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Optimized dendritic cell-based immunotherapy for melanoma: the TriMix-formula

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Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Since decades, the main goal of tumor immunologists has been to increase the capacity of the immune system to mediate tumor regression. In this regard, one of the major focuses of cancer immunotherapy has been the design of vaccines promoting strong tumor-specific cytotoxic T lymphocyte responses in cancer patients. Here, dendritic cells (DCs) play a pivotal role as they are regarded as nature’s adjuvant and as such have become the natural agents for antigen delivery in order to finally elicit strong T cell responses (Villadangos and Schnorrer in Nat Rev Immunol 7:543–555, 2007; Melief in Immunity 29:372–383, 2008; Palucka and Banchereau in Nat Rev Cancer 12:265–277, 2012; Vacchelli et al. in Oncoimmunology 2:e25771, 2013; Galluzzi et al. in Oncoimmunology 1:1111–1134, 2012). Therefore, many investigators are actively pursuing the use of DCs as an efficient way of inducing anticancer immune responses. Nowadays, DCs can be generated at a large scale in closed systems, yielding sufficient numbers of cells for clinical application. In addition, with the identification of tumor-associated antigens, which are either selectively or preferentially expressed by tumors, a whole range of strategies using DCs for immunotherapy have been designed and tested in clinical studies. Despite the evidence that DCs loaded with tumor-associated antigens can elicit immune responses in vivo, clinical responses remained disappointingly low. Therefore, optimization of the cellular product and route of administration was urgently needed. Here, we review the path we have followed in the development of TriMixDC-MEL, a potent DC-based cellular therapy, discussing its development as well as further modifications and applications.

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Abbreviations

API:

Active pharmaceutical ingredient

caTLR4:

Constitutive active form of Toll-like receptor 4

CD40L:

CD40 ligand

CTLA-4:

Cytotoxic T-Lymphocyte antigen 4

CTLs:

Cytotoxic T lymphocytes

DCs:

Dendritic cells

DTH:

Delayed-type hypersensitivity

GM-CSF:

Granulocyte/macrophage colony-stimulating factor

GMP:

Good manufacturing practice

HBSS:

Hanks balanced salt solution

HLA:

Human leukocyte antigen

i.d.:

Intradermal

i.n.:

Intranodal

i.v.:

Intravenous

mAbs:

Monoclonal antibodies

MP:

Medicinal product

NGS:

Next-generation sequencing

SKILs:

Skin-infiltrating lymphocytes

TH1:

T helper 1

TLR:

Toll-like receptor

Treg:

Regulatory T cell

TriMixDC-MEL:

TriMixDCs co-electroporated with mRNA encoding a fusion of DC-LAMP and one of four melanoma-associated antigens: gp100, tyrosinase, MAGE-A3 and MAGE-C2

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Acknowledgments

We thank the patients for their participation in the clinical studies, their families and caregivers, the staff of the Laboratorium of Molecular and Cellular Therapy (LMCT) and the Dendritic Cell Bank for their technical assistance and eTheRNA for providing mRNA. The work described was supported by grants from the Interuniversity Attraction Poles Program—Belgian State (P7/39)—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.

Conflict of interest

The use of dendritic cells electroporated with tumor antigen mRNA and TriMix is the topic of a patent (W2009/034172) on which Dr. A. Bonehill and Prof. Dr. K. Thielemans are filed as inventors. None of the authors receive any support or remuneration related to this platform. No potential conflict of interests were disclosed.

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Authors and Affiliations

  1. Laboratory of Molecular and Cellular Therapy & Dendritic Cell-bank, Vrije Universiteit Brussel, Laarbeeklaan 103E, 1090, Brussels, Belgium

    Sandra Van Lint, Sofie Wilgenhof, Carlo Heirman, Jurgen Corthals, Karine Breckpot, Aude Bonehill & Kris Thielemans

  2. Department of Medical Oncology, University Hospital Brussel (UZ Brussel), Brussels, Belgium

    Sofie Wilgenhof, Bart Neyns & Kris Thielemans

Authors
  1. Sandra Van Lint
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  2. Sofie Wilgenhof
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  6. Aude Bonehill
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  7. Bart Neyns
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  8. Kris Thielemans
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Corresponding author

Correspondence to Kris Thielemans.

Additional information

Sandra Van Lint and Sofie Wilgenhof contributed equally to this work.

This paper is a Focussed Research Review based on a presentation given at the 19th Danish Cancer Society Symposium in Copenhagen, Denmark, 23rd–25th September 2013, on the topic “Immunotherapy of Cancer—Present Status and Future Promise”. It is part of a CII series of Focussed Research Reviews and meeting report.

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Van Lint, S., Wilgenhof, S., Heirman, C. et al. Optimized dendritic cell-based immunotherapy for melanoma: the TriMix-formula. Cancer Immunol Immunother 63, 959–967 (2014). https://doi.org/10.1007/s00262-014-1558-3

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