2. Academic Validation
  3. Adoptive cell therapy with macrophage-drug conjugates facilitates cytotoxic drug transfer and immune activation in glioblastoma models

Adoptive cell therapy with macrophage-drug conjugates facilitates cytotoxic drug transfer and immune activation in glioblastoma models

  • Sci Transl Med. 2025 Jun 18;17(803):eadr4058. doi: 10.1126/scitranslmed.adr4058.
Miaomiao Sun 1,  Maciej Bialasek 2 3,  Maud Mayoux 4,  Meng-Syuan Lin 5,  Alicia Buck 1,  Ilona Marszałek 2,  Bartłomiej Taciak 2 3,  Marcel Bühler 1,  Małgorzata Górczak 2 3,  Paulina Kucharzewska 2 3,  Daria Kurpiel 2,  Małgorzata Siemińska 2,  Julia Nowakowska 2 3,  Jan Brancewicz 2,  Konrad Gabrusiewicz 2,  Waldemar Lipiński 2,  Sibylle Pfammatter 6,  Steve Pascolo 7,  Gregor Hutter 8 9,  Lubomir Bodnar 10,  Berend Snijder 11,  Luca Regli 12,  Michael Weller 1,  Martin Baumgartner 5,  Sonia Tugues 4 13,  Tomasz P Rygiel 2 14,  Magdalena Krol 2 3,  Tobias Weiss 1
Affiliations

Affiliations

  • 1 Department of Neurology, Clinical Neuroscience Center, University Hospital Zurich and University of Zurich, 8091 Zurich, Switzerland.
  • 2 Cellis AG, 8002 Zurich, Switzerland.
  • 3 Center of Cellular Immunotherapies, Warsaw University of Life Sciences, 02-787 Warsaw, Poland.
  • 4 Innate Lymphoid Cells and Cancer, Institute of Experimental Immunology, University of Zurich, 8057 Zurich, Switzerland.
  • 5 Pediatric Molecular Neuro-Oncology Research, Division of Oncology, University Children's Hospital Zürich, 8008 Zürich, Switzerland.
  • 6 Functional Genomics Center Zurich, ETH/University of Zurich, 8057 Zurich, Switzerland.
  • 7 Department of Dermatology, University Hospital Zurich and University of Zurich, 8091 Zurich, Switzerland.
  • 8 Brain Tumor Immunotherapy and Biology Laboratory, Department of Biomedicine, University of Basel, 4031 Basel, Switzerland.
  • 9 Department of Neurosurgery, University Hospital Basel, 4031 Basel, Switzerland.
  • 10 Faculty of Medical and Health Sciences, Siedlce University of Natural Sciences and Humanities, 08-110 Siedlce, Poland.
  • 11 Institute of Molecular Systems Biology, Department of Biology, ETH Zurich, 8049 Zurich, Switzerland.
  • 12 Department of Neurosurgery, Clinical Neuroscience Center, University Hospital Zurich and University of Zurich, 8091 Zurich, Switzerland.
  • 13 Department of Immunology, Medical Faculty Mannheim, Mannheim Institute for Innate Immunosciences (MI3), 68167 Mannheim, Germany.
  • 14 Laboratory of Immunology, Mossakowski Medical Research Institute, Polish Academy of Sciences, 02-106 Warsaw, Poland.
PMID: 40531966 DOI: 10.1126/scitranslmed.adr4058
Abstract

The treatment of solid tumors faces substantial hurdles because of inadequate drug delivery and the immunosuppressive tumor microenvironment. To address these challenges, we developed a therapeutic platform using macrophages loaded with ferritin-drug conjugates, referred to as macrophage-drug conjugates (MDC), and applied it to glioblastoma, an immunologically cold solid tumor. MDC loaded with ferritin-conjugated monomethyl Auristatin E enabled efficient, cell contact-dependent transfer of the payload by a mechanism involving transfer of iron-binding proteins, from either mouse or human macrophages preferentially into glioma cells. This targeted delivery and therapeutic efficacy was demonstrated across in vitro coculture systems, ex vivo assays using dissociated glioblastoma patient tumor samples, and in vivo using orthotopic glioblastoma mouse models, all while maintaining a favorable preclinical safety profile evidenced by minimal systemic toxicity and localized drug biodistribution. Beyond direct tumor cell killing leading to significant tumor regression and prolonged survival in these models, MDC therapy reprogrammed the immunosuppressive tumor microenvironment. Immune profiling by spectral flow cytometry revealed enhanced infiltration and activation of cytotoxic T lymphocytes and B lymphocytes while reducing immunosuppressive regulatory T cells. This culminated in a robust, durable, T cell-dependent antitumor immune response, the necessity of which was confirmed through studies in immunodeficient mouse models and by lymphocyte depletion, and which conferred protection against tumor rechallenge. The combined cytotoxic and immunomodulatory effects highlight the potential of MDC therapy as a promising strategy for glioblastoma treatment and support its further clinical development.

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