Comprehensive immunotherapy combined with intratumoral injection of zoledronate-pulsed dendritic cells, intravenous adoptive activated T lymphocyte and gemcitabine in unresectable locally advanced pancreatic carcinoma: a phase I/II trial

Abstract

Dendritic cell (DC)-based vaccines prepared using various antigen loading methods have been studied for cancer immunotherapy. The in vivo provocation of immunity by the direct injection of DCs without using tumor-specific antigens into tumors after apoptosis-inducing chemotherapy is more applicable. We previously reported that zoledronate-pulsed DCs (Zol-DCs) may induce tumor-antigen-specific CD8+ T cells by activating Vγ9γδT cells. In this report, we studied the feasibility, safety, and efficacy of a comprehensive immunotherapy involving the combined intratumoral injection of Zol-DC, gemcitabine (GEM) and αβT cells in locally advanced pancreatic carcinoma. Seven of 15 patients showed a stable disease (SD) and most of the patients showed long-term clinical responses. The FACT-BRM score was significantly higher in the patients with SD. Additionally the CD8+/Treg ratio significantly increased in SD patients after treatment. The median over-all survival and progression-free-survival of 15 patients were 12.0 months and 5.5 months, respectively. Patients with a pretreatment neutrophil/lymphocyte ratio (NLR) lower than 5.0 showed significantly longer survival. Even in an analysis limited to the patients with an NLR lower than 5.0, the patients whose CD8+/Treg ratio increased more than twofold tended to survive longer. In conclusion, the comprehensive immunotherapy using Zol-DCs, systemic αβT cells, and GEM may synergistically show a therapeutic effect on locally advanced pancreatic carcinoma. By using appropriate and precise biomarkers, such as NLR and CD8+/Treg ratio, the present comprehensive immunotherapy could be more beneficial for patients with pancreatic carcinoma.