DNA vaccines targeting dendritic cells for the immunotherapy of cancer.

Abstract

Cytotoxic T lymphocytes (CTL) play a crucial role in the host’s immune response to cancer. The adoptive transfer of tumor-specific CTL can mediate the regression of established tumors in experimental animal models1 as well as in some patients with melanoma2. Recently, a number of genes encoding tumor-associated antigens (TAA) and their peptide products, which are recognized by cytotoxic T lymphocytes in the context of major histocompatibility complex (MHC) class I molecules, have been identified for both murine and human tumors3,4. These insights now need to be translated into the development and application of novel immunotherapies designed to elicit tumor antigen-specific T cells. Dendritic cells (DC) are believed to be critical for the induction of primary, cell-mediated immune responses5,6. Using freshly isolated, as well as, cultured DC pulsed with peptides constituting relevant CTL-defined epitopes, we and others have been able to induce protective and therapeutic antitumor immune responses in mouse tumor models7–13. Furthermore, autologous cultured human DC pulsed with synthetic melanoma peptides were able to stimulate antigen-specific CTL capable of lysing HLA-matched allogeneic melanoma cells that naturally express these epitopes in vitro 14–16. As an alternative to synthetic peptides, that may restrict the immune response to defined tumor-associated epitopes with known MHC restriction, the use of plasmid DNA or recombinant viruses encoding tumor-associated antigens has recently been investigated for the immunotherapy of cancer17–22. Direct inoculation of naked DNA into the skin or muscle of animals results in both humoral and cellular immune responses.