Combined immunotherapy and antiangiogenic therapy of cancer with microencapsulated cells.
An alternative form of gene therapy involves immunoisolation of a nonautologous cell line engineered to secrete a therapeutic product. Encapsulation of these cells in a biocompatible polymer serves to protect these allogeneic cells from host-versus-graft rejection while recombinant products and nutrients are able to pass by diffusion. This strategy was applied to the treatment of cancer with some success by delivering either interleukin 2 or angiostatin. However, as cancer is a complex, multifactorial disease, a multipronged approach is now being developed to attack tumorigenesis via multiple pathways in order to improve treatment efficacy. A combination of immunotherapy with angiostatic therapy was investigated by treating B16-F0/neu melanoma-bearing mice with intraperitoneally implanted, microencapsulated mouse myoblasts (C2C12) genetically modified to deliver angiostatin and an interleukin 2 fusion protein (sFvIL-2). The combination treatment resulted in improved survival, delayed tumor growth, and increased histological indices of antitumor activity (apoptosis and necrosis). In addition to improved efficacy, the combination treatment also ameliorated some of the undesirable side effects from the individual treatments that have led to the previous failure of the single treatments, for example, inflammatory response to IL-2 or vascular mimicry due to angiostatin. In conclusion, the combination of immuno- and antiangiogenic therapies delivered by immunoisolated cells was superior to individual treatments for antitumorigenesis activity, not only because of their known mechanisms of action but also because of unexpected protection against the adverse side effects of the single treatments. Thus, the concept of a "cocktail" strategy, with microencapsulation delivering multiple antitumor recombinant molecules to improve efficacy, is validated.
Cirone
Pasquale
P
Department of Biology, McMaster University, Hamilton, ON, L8N 3Z5, Canada.
Bourgeois
Jacqueline M
JM
Shen
Feng
F
Chang
Patricia L
PL
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D043168:Angiostatins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D002470:Cell Survival; D016207:Cytokines / Q000378:metabolism; D004339:Drug Compounding; D004730:Endothelium, Vascular / Q000166:cytology; D004797:Enzyme-Linked Immunosorbent Assay; D015316:Genetic Therapy / Q000379:methods; D007150:Immunohistochemistry; D007167:Immunotherapy / Q000379:methods*; D007376:Interleukin-2 / Q000235:genetics / Q000378:metabolism; D008213:Lymphocyte Activation; D008546:Melanoma, Experimental / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D009336:Necrosis; D009369:Neoplasms / Q000235:genetics* / Q000628:therapy*; D011994:Recombinant Proteins / Q000737:chemistry; D013154:Spleen / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism; D013997:Time Factors; D019076:Transgenes; D014841:von Willebrand Factor / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D016207:Cytokines; D007376:Interleukin-2; D011994:Recombinant Proteins; D014841:von Willebrand Factor; D043168:Angiostatins