ACTIVE SPECIFIC IMMUNOTHERAPY WITH HAPTEN-MODIFIED AUTOLOGOUS MELANOMA CELL VACCINE

We have developed a novel approach to cancer immunotherapy - an autolo gous whole-cell vaccine modified with the hapten dinitrophenyl (DNP). This approach elicits significant inflammatory responses in metastatic sites and some objective tumor responses. Post-surgical adjuvant immu notherapy with DNP-modified melanoma vaccine in a setting of micrometa static disease produces significant survival prolongation in stage III melanoma patients. Histologically, the inflammatory responses of the tumor consist of infiltration by lymphocytes, the majority of which ar e CD8+, HLA-DR+ T cells. T cells from these lesions tend to have mRNA for interferon gamma. T cell receptor analysis suggests that the tumor -infiltrating T cells are clonally expanded. DNP-modified vaccine also induces T cells in the peripheral blood, which respond to DNP-modifie d autologous cells in a hapten-specific, MHC-restricted manner. Moreov er, a T cell line generated from these lymphocytes responded to only a single HPLC fraction of MHC-associated, DNP-modified tumor peptides. Since inflammatory responses in metastases were not consistently assoc iated with dramatic tumor regression, we considered the possibility of immunosuppression at the tumor site. We found that mRNA for the anti- inflammatory cytokine, interleukin-10 (IL-10) is expressed in most met astatic melanoma tissues and subsequently demonstrated that IL-10 prot ein is produced by melanoma cells. Thus the efficacy of DNP vaccine co uld be further enhanced by inhibition of IL-10 production or binding. Finally, we expect these results obtained with melanoma to be applicab le to other human cancers.