REACtiVe-2: phase I evaluation of dendritic cell vaccination and agonistic CD40 therapy following (m)FOLFIRINOX in metastatic pancreatic cancer

Songul Kucukcelebi, Freek R. van ‘t Land, Sjoerd H. van der Burg, Ferry A. L. M. Eskens, Marjolein Y. V. Homs, Marcella Willemsen, Anne Onrust- van Schoonhoven, Nina E. M. Rozendaal, Amine Fellah, Disha Vadgama, Miranda Moskie, Koen Bezemer, Michail Doukas, Casper W. F. van Eijck, Ralph Stadhouders, Judith de Vos-Geelen, Aniek E. van Diepen, Ilona Enninga, Rob Meijer, Sumeet V. Ambarkhane, Peter Ellmark, Joachim G. J. V. Aerts (), Christianne Groeneveldt and Casper H. J. van Eijck ()
Additional contact information
Songul Kucukcelebi: Erasmus MC Cancer Institute, Department of Surgery
Freek R. van ‘t Land: Erasmus MC Cancer Institute, Department of Surgery
Sjoerd H. van der Burg: Leiden University Medical Center, Department of Medical Oncology, Oncode Institute
Ferry A. L. M. Eskens: Erasmus MC Cancer Institute, Department of Medical Oncology
Marjolein Y. V. Homs: Erasmus MC Cancer Institute, Department of Medical Oncology
Marcella Willemsen: Erasmus MC Cancer Institute, Department of Pulmonary Medicine
Anne Onrust- van Schoonhoven: Erasmus MC Cancer Institute, Department of Pulmonary Medicine
Nina E. M. Rozendaal: Erasmus MC Cancer Institute, Department of Pulmonary Medicine
Amine Fellah: Erasmus MC Cancer Institute, Department of Pulmonary Medicine
Disha Vadgama: Erasmus MC Cancer Institute, Department of Pulmonary Medicine
Miranda Moskie: Erasmus MC Cancer Institute, Department of Pulmonary Medicine
Koen Bezemer: Erasmus MC Cancer Institute, Department of Pulmonary Medicine
Michail Doukas: Erasmus University Medical Center, Department of Pathology
Casper W. F. van Eijck: Erasmus MC Cancer Institute, Department of Pulmonary Medicine
Ralph Stadhouders: Erasmus MC Cancer Institute, Department of Pulmonary Medicine
Judith de Vos-Geelen: Maastricht University Medical Centre, Division of Medical Oncology, Department of Internal Medicine, GROW – Research Institute for Oncology & Reproduction
Aniek E. van Diepen: Maastricht University Medical Centre, Division of Medical Oncology, Department of Internal Medicine, GROW – Research Institute for Oncology & Reproduction
Ilona Enninga: 5223DE, Amphera B.V., Onderwijsboulevard 225
Rob Meijer: 5223DE, Amphera B.V., Onderwijsboulevard 225
Sumeet V. Ambarkhane: Alligator Bioscience AB
Peter Ellmark: Alligator Bioscience AB
Joachim G. J. V. Aerts: Erasmus MC Cancer Institute, Department of Pulmonary Medicine
Christianne Groeneveldt: Erasmus MC Cancer Institute, Department of Pulmonary Medicine
Casper H. J. van Eijck: Erasmus MC Cancer Institute, Department of Surgery

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract In pancreatic ductal adenocarcinoma (PDAC), the dense desmoplastic stroma and insufficient infiltrating T cells represent a significant barrier to effective immunotherapy. In this phase I, dose-escalation study, previously registered at the Dutch Trial Register and later on at ClinicalTrial (NCT05650918), we administer an autologous dendritic cell (DC) vaccine (MesoPher) with an agonistic CD40-specific antibody (mitazalimab) to metastatic PDAC patients (n = 16) after (m)FOLFIRINOX treatment. We included patients with WHO performance status 0-1 with accessible metastatic lesions, and excluded patients with history of previous immunotherapy or malignant ascites. Primary objectives include safety and tolerability. Immune modulation and clinical outcomes are monitored as secondary objectives. MesoPher (25 × 106 DCs) is co-administered with 300, 600, or 1200 μg/kg mitazalimab. MesoPher/mitazalimab therapy is safe and well-tolerated, and the primary endpoint is met. One transient dose-limiting toxicity (DLT) is observed (grade 3 fever). MesoPher/mitazalimab induces a systemic increase in activated and vaccine-specific T cell responses. In post-therapy tumor biopsies, increased T cell infiltration and decreased collagen deposition are observed. No objective radiological response is observed, but eight patients (50%) show stable disease after three administrations. In conclusion, MesoPher/mitazalimab combination therapy is safe and tolerable in patients with metastatic PDAC and enhances systemic immune activation and local immune responses. Future research should evaluate the efficacy of this promising approach as maintenance therapy shortly after completing chemotherapy.

Date: 2025
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DOI: 10.1038/s41467-025-66092-1

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