DENDRITIC CELLS INFECTED WITH POXVIRUSES ENCODING - MART-1 MELAN-A SENSITIZE T-LYMPHOCYTES IN-VITRO

Dendritic cells (DC) are potent professional antigen-presenting cells that can activate naive T lymphocytes and initiate cellular immune res ponses. As adjuvants, DC may be useful in enhancing the immunogenicity of tumor antigens and mediating tumor regression. Endogenous expressi on of antigen by DC offers the potential advantage of allowing prolong ed constitutive presentation of endogenously processed epitopes and ex ploitation of multiple restriction elements for the presentation of th e same antigen. in this report, we show that human DC are (a) capable of infection by recombinant poxviruses encoding melanoma-associated an tigen (MAA) genes and (b) capable of efficiently processing and presen ting these MAA to cytotoxic T cells, In 6/6 HLA A0201-expressing mela noma patients tested, the virally driven expression of MART-1/Melan A MAA by DC was sufficient to generate CD8(+) T lymphocytes that could r ecognize naturally processed epitopes on tumor cells. In most cases, s pecific anti-MART-1 reactivity could be detected after a single stimul ation.,Analysis of epitope dominance revealed that the amino acid sequ ence recognized by these cytotoxic T lymphocytes (CTL) corresponded to the MART-1(27.35) residues previously shown to be most commonly recog nized by cytotoxic T lymphocytes expanded from metastatic melanoma les ions. These data show that the virally driven expression of MAA by DC can be exploited for the efficient induction of clinically relevant cy totoxic T-cell responses. This has clinical implications for active im munization therapy, and currently vaccine trials have been proposed fo r patients with metastatic melanoma.