A novel approach to tumor suppression with microencapsulated recombinant cells.
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.
Department of Biology, McMaster University, Hamilton, Ontario, Canada, L8N 3Z5.
Pasquale
P
Cirone
Jacqueline M
JM
Bourgeois
Richard C
RC
Austin
Patricia L
PL
Chang
D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D017690:Cell Transplantation; D004339:Drug Compounding; D005240:Feasibility Studies; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000235:genetics* / Q000627:therapeutic use; D007376:Interleukin-2 / Q000235:genetics* / Q000627:therapeutic use; D008546:Melanoma, Experimental / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000628:therapy*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000627:therapeutic use
D007135:Immunoglobulin Variable Region; D007376:Interleukin-2; D018719:Erb-b2 Receptor Tyrosine Kinases; D011993:Recombinant Fusion Proteins