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. 2015 Apr 1;4(8):e1019197.
doi: 10.1080/2162402X.2015.1019197. eCollection 2015 Aug.

Intranodal vaccination with mRNA-optimized dendritic cells in metastatic melanoma patients

Kalijn F Bol  1 , Carl G Figdor  2 , Erik Hjg Aarntzen  3 , Marieke Eb Welzen  4 , Michelle M van Rossum  5 , Willeke Am Blokx  6 , Mandy Wmm van de Rakt  2 , Nicole M Scharenborg  2 , Annemiek J de Boer  2 , Jeanette M Pots  2 , Michel Am Olde Nordkamp  2 , Tom Gm van Oorschot  2 , Roel Dm Mus  7 , Sandra Aj Croockewit  8 , Joannes Fm Jacobs  9 , Gerold Schuler  10 , Bart Neyns  11 , Jonathan M Austyn  12 , Cornelis Ja Punt  13 , Gerty Schreibelt  2 , I Jolanda M de Vries  1
Affiliations

Intranodal vaccination with mRNA-optimized dendritic cells in metastatic melanoma patients

Kalijn F Bol et al. Oncoimmunology. .

Abstract

Autologous dendritic cell (DC) therapy is an experimental cellular immunotherapy that is safe and immunogenic in patients with advanced melanoma. In an attempt to further improve the therapeutic responses, we treated 15 patients with melanoma, with autologous monocyte-derived immature DC electroporated with mRNA encoding CD40 ligand (CD40L), CD70 and a constitutively active TLR4 (caTLR4) together with mRNA encoding a tumor-associated antigen (TAA; respectively gp100 or tyrosinase). In addition, DC were pulsed with keyhole limpet hemocyanin (KLH) that served as a control antigen. Production of this DC vaccine with high cellular viability, high expression of co-stimulatory molecules and MHC class I and II and production of IL-12p70, was feasible in all patients. A vaccination cycle consisting of three vaccinations with up to 15×106 DC per vaccination at a biweekly interval, was repeated after 6 and 12 months in the absence of disease progression. mRNA-optimized DC were injected intranodally, because of low CCR7 expression on the DC, and induced de novo immune responses against control antigen. T cell responses against tyrosinase were detected in the skin-test infiltrating lymphocytes (SKIL) of two patients. One mixed tumor response and two durable tumor stabilizations were observed among 8 patients with evaluable disease at baseline. In conclusion, autologous mRNA-optimized DC can be safely administered intranodally to patients with metastatic melanoma but showed limited immunological responses against tyrosinase and gp100.

Keywords: DC vaccines; dendritic cell; immunotherapy; mRNA electroporation; melanoma.

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Figures

Figure 1.
Figure 1.
mRNA-optimized dendritic cell (DC) vaccine characteristics. Expression of HLA-ABC, HLA-DR/DP, HLA-DQ, CD80, CD86, CD70 and CD40L was measured by flow cytometry on DC of all patients (A). Tumor antigen expression of gp100 and tyrosinase by DC 4 h after electroporation with mRNA encoding gp100 and tyrosinase (B). Data are shown as percentage of positive DC of the first DC vaccine of each patient. The production of IL-12p70 by DC was measured in the supernatants 16 h after induction of maturation (C). Each dot represents the first DC vaccine of a patient.
Figure 2.
Figure 2.
KLH-specific immune responses before and after dendritic cell (DC) vaccination. KLH-specific T cell proliferation was analyzed after each DC vaccination during the first vaccination cycle in peripheral blood mononuclear cells of melanoma patients. The proliferative response to KLH is given as a proliferation index (proliferation with KLH/proliferation without KLH) (A). KLH-specific IgG (B), IgA (C) and IgM antibodies (D) were quantitatively measured before and after each vaccination cycle in sera of vaccinated patients. The best Ig response was shown for each patient. Each dot represents 1 patient or the number of patients as indicated.
Figure 3.
Figure 3.
Induration at the delayed type hypersensitivity (DTH) skin tests after cycle 1. DTH skin tests were performed after each series of vaccinations. Cytokine-matured dendritic cells (cDC) or mRNA-optimized DC (mRNA DC) electroporated with gp100-encoding mRNA or tyrosinase-encoding were injected intradermally in the skin of the back of the patients at four different sites. The maximum diameter of induration was measured after 48 h. Induration after the first vaccination cycle is shown. Dots representing the same patient are connected with a line.
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