition of tumor antigens at the site of injection followed by migration to lymph node and spleen. Here we have used adenoviral vectors, able to efficiently infect both murine and human DC, to deliver IL-12, IL-18, and GM/CSF and the costimulatory molecules B7.1 and CD40L, either alone or in combination, to bone marrow-derived DC (BmDC). We showed that the genetic modification of DCs to overexpress IL-12, UM/CSF, and CD40L significantly enhanced their ability to stimulate a systemic immune response following intra-tumoral injection. In addition we have used adenoviral gene transfer of members of the TNF family able to stimulate apoptosis, FasL and TRAIL, to render DC direct, potent mediators of tumor cell apoptosis. We demonstrate that the genetic modification of DCs by adenoviral infection to overexpress IL-12, IL-18, and GM/CSF significantly enhanced their ability to stimulate a systemic immune response in the murine breast tumor TS/A following intra-tumoral injection. Furthermore, expression of FasL and TRAIL on DC resulted in a stronger anti-tumor response following intra-tumoral delivery. The anti-tumor effect of different genetically modified-DC was mediated, in part, by the induction of specific CTL activity against the tumor. The genetic modification DC to express one or more immuno-stimulatory molecules was able to augment NK cells and CTL cytolytic activity and IFN-gamma production for subsequent immune anti-tumor responses locally as well as systemically. We currently are examining the optimal combination of genes in order to induce the most effective anti-tumor response following intra-tumoral infection of the genetically modified DC. Our research is expected to lead Phase clinical trial to assess the feasibility and efficacy of treating and preventing breast cancer by intra-tumor injection of genetically modified DCs.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2003
- Accession Number
- ADA425184
Entities
People
- Seon-hee Kim
Organizations
- University of Pittsburgh