Vaccination with dendritic cells pulsed with apoptotic tumors in combination with anti-OX40 and anti-4-1BB monoclonal antibodies induces T cell-mediated protective immunity in Her-2/neu transgenic mice.
ABSTRACT Tumor cells express tumor-associated antigens (TAAs), which can serve as targets for the immune system. However, the majority of TAAs are overexpressed products of normal cellular genes; as such, self-tolerance mechanisms have hindered their use for the induction of effective antitumor responses. One such normal self-protein is the growth factor receptor Her-2/neu, which is overexpressed in 25-35% of all mammary carcinomas in humans. In previous studies, we have demonstrated that Her-2/neu mice are functionally tolerant to neu antigens and contain only a low avidity T-cell repertoire to neu antigens. However, this residual low-avidity T-cell repertoire has antitumor activity. In this study, we compared the immune responses of Her-2/neu mice immunized with dendritic cells (DCs) pulsed with soluble neu protein or with apoptotic tumor cells. Analysis of the antitumor response shows that Her-2/neu mice vaccinated with DCs pulsed with Her-2/neu antigens retard tumor growth; however, vaccination with DCs pulsed with apoptotic tumor cells induces a stronger antitumor effect. Administration of multiple immunizations in combination with the costimulatory agonist anti-OX40 or anti-4-1BB MAb significantly enhanced the immune responses in these mice, resulting in complete tumor rejection if the tumor burden was small and substantial tumor reduction with a larger tumor burden. These results have important implications for the design of tumor vaccination strategies, suggesting that the use of vaccines that stimulate a broad immune response in combination with costimulatory molecules as immunomodulators could significantly improve the antitumor immune response in tolerant hosts.
Article: Enhanced antitumor effect against human telomerase reverse transcriptase (hTERT) by vaccination with chemotactic-hTERT gene-modified tumor cell and the combination with anti-4-1BB monoclonal antibodies.[show abstract] [hide abstract]
ABSTRACT: Human telomerase reverse transcriptase (hTERT) represents an attractive target for cancer immunotherapy because hTERT is reactivated in most human tumors. In an attempt to develop an effective vaccine against most human cancers, we constructed chemotactic-hTERT vaccine. Two hTERT fragments encoding multiple cytotoxic T lymphocyte and T helper cell epitopes were fused as a tumor antigen (named Te). The plasmid based DNA vaccine (pCCL21-Te-Fc) was constructed by linking human CCL21 and IgG Fc gene sequences to each end of Te. In poorly immunogenic B16F10 mouse melanoma model, DNA (pCCL21-Te-Fc) vaccination significantly inhibited tumor growth and all of the mice were dead by day 52. The immunization with pCCL21-Te-Fc-modified tumor cells (B16/CCL21-Te-Fc) resulted in a higher antitumor effect than DNA vaccination and 25% of tumor-bearing mice achieved long-term survival (> 120 days). The combined therapy of B16/CCL21-Te-Fc plus anti-4-1BB MAbs further enhanced the immune response, resulting in 75% of tumor-bearing mice achieved long-term survival (> 120 days) in subcutaneous model and few lung nodules in pulmonary metastasis model. Rechallenge experiment showed that a persistent memory response was successfully induced by the combined therapy. In vivo depletion of lymphocytes indicated that CD8+ T cells were essential in the antitumor activity induced by B16/CCL21-Te-Fc plus anti-4-1BB MAbs, whereas NK cells and CD4+ T cells played substantial roles. The CTL activity induced by pCCL21-Te-Fc-transfected PBMCs specifically lysed a variety of human leukocyte antigen-matched and hTERT-positive human tumor cells, suggesting pCCL21-Te-Fc could serve as a vaccine against most human cancers.International Journal of Cancer 11/2006; 119(8):1886-96. · 5.44 Impact Factor