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<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<sup>6</sup> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月28日

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  • 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,
  • Casper H. J. van Eijck

摘要

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.