Cancer therapy with DNA-based vaccines.
The development of DNA-based vaccines arises from the knowledge that weakly immunogenic, tumor-associated antigens (TAAs), the products of mutant or dysregulated genes in the malignant cells, are expressed in a highly immunogenic form by antigen presenting cells. We successfully prepared vaccines that were effective in the treatment of cancer in mice by transfection of DNA from breast cancer cells into a mouse fibroblast cell line (LM). Fibroblasts express MHC class I-determinants along with B7.1, a co stimulatory molecule. (Classic studies indicate that transfection of genomic DNA can stably alter both the genotype and the phenotype of the cells that take-up the exogenous DNA.) The fibroblasts were transfected with sheared, unfractionated genomic DNA from a breast adenocarcinoma that arose spontaneously in a C3H/He mouse (H-2(k)). To increase their non-specific immunogenic properties, the fibroblasts were modified before transfection to express allogeneic MHC-determinants (H-2K(b)) and to secrete IL-2. Afterward, the IL-2-secreting semi allogeneic cells were co transfected with DNA from the spontaneous breast neoplasm, along with a plasmid (pHyg) conferring resistance to hygromycin. Pooled colonies of hygromycin-resistant cells were then tested in C3H/He mice for their immunotherapeutic properties against the growth of the breast neoplasm. The results indicated that tumor-bearing mice immunized with the transfected cells survived significantly longer than mice in various control groups. Similar beneficial effects were seen in C57BL/6 mice injected with a syngeneic melanoma cells and semi allogeneic, IL-2-secreting fibroblasts transfected with DNA from the melanoma cells. The immunity was mediated by CD8(+) T cells and was specific for the type to tumor from which the DNA was obtained.
Cohen
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EP
Department of Microbiology and Immunology (M/C 790), University of Illinois College of Medicine, Chicago, IL 60612, USA. epcohen@uic.edu
D000818:Animals; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D018929:Cell Culture Techniques; D002460:Cell Line; D004273:DNA, Neoplasm / Q000235:genetics / Q000276:immunology; D018014:Gene Transfer Techniques; D006801:Humans; D016233:Immunotherapy, Active; D009369:Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D019444:Vaccines, DNA / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*
D019496:Cancer Vaccines; D004273:DNA, Neoplasm; D019444:Vaccines, DNA