Combination of interleukin-12 gene therapy, metronomic cyclophosphamide and DNA cancer vaccination directs all arms of the immune system towards tumor eradication

Denies, Sofie; Cicchelero, Laetitia; Audenhove, Isabel Van; Sanders, Niek N.

doi:10.1016/j.jconrel.2014.05.045

Cited by 32 publications

(21 citation statements)

References 45 publications

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“…Although remarkable cure rates have been described with intratumoural IL‐12 pDNA administration in rodent cancer models, similar successes can thus far not be claimed in dogs and men with spontaneous cancer . In the majority of preclinical studies with mice, the impact that slowly progressing tumours exert on the adaptive immune system is not taken into account .…”

Section: Discussionmentioning

confidence: 99%

Intratumoural interleukin 12 gene therapy stimulates the immune system and decreases angiogenesis in dogs with spontaneous cancer

Cicchelero

Denies

Haers

et al. 2016

Vet Comparative Oncology

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Interleukin 12 (IL-12) is a powerful immunostimulatory cytokine with a strong antitumoural activity. In this work, the immunological, anti-angiogenic and clinical effects of three consecutive intratumoural IL-12 electrogene therapy (EGT) treatments were evaluated in nine dogs with spontaneous cancer. In all the dogs, tumour biopsies and blood samples were taken prior, during and after the intratumoural IL-12 EGT (on days 1, 8, 35 and 1, 3, 8, 15, 35, respectively). An initial decrease in immune cells was followed by an increase above baseline 1-3 weeks after treatment initiation. Interestingly, the decrease in peripheral leukocytes 2 days after the first intratumoural IL-12 EGT coincided with erythema and tumour swelling. Transient increases of IL-12 and interferon γ were measured in the serum and the tumour tissue, whereas IL-10 transiently increased only in the serum. The effect of intratumoural IL-12 EGT on the levels of IL-24 and vascular endothelial growth factor in the sera and tumour biopsies differed per dog. Via contrast-enhanced ultrasound (US) (on days 1, 8 and 35), we demonstrated that intratumoural IL-12 EGT resulted in a significant decrease of the relative blood volume and blood flow speed in the tumour compared with baseline. Metastases were present in two dogs. In one of these dogs, IL-12 EGT of the primary tumour caused a transient partial regression of the metastases, but not of the primary tumour. The second dog with metastases did not survive long enough to complete the entire treatment cycle. Despite encouraging immunostimulatory and anti-angiogenic effects after intratumoural IL-12 EGT, no clinically relevant outcomes were observed in this study, as persistent tumour regression could not be obtained. On the other hand, the laboratory and US results hold great promise for combinatorial strategies of intratumoural IL-12 EGT with conventional antitumour (immuno)therapies.

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Section: Discussionmentioning

confidence: 99%

Intratumoural interleukin 12 gene therapy stimulates the immune system and decreases angiogenesis in dogs with spontaneous cancer

Cicchelero

Denies

Haers

et al. 2016

Vet Comparative Oncology

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“…Injections were performed intradermally on one or both flanks of the mice using a 29G insulin needle (VWR, The Netherlands). Electroporation, when used, was executed immediately after each injection with a 2-needle array electrode containing 4 needles per row of 4 mm (AgilePulse, BTX Harvard Apparatus, Massachusetts, USA) as previously described [32]. In brief, 2 short high-voltage pulses were given (450V, 0.05ms) followed by 8 long low-voltage pulses (100V, 10ms) and an interval of 300ms between each pulse.…”

Section: Injection Electroporation and Lipid Nanoparticlesmentioning

confidence: 99%

Expression kinetics and innate immune response after electroporation and lipid nanoparticle mediated delivery of a self-amplifying mRNA in the skin of mice

Huysmans

Zhong

Temmerman

et al. 2019

Preprint

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word count: 148 Manuscript word count: 4988 Number of references: 55 Number of figures: 8 Number of tables: 1 2 / 28 Graphical abstract AbstractIn this work we studied the expression kinetics and innate immune response of a self-amplifying mRNA (sa-RNA) after electroporation and lipid nanoparticle (LNP) mediated delivery in the skin of mice. Intradermal electroporation of the sa-RNA resulted in a plateau-shaped expression with the plateau between day 3 and 10. The overall protein expression of sa-RNA was significant higher than that obtained after electroporation of pDNA or non-replication mRNAs. Moreover, intradermal electroporation of sa-RNA induced a short-lived innate immune response that did not affect the expression of the sa-RNA. A complete different expression profile and innate immune response was observed when LNPs were used. The expression peaked 24h after intradermal injection of sa-RNA-LNPs and subsequently showed a sharp drop. This drop can be explained by the strong innate immune response elicited by the sa-RNA-LNPs 4h after injection. Interestingly, sa-RNA-LNPs were able to transfection the draining lymph nodes after intradermal injection.

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“…54 Briefly, serum of each mouse was 1/8 diluted in FACS Buffer. Washed EO771 cells (1.25£10 5 ) were resuspended in 50 mL of this diluted serum and incubated for 1 h at 37 C, 5% CO 2 and 95% relative humidity.…”

Section: Humoral Responsementioning

confidence: 99%

Can dendritic cells improve whole cancer cell vaccines based on immunogenically killed cancer cells?

et al. 2015

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Combination of interleukin-12 gene therapy, metronomic cyclophosphamide and DNA cancer vaccination directs all arms of the immune system towards tumor eradication

Cited by 32 publications

References 45 publications

Intratumoural interleukin 12 gene therapy stimulates the immune system and decreases angiogenesis in dogs with spontaneous cancer

Intratumoural interleukin 12 gene therapy stimulates the immune system and decreases angiogenesis in dogs with spontaneous cancer

Expression kinetics and innate immune response after electroporation and lipid nanoparticle mediated delivery of a self-amplifying mRNA in the skin of mice

Can dendritic cells improve whole cancer cell vaccines based on immunogenically killed cancer cells?

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