TY - JOUR
T1 - REACtiVe-2
T2 - phase I evaluation of dendritic cell vaccination and agonistic CD40 therapy following (m)FOLFIRINOX in metastatic pancreatic cancer
AU - Kucukcelebi, Songul
AU - van ‘t Land, Freek R.
AU - van der Burg, Sjoerd H.
AU - Eskens, Ferry A.L.M.
AU - Homs, Marjolein Y.V.
AU - Willemsen, Marcella
AU - Onrust-van Schoonhoven, Anne
AU - Rozendaal, Nina E.M.
AU - Fellah, Amine
AU - Vadgama, Disha
AU - Moskie, Miranda
AU - Bezemer, Koen
AU - Doukas, Michail
AU - van Eijck, Casper W.F.
AU - Stadhouders, Ralph
AU - de Vos-Geelen, Judith
AU - van Diepen, Aniek E.
AU - Enninga, Ilona
AU - Meijer, Rob
AU - Ambarkhane, Sumeet V.
AU - Ellmark, Peter
AU - Aerts, Joachim G.J.V.
AU - Groeneveldt, Christianne
AU - van Eijck, Casper H.J.
N1 - Funding Information:
The authors want to express their gratitude to the apheresis unit of the Department of Hematology for performing the leukapheresis procedures and to the Advanced Therapy Medicinal Product (ATMP) laboratory for their role in vaccine production and delivery. The authors thank the Laboratory of Tumor Immunology for their assistance in the fresh enumeration of leukocytes. The authors thank the Department of Medical Oncology, including its nurses and planners, for their efforts in patient planning, admission, and monitoring. The authors thank Judith Verhagen-Oldenampsen for her contributions as a trial manager and for coordinating the communication with the ethical committees. Above all, the authors express their deepest gratitude to the patients who participated in the REACtiVe-2 trial, whose invaluable contributions made this research possible, and their families for their support. This work was funded by the Elisabeth Foundation, a named fund within the Erasmus Trustfonds (project REACtiVe-2) and the Survival with Pancreatic Cancer Foundation (in Dutch: Stichting Overleven met Alvleesklierkanker) (SOAK 17.06). Mitazalimab is provided by Alligator Bioscience AB. PheraLys is provided by Amphera. Both Alligator Bioscience AB and Amphera were not involved in study design, data collection, data analysis, or manuscript writing.
Publisher Copyright:
© The Author(s) 2025.
PY - 2025/12/1
Y1 - 2025/12/1
N2 - 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.
AB - 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.
U2 - 10.1038/s41467-025-66092-1
DO - 10.1038/s41467-025-66092-1
M3 - Article
SN - 2041-1723
VL - 16
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 10609
ER -