A Novel Approach to Tumor Suppression with Microencapsulated Recombinant Cells

Abstract

A novel approach to cancer gene therapy is to implant microcapsules containing nonautologous cells engineered to secrete molecules with antineoplastic properties. The efficacy of this treatment is now tested in a mouse model bearing HER-2/neu-positive tumors. Nonautologous mouse myoblasts (C(2)C(12)) were genetically modified to secrete interleukin-2 linked to the Fv region of a humanized antibody with affinity to HER-2/neu. The resulting fusion protein, sFvIL-2, would encompass immune-stimulatory cytokine activity now targeted to the HER-2/neu-expressing tumor. These recombinant cells were then immunoprotected with alginate-poly-L-lysine-alginate microcapsules before implantation into tumor-bearing mice. Treatment with these encapsulated cells led to a delay in tumor progression and prolonged survival of the animals. The long-term efficacy was limited by an inflammatory reaction against the implanted microcapsules probably because of the secreted cytokine and antigenic response against the xenogeneic fusion protein itself. However, over the short term (initial 2 weeks), efficacy was confirmed when a significant amount of biologically active interleukin-2 was detected systemically, and targeting of the fusion protein to the HER-2/neu-expressing tumor was shown immunohistochemically. The tumor suppression in the treated animals was associated with increased apoptosis and necrosis in the tumor tissue, thus demonstrating successful targeting of the antiproliferative effect to the tumors by this delivery paradigm. In conclusion, this new approach to systemic cancer gene therapy needs to be modified to provide long-term delivery, but has demonstrated short-term efficacy and potential to become a cost-effective, benign, and non-viral-based adjunct to the current armory of anticancer strategies.

Cell vehicle targeting strategies

“…To this end, producer cells are often transplanted as 'artificial glands' immobilized in matrixes or supportive devices that keep cells at the transplant site. 10 In this mode the biotherapeutics produced by the cells are intended to act locally at the site of cell implantation, or to act remotely if secreted into circulation. In contrast to immobilized cell transplantation, numerous applications require delivery of the therapeutic agent to key sites of pathology that generally exist remotely from the site of injection.…”

A multiprong approach to cancer gene therapy by coencapsulated cells

“…10,30 The sFvIL-2 fusion protein consisted of a humanized, single-chain antibody Fv region with affinity to HER2, fused to human IL-2. The angiostatin used consisted of kringle regions 1-4 of plasminogen (K1-4) fused to a hemagglutinin tag (HA).…”

“…10,30 The expression of angiostatin from C 2 C 12 AST cells increased about twofold; this may represent the improved growth conditions for expression of the angiostatin construct within the peritoneal cavity compared to culture media. However, this was not reflected in the expression of sFvIL-2 from the C 2 C 12 sFvIL-2 cells.…”

“…7,9 We have used a more direct approach for the treatment of cancer by delivering interleukin-2 (IL-2), to stimulate the immune rejection of tumor cells. 10 An IL-2 fusion protein targeted to the HER2/neu receptor on tumor cells was delivered from genetically modified encapsulated cells to treat murine solid tumors overexpressing the HER2/neu receptor. 10 However, efficacy was limited by a gross neutrophil-driven inflammatory response to the IL-2 biological activity, leading to death of the encapsulated cells and cessation of cytokine delivery.…”

“…10 An IL-2 fusion protein targeted to the HER2/neu receptor on tumor cells was delivered from genetically modified encapsulated cells to treat murine solid tumors overexpressing the HER2/neu receptor. 10 However, efficacy was limited by a gross neutrophil-driven inflammatory response to the IL-2 biological activity, leading to death of the encapsulated cells and cessation of cytokine delivery. Hence, although efficacious in suppressing tumor growth initially, this immune therapy protocol only produced a transient effect, with the tumors resuming growth after a delay of B2 weeks.…”