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 tumors^3,4. 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 responses^5,6. 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 models^7–13. 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 cancer^17–22. Direct inoculation of naked DNA into the skin or muscle of animals results in both humoral and cellular immune responses.