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 ol 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 fi om 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 fi om 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. (C) 2000 Elsevier Science B.V. All rights reserved.