A multiprong approach to cancer gene therapy by coencapsulated cells.
Immune-isolation of nonautologous cells with microencapsulation protects these cells from graft rejection, thus allowing the same recombinant therapeutic cell line to be implanted in different recipients. This approach was successful in treating HER2/neu-expressing tumors in mice by delivering an interleukin-2 fusion protein (sFvIL-2), or angiostatin. However, treatment with interleukin-2 led to profuse inflammation, while angiostatin delivery did not result in long-term tumor suppression, in part due to endothelial cell-independent neovascularization (vascular mimicry). We hypothesize that coencapsulating the two producer cells in the same microcapsules may enhance the efficacy and ameliorate the above side effects. Hence, B16-F0/neu tumor-bearing mice were implanted with sFvIL-2- and angiostatin-secreting cells coencapsulated in the same alginate-poly-L-lysine-alginate microcapsules. However, this protocol only produced an incremental but not synergistic improvement, as measured with greater tumor suppression and improved survival. Compared to the single sFvIL-2 treatment, the coencapsulation protocol showed improved efficacy associated with: mobilization of sFvIL-2 from the spleen; a higher level of cytokine delivery systemically and to the tumors; increased tumor and tumor-associated endothelial cell apoptosis; and a reduced host inflammatory response. However, compared to the single angiostatin treatment, the efficacy was reduced, primarily due to a "bystander" effect in which the angiostatin-secreting cells suffered similar transgene silencing as the coencapsulated cytokine-secreting cells. Nevertheless, the level of "vascular mimicry" of the single angiostatin treatment was significantly reduced. Hence, while there was no synergy in efficacy, an incremental improvement and some reduction in undesirable side effects of inflammation and vascular mimicry were achieved over the single treatments.
Cirone
Pasquale
P
Department of Biology, McMaster University, Hamilton, Ontario, Canada L8N 3Z5.
Shen
Feng
F
Chang
Patricia L
PL
D000464:Alginates / Q000737:chemistry; D043168:Angiostatins / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation; D007376:Interleukin-2 / Q000235:genetics*; D008198:Lymph Nodes / Q000378:metabolism; D008546:Melanoma, Experimental / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D009336:Necrosis; D009369:Neoplasms / Q000628:therapy*; D009374:Neoplasms, Experimental / Q000628:therapy; D009389:Neovascularization, Pathologic; D011107:Polylysine / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013154:Spleen / Q000378:metabolism; D013997:Time Factors; D019076:Transgenes; D014471:Umbilical Veins / Q000166:cytology; D014841:von Willebrand Factor / Q000378:metabolism
D000464:Alginates; D016207:Cytokines; D007376:Interleukin-2; D011993:Recombinant Fusion Proteins; D014841:von Willebrand Factor; D011107:Polylysine; D043168:Angiostatins