Dendritic Cell-Based Immunotherapy in Patients With Resected Pancreatic Cancer

Abstract

Purpose: Immunotherapies have shown limited responses in patients with advanced pancreatic cancer. Recently, we reported that dendritic cell (DC)-based immunotherapy induced T-cell responses against pancreatic cancer antigens. The primary objective of this study was to determine the efficacy of DC-based immunotherapy to prevent recurrence of disease.

Methods: This was a single-center, open-label, single-arm, combined phase I/II trial. The primary end point was the 2-year recurrence-free survival (RFS) rate. A 2-year RFS rate of ≥60% was defined as a clinically meaningful improvement. We included patients with pancreatic cancer after resection and completion of standard-of-care (SOC) treatment without recurrent disease on cross-sectional imaging. Patients were treated with autologous DCs pulsed with an allogeneic mesothelioma tumor cell lysate, comprising antigens also expressed in pancreatic ductal adenocarcinoma.

Results: Thirty-eight patients were included in the analysis of the primary end point (47% male, 53% female). The median age was 62 years (IQR, 55-68). Twenty-eight patients (74%) received five DC vaccinations and completed the study protocol. Three patients (8%) received four vaccinations, and seven patients (16%) received three vaccinations. After a median follow-up of 25.5 months, 26 patients (68%) had not developed recurrence of disease. The estimated 2-year RFS was 64%. Vaccination led to the enrichment of circulating activated CD4+ T cells and the detection of treatment-induced immune responses in vitro. T-cell receptor-sequencing analyses of a resected solitary lung metastasis showed influx of vaccine-specific T cells.

Conclusion: This study reached its primary end point of a 2-year RFS rate of ≥60% following pancreatectomy after SOC treatment and adjuvant DC-based immunotherapy in patients with pancreatic cancer. These results warrant a future randomized trial.

FIG 1.

Clinical study summary. (A) Schematic treatment overview. (B) Flowchart of patient inclusion and analyses. (C) RFS from the date of resection, estimated by the Kaplan-Meier method. (D) OS from the date of resection, estimated by the Kaplan-Meier method. CT, computed tomography; DC, dendritic cell; DTH, delayed-type hypersensitivity; OS; overall survival; PBMC, peripheral blood mononuclear cell; RFS, recurrence-free survival.

FIG 2.

Flow cytometry analysis revealed peripheral blood T-cell activation after DC therapy. (A) Increased frequencies of HLA-DR– and PD-1–positive CD4+ T helper cells after DC therapy (n = 23). (B) Frequencies of HLA-DR– and PD-1–positive CD4+ T helper cells correlated (R² = 0.32; P = .0044) in week 6 (n = 23). (C) Increased frequencies of HLA-DR–, ICOS-, Ki-67–, PD-1–, PD-1– and Ki-67–, and CD39-positive CD4+ central memory T cells after DC therapy (n = 21). (D) Increased frequencies of HLA-DR– and CD39-positive CD4+ effector memory T cells after DC therapy (n = 23). (E) Increased frequencies of CD28-, CD39-, and LAG-3–positive CD4+ Temra T cells after DC therapy (n = 19). *P ≤ .05; **P ≤ .01; ***P ≤ .001. DC, dendritic cell; HLA-DR, human leukocyte antigen-DR isotype; ICOS, inducible T-cell costimulator.

FIG 3.

Flow cytometry analysis revealed peripheral blood T-cell activation and cytokine production upon coculture with the DC vaccine. (A) Increased frequencies of 4-1BB–, CD25-, CD69-, and ICOS-positive CD4+ T cells after a coculture with the DC vaccine (n = 12). (B) Increased frequencies of 4-1BB–positive CD8+ T cells after a coculture with the DC vaccine (n = 12). (C) Increased frequencies of CD107a-positive CD4+ T cells after a coculture with the DC vaccine (n = 12). (D) Increased frequencies of CD107a-positive, IFN-γ–positive, and co-expressing CD8+ T cells after a coculture with the DC vaccine (n = 12). *P ≤ .05; **P ≤ .01; ***P ≤ .001. DC, dendritic cell; ICOS, inducible T-cell costimulator.

FIG 4.

Case report of RT002. (A, B) Clinical course of patient RT002. Patient underwent a distal pancreatosplenectomy, adjuvant chemotherapy, and DC therapy. Later, the patient underwent a lobectomy for a solitary lung metastasis. At data cutoff, she is alive without recurrence 57 and 22 months after pancreatectomy and lobectomy, respectively. (C) T-cell receptor sequencing of the primary tumor, the metastasis, and a DTH skin test and biopsy against the vaccine revealed 13 overlapping TCR clonotypes between the skin biopsy and the lung metastasis after DC therapy. (D) Immunohistochemistry staining revealed high infiltration of CD4+ T cells and, to a lesser extent, infiltration in CD8+ cells. DC, dendritic cell; DTH, delayed-type hypersensitivity; TCR, T-cell receptor.