Immuno-isolation gene therapy: A novel approach to immunotherapy and antiangiogenic therapy of cancer.

摘要

The 'Holy-Grail' of tissue transplantation is to be able to generate tissue in vitro that can be transplanted to different hosts without immune rejection. To this end, an approach was adopted for gene therapy by encapsulating a genetically modified nonautologous cell line within immunoprotective microcapsules fabricated from a biocompatible polymer, alginate. Under such immunological protection, the same cell line can be implanted into different hosts without graft rejection. From this, the first hypothesis of this thesis was that immunoisolation gene therapy could effectively treat a mouse melanoma model by immunotherapy with sFvIL-2. This was tested in a model involving the treatment of a B16-F0/neu melanoma with encapsulated cells secreting an sFv antibody-IL-2 fusion protein. While transiently successful at delaying tumor growth, long-term efficacy was limited by a cytokine-driven inflammatory response. In another approach, an angiostatic product (angiostatin) was delivered instead and was effective in suppressing tumor growth. However, angiostatin treated tumors developed an atypical vasculature whereby the erythrocyte-tumor interface lacked endothelial cells (termed "vascular mimicry") thus allowing the tumors to escape eventually from suppression. It was then hypothesized that the combination of immunotherapy and antiangiogenic therapy by immuno-isolation-based gene therapy could offer a complementary and synergistic advantage. This was tested by two approaches: one to co-encapsulate the different cell types together; the other to implant of different capsule types separately in a more optimized schedule. The co-encapsulation approach was unsuccessful at improving upon the individual treatments due to inflammation driven by the secreted sFVIL-2. However, separation of angiostatin- from the sFvIL-2-secreting cells into different capsule types for implantation was successful at eliminating tumors. Complete responders to the combined treatment were subsequently resistant to further challenge by B16-F0/neu tumors, thus confirming a protective response in the host. In conclusion, the combination of immuno and anti-angiogenic therapies delivered by immunoisolated cells illustrates a new approach to cancer gene therapy.