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

Kucukcelebi, Songul ; van 't Land, Freek R ; van der Burg, Sjoerd H ; Eskens, Ferry A L M ; Homs, Marjolein Y V ; Willemsen, Marcella ; Onrust-van Schoonhoven, Anne ; Rozendaal, Nina E M ; Fellah, Amine and Vadgama, Disha , et al. (2025) In Nature Communications 16.
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... (More)

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 × 10
6 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.

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Contribution to journal
publication status
published
subject
keywords
Humans, Pancreatic Neoplasms/therapy, Dendritic Cells/immunology, Male, Cancer Vaccines/immunology, Middle Aged, Female, Aged, CD40 Antigens/agonists, Carcinoma, Pancreatic Ductal/therapy, Vaccination, Adult, Antineoplastic Combined Chemotherapy Protocols/therapeutic use, Treatment Outcome, Neoplasm Metastasis, Immunotherapy/methods
in
Nature Communications
volume
16
article number
10609
pages
15 pages
publisher
Nature Publishing Group
external identifiers
  • pmid:41315287
ISSN
2041-1723
DOI
10.1038/s41467-025-66092-1
language
English
LU publication?
yes
additional info
© 2025. The Author(s).
id
88cde1f4-88b8-4cf8-857e-8b849346cf0b
date added to LUP
2025-12-01 09:11:15
date last changed
2025-12-02 16:56:27
@article{88cde1f4-88b8-4cf8-857e-8b849346cf0b,
  abstract     = {{<p>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 × 10<br>
 6 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.<br>
 </p>}},
  author       = {{Kucukcelebi, Songul and van 't Land, Freek R and van der Burg, Sjoerd H and Eskens, Ferry A L M and Homs, Marjolein Y V and Willemsen, Marcella and Onrust-van Schoonhoven, Anne and Rozendaal, Nina E M and Fellah, Amine and Vadgama, Disha and Moskie, Miranda and Bezemer, Koen and Doukas, Michail and van Eijck, Casper W F and Stadhouders, Ralph and de Vos-Geelen, Judith and van Diepen, Aniek E and Enninga, Ilona and Meijer, Rob and Ambarkhane, Sumeet V and Ellmark, Peter and Aerts, Joachim G J V and Groeneveldt, Christianne and van Eijck, Casper H J}},
  issn         = {{2041-1723}},
  keywords     = {{Humans; Pancreatic Neoplasms/therapy; Dendritic Cells/immunology; Male; Cancer Vaccines/immunology; Middle Aged; Female; Aged; CD40 Antigens/agonists; Carcinoma, Pancreatic Ductal/therapy; Vaccination; Adult; Antineoplastic Combined Chemotherapy Protocols/therapeutic use; Treatment Outcome; Neoplasm Metastasis; Immunotherapy/methods}},
  language     = {{eng}},
  month        = {{11}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{REACtiVe-2 : phase I evaluation of dendritic cell vaccination and agonistic CD40 therapy following (m)FOLFIRINOX in metastatic pancreatic cancer}},
  url          = {{http://dx.doi.org/10.1038/s41467-025-66092-1}},
  doi          = {{10.1038/s41467-025-66092-1}},
  volume       = {{16}},
  year         = {{2025}},
}