Dendritic cell-based xenoantigen vaccination for prostate cancer immunotherapy

Many tumor-associated Ags represent tissue differentiation Ags that are poo rly immunogenic. Their weak immunogenicity may be due to immune tolerance t o self-Ags. Prostatic acid phosphatase (PAP) is just such an Ag that is exp ressed by both normal and malignant prostate tissue. We have previously dem onstrated that PAP can be immunogenic in a rodent model. However, generatio n of prostate-specific autoimmunity was seen only when a xenogeneic homolog of PAP was used as the immunogen. To explore the potential role of xenoant igen immunization in cancer patients, we performed a phase I clinical trial using dendritic cells pulsed with recombinant mouse PAP as a tumor vaccine . Twenty-one patients with metastatic prostate cancer received two monthly vaccinations of xenoantigen-loaded dendritic cells with minimal treatment-a ssociated side effects. All patients developed T cell immunity to mouse PAP following immunization. Eleven of the 21 patients also developed T cell pr oliferative responses to the homologous self-Ag. These responses were assoc iated with Ag-specific IFN-gamma and/or TNF-alpha secretion, but not IL-4, consistent with induction of Th1 immunity. Finally, 6 of 21 patients had cl inical stabilization of their previously progressing prostate cancer. All s ix of these patients developed T cell immunity to human PAP following vacci nation. These results demonstrate that xenoantigen immunization can break t olerance to a self-Ag in humans, resulting in a clinically significant anti tumor effect.