Dendritic Cell Vaccines Are Superior to Idiotype-KLH Protein Vaccines at Priming a Therapeutic, Tumor-Specific Immunity Against Multiple Myeloma.

Abstract

Idiotype (Id) protein secreted by myeloma cells is the best-characterized tumor-specific antigen and has been used in clinical vaccination trials administered either as Id-keyhole limpet hemocyanin (KLH) protein vaccines or as Id-pulsed dendritic cell (DC) vaccines. In this study, we used the 5TGM1 myeloma murine model to compare the efficacy of Id-KLH (protein vaccines) versus DCs pulsed with Id-KLH (DC vaccines), two formulas commonly used in clinical trials, to induce tumor-specific immunity, to protect mice from developing myeloma, and to treat myeloma-bearing mice. Vaccinations consisted of three weekly, subcutaneous injections of the protein conjugates (100 μg/injection) or Id-KLH-pulsed, bone marrow-derived mature DCs (106 cells/injection). Following each vaccination, GM-CSF (200 ng/day/mouse) was injected subcutaneously (adjacent to the vaccination sites) for three consecutive days. We found that, although the protein vaccines induced significantly higher titers of specific antibodies, DC vaccines were superior at inducing tumor-specific, cellular immune responses, evident by increased IFN-γ production, T cell proliferation, and cytotoxic T cell activities against the tumor cells. As prophylactic treatments, protein and DC vaccines were equally efficient at protecting mice from subsequent tumor challenge. However, only DC vaccines induced therapeutic immunity in tumor-bearing mice: DC vaccinations not only retarded tumor growth but also eradicated established tumors in more than 50% of mice, which was associated with an induction of potent, tumor-specific type-1 (IFN-γ) and type-2 (IL-4) T-cell responses. DC-vaccinated mice also showed a more pronounced increase in the percentages of CD8+ T cells in their spleens after in vitro stimulation with irradiated myeloma cells and increased tumor-specific cytotoxicity in enriched CD8+ T cells over the whole splenic cells, suggesting that CD8+ T cells play a major role in killing tumor cells in vivo. Furthermore, surviving mice were also protected from rechallenge with the myeloma cells, indicating that memory T cells existed and were functional. Thus, our results show that Id-based DC vaccines may be a favorable vaccine for immunotherapy in MM. Further studies are required to optimize DC vaccination protocols to achieve therapeutic efficacy in clinical trials.