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Intravenous and intradermal TriMix-dendritic cell therapy results in a broad T-cell response and durable tumor response in a chemorefractory stage IV-M1c melanoma patient

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Abstract

Dendritic cells (DCs) electroporated with mRNA encoding CD70, CD40L and a constitutively active toll-like receptor 4 (TriMix-DC) have an increased T-cell stimulatory capacity. In a prospective phase IB clinical trial, we treated melanoma patients with intradermal and intravenous injections of autologous TriMix-DC co-electroporated with mRNA encoding full-length MAGE-A3, MAGE-C2, tyrosinase and gp100. We report here the immunological and clinical results obtained in one patient with a particularly favorable outcome. This patient had stage IV-M1c melanoma with documented progression during dacarbazine chemotherapy and received 5 TriMix-DC injections. Following DC therapy, a broad CD8+ T-cell response against multiple epitopes derived from all four treatment antigens was found in the blood and among T cells derived from DTH biopsy. In addition, CD4+ T cells recognizing different MAGE-A3-derived epitopes were detected in DTH-derived cells. A spontaneous anti-MAGE-C2 CD8+ T-cell response was present prior to TriMix-DC therapy and increased during treatment. The tumor response was assessed with 18-fluorodeoxyglucose-positron emission/computed tomography. We documented a partial tumor response according to RECIST criteria with a marked reduction in 18F-FDG-uptake by lung, lymph node and bone metastases. The patient remains free from progression after 12 months of follow-up. This case report indicates that administration of autologous TriMix-DC by the combined intradermal and intravenous route can mediate a durable objective tumor response accompanied by a broad T-cell response in a chemorefractory stage IV-M1c melanoma patient.

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Acknowledgments

We thank Katrien Van den Bossche and Cindy Aerts for data management; Elsy Vaeremans, Xavier Debaere, Gwenny De Metter, Chiraz Mamhmoud and Carine Wartel for their technical assistance and the department of radiotherapy of the UZ Brussels for the irradiation of the EBV-B cells. The authors also thank Dr. P. Coulie (de Duve Institute, Université catholique de Louvain, Brussels, Belgium) and Dr. P. van der Bruggen (Ludwig Institute for Cancer Research, Brussels Branch) for careful and critical reading of the manuscript. This work was supported by grants from the Interuniversity Attraction Poles Program—Belgian State—Belgian Science Policy, the National Cancer Plan of the Federal Ministry of Health, the Stichting tegen Kanker, the Vlaamse Liga tegen Kanker, an Integrated Project and a Network of Excellence sponsored by the EU FP-6, an IWT-TBM program, the Fonds voor Wetenschappelijk Onderzoek Vlaanderen (FWO-Vlaanderen) and the Willy Gepts Wetenschappelijk Fonds of the UZ Brussel. S. W. is a PhD fellow and A. B. is a postdoctoral fellow of the FWO-Vlaanderen.

Conflict of interest

TriMix-DCs are the topic of a current patent application (WO2009/034172). AB and KT are mentioned as inventors of this application. None of the authors involved in this study receives any form of support or remuneration related to this platform.

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Authors and Affiliations

  1. Laboratory of Molecular and Cellular Therapy, Department of Immunology-Physiology, Vrije Universiteit Brussel, Laarbeeklaan 103/E235, 1090, Brussels, Belgium

    An M. T. Van Nuffel, Daphné Benteyn, Sofie Wilgenhof, Jurgen Corthals, Carlo Heirman, Bart Neyns, Kris Thielemans & Aude Bonehill

  2. The Dendritic Cell Bank, Vrije Universiteit Brussel, Brussels, Belgium

    An M. T. Van Nuffel, Daphné Benteyn, Sofie Wilgenhof, Jurgen Corthals, Carlo Heirman, Bart Neyns, Kris Thielemans & Aude Bonehill

  3. The Department of Medical Oncology, Universitair Ziekenhuis Brussel, Brussels, Belgium

    Sofie Wilgenhof, Bart Neyns & Kris Thielemans

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  1. An M. T. Van Nuffel
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  2. Daphné Benteyn
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  8. Aude Bonehill
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Correspondence to Aude Bonehill.

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An M. T. Van Nuffel, Daphné Benteyn and Sofie Wilgenhof contributed equally to this work.

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Van Nuffel, A.M.T., Benteyn, D., Wilgenhof, S. et al. Intravenous and intradermal TriMix-dendritic cell therapy results in a broad T-cell response and durable tumor response in a chemorefractory stage IV-M1c melanoma patient. Cancer Immunol Immunother 61, 1033–1043 (2012). https://doi.org/10.1007/s00262-011-1176-2

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