Monitoring T-cell responses in a phase II study of AGS-003, an autologous dendritic cell-based therapy in patients with newly diagnosed advanced stage renal cell carcinoma in combination with sunitinib.

Abstract

2532 Background: Dendritic cells (DC) are a powerful tool for stimulating cell-mediated immunity through the effects of CD4+ and CD8+ T cells. This phase II study investigated AGS-003, an autologous amplified tumor RNA-loaded DC–based immunotherapy in patients with RCC in combination with sunitinib. AGS-003 stimulates proliferation of CD28 expressing cytotoxic T lymphocytes (CTL), targeted directly to autologous RCC tumor antigens. While sunitinib is capable of inducing tumor regression through inhibition of VEGF activity, it also possesses non-specific immune modulatory effects, which include a noted decrease in regulatory T cells. Therefore, the combination of AGS-003 and sunitinib could result in synergistic effects over that which could be achieved with either modality alone. Methods: Immune monitoring (IM) analysis using multiparametric flow cytometry was performed on PBMC isolated from blood draws collected prior to treatment and after treatment with AGS-003 during combination administration with sunitinib. Results: Results revealed that for all subjects tested, there was a decrease in the percentage of T regulatory cells during combination treatment with AGS-003 and sunitinib compared to pre-therapy baseline levels. With the exception of one outlier, there was a correlation between decreased regulatory T cells and PFS (r2=0.7662). Also, patients treated concurrently with AGS-003 in the presence of sunitinib were able to expand CD28+ memory CTL with a broad range of effector functions. The expansion of tumor antigen-reactive CD28+ CTL revealed a trend between PFS and the change in CD28+ effector memory CTL post-treatment. Nine of 11 subjects with PFS of >10 months demonstrated CTL population increases whereas 2 of 4 subjects with PFS <10 months showed increases in this specific CTL population. Conclusions: We conclude that the combination of sunitinib and AGS-003 can decrease the percentage of T regulatory cells with a concurrent expansion of CD28+ effector memory CTL thereby overcoming tumor-induced immunosuppression and potentially leading to better clinical outcome in terms of PFS.