Abstract
4128 Background: The efficacy of immunotherapy with monocyte derived dendritic cells (MoDC) is controlled via immune checkpoints, among them the PD-1/PDL-1 pathway. PDL-1 expressed on DC delivers an inhibitory signal to T-cells upon binding to PD-1 expressed on activated T-cells. Blocking of PDL-1 on DC may lead to improved efficacy of DC therapy for pancreatic cancer. Methods: After isolating monocytes from peripheral blood of n = 44 patients with stage IV pancreatic cancer, who failed first-line chemotherapy, antigen primed MoDC were generated using standard protocols. Patients included in the follow-up analysis received a minimum of 3 vaccines. 10 patients received MoDC modified by PDL-1 blockade after failure of previous DC therapy. PDL-1 blockade was performed by adding soluble CD80 or anti-PDL-1 to MoDC. Cytokine release and T-cell activity were measured exemplary using a mixed lymphocyte culture (MLC). Results: Median survival after onset of DC-therapy was 8 months with MoDC alone (18 months after primary diagnosis) with longest follow up of 36 months (49 months after primary diagnosis). We could induce a secondary stabilisation (4 to 8 months) in 5 from 10 patients, who failed to respond to previous DC therapy by using MoDC modified by PDL-1 blockade. Cytokine measurement using MLC, which was exemplarily performed, shows a change in the cytokine release upon PDL-1 blockade. Conclusions: An effective immune response requires both the inhibition of inhibitory signals and the activation of an antigen specific T-cell response. The efficacy of dendritic-cell based therapy may be improved by blockade of PDL-1 on dendritic cells to avoid an inhibitory signal and thus improve the T-cell specific response. Further investigations are necessary to ascertain whether the combination of systemic anti PD1-therapy with DC therapy using MoDC modified with PDL-1 blockade may further enhance therapeutic efficacy in solid tumors.
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