Cancer Immunology, Immunotherapy

, Volume 63, Issue 9, pp 959–967 | Cite as

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

  • Sandra Van Lint
  • Sofie Wilgenhof
  • Carlo Heirman
  • Jurgen Corthals
  • Karine Breckpot
  • Aude Bonehill
  • Bart Neyns
  • Kris Thielemans
Focussed Research Review

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.

Keywords

19th Danish Cancer Society Symposium 2013 Dendritic cell mRNA Immunotherapy Cancer 

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

Notes

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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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Sandra Van Lint
    • 1
  • Sofie Wilgenhof
    • 1
    • 2
  • Carlo Heirman
    • 1
  • Jurgen Corthals
    • 1
  • Karine Breckpot
    • 1
  • Aude Bonehill
    • 1
  • Bart Neyns
    • 2
  • Kris Thielemans
    • 1
    • 2
  1. 1.Laboratory of Molecular and Cellular Therapy & Dendritic Cell-bankVrije Universiteit BrusselBrusselsBelgium
  2. 2.Department of Medical OncologyUniversity Hospital Brussel (UZ Brussel)BrusselsBelgium

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