Sequential administration of a MVA-based MUC1 cancer vaccine and the TLR9 ligand Litenimod (Li28) improves local immune defense against tumors

Schaedler, Emmanuelle; Remy-Ziller, Christelle; Hortelano, Julie; Kehrer, Nadine; Claudepierre, Marie-Christine; Gatard, Tanja; Jakobs, Christopher; Préville, Xavier; Carpentier, Antoine F.; Rittner, Karola

doi:10.1016/j.vaccine.2016.12.020

Cited by 17 publications

(7 citation statements)

References 24 publications

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“…Preclinical combination immunotherapy studies have been performed to further improve its efficacy. Sequential administration of a MVA-MUC1 cancer vaccine and the TLR9 ligand, Litenimod, improved local immune defense against tumors [59]. In another study, first MVA-βGal and MVA-MUC1 treatments were used to treat mice with established CT26 colon carcinomas.…”

Section: Biology Of Vaccinia Virusmentioning

confidence: 99%

Vaccinia virus-mediated cancer immunotherapy: cancer vaccines and oncolytics

Guo

et al. 2019

j. immunotherapy cancer

219

170

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Cancer vaccines and oncolytic immunotherapy are promising treatment strategies with potential to provide greater clinical benefit to patients with advanced-stage cancer. In particular, recombinant vaccinia viruses (VV) hold great promise as interventional agents. In this article, we first summarize the current understanding of virus biology and viral genes involved in host-virus interactions to further improve the utility of these agents in therapeutic applications. We then discuss recent findings from basic and clinical studies using VV as cancer vaccines and oncolytic immunotherapies. Despite encouraging results gleaned from translational studies in animal models, clinical trials implementing VV vectors alone as cancer vaccines have yielded largely disappointing results. However, the combination of VV vaccines with alternate forms of standard therapies has resulted in superior clinical efficacy. For instance, combination regimens using TG4010 (MVA-MUC1-IL2) with first-line chemotherapy in advanced-stage non-small cell lung cancer or combining PANVAC with docetaxel in the setting of metastatic breast cancer have clearly provided enhanced clinical benefits to patients. Another novel cancer vaccine approach is to stimulate anti-tumor immunity via STING activation in Batf3-dependent dendritic cells (DC) through the use of replication-attenuated VV vectors. Oncolytic VVs have now been engineered for improved safety and superior therapeutic efficacy by arming them with immune-stimulatory genes or pro-apoptotic molecules to facilitate tumor immunogenic cell death, leading to enhanced DC-mediated cross-priming of T cells recognizing tumor antigens, including neoantigens. Encouraging translational and early phase clinical results with Pexa-Vec have matured into an ongoing global phase III trial for patients with hepatocellular carcinoma. Combinatorial approaches, most notably those using immune checkpoint blockade, have produced exciting pre-clinical results and warrant the development of innovative clinical studies. Finally, we discuss major hurdles that remain in the field and offer some perspectives regarding the development of next generation VV vectors for use as cancer therapeutics.

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Section: Biology Of Vaccinia Virusmentioning

confidence: 99%

Vaccinia virus-mediated cancer immunotherapy: cancer vaccines and oncolytics

Guo

et al. 2019

j. immunotherapy cancer

219

170

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“…To assess whether our observations in the mouse model were valid also in human cells, we stimulated with the two PRRs agonists human monocyte-derived macrophages generated according to Mia et al [ 21 ]. We tested the effect of NAB2 on macrophages because in our previous published [ 22 ] and unpublished work, we observed that the anti-tumoral effect of PRR stimulation combined with a prophylactic vaccine was dependent on the activation status and cytokine profile of tumor-infiltrating macrophages. A combination of M-CSF, IL-4/IL-10/TGF-β yielded a phenotype of adherent CD206+CD163+ macrophages with downregulated CD86 expression.…”

Section: Resultsmentioning

confidence: 99%

NAB2 is a novel immune stimulator of MDA-5 that promotes a strong type I interferon response

et al. 2017

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Novel adjuvants are needed to increase the efficacy of vaccine formulations and immune therapies for cancer and chronic infections. In particular, adjuvants that promote a strong type I IFN response are required, since this cytokine is crucial for the development of efficient anti-tumoral and anti-viral immunity. Nucleic acid band 2 (NAB2) is a double-stranded RNA molecule isolated from yeast and identified as an agonist of the pattern-recognition receptors TLR3 and MDA-5. We compared the ability of NAB2 to activate innate immunity with that of poly(I:C), a well-characterized TLR3 and MDA-5 agonist known for the induction of type I IFN. NAB2 promoted stronger IFN-α production and induced a higher activation state of both murine and human innate immune cells compared to poly(I:C). This correlated with a stronger activation of the signalling pathway downstream of MDA-5, and IFN-α induction was dependent on MDA-5. Upon injection, NAB2 induced higher levels of serum IFN-α in mice than poly(I:C). These results suggest that NAB2 has the potential to become an efficient adjuvant for the induction of type-I IFN responses in therapeutic immunization against cancer or infections.

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“…Another possibility could be the direct depletion of macrophages, which has experimentally been undertaken in tumors 38 , 39 . However, this could affect also antitumoral macrophages, leading to lower survival rates 40 . An elegant way to recruit macrophages for an antitumoral response starts at its very beginning through activating pattern recognition receptors as e.g.…”

Section: Discussionmentioning

confidence: 99%

“…An elegant way to recruit macrophages for an antitumoral response starts at its very beginning through activating pattern recognition receptors as e.g. TLR9 40 . Those therapies may also have an impact on the composition of macrophages and lymphocytes in the tumor draining lymph nodes, which yet remains to be characterized.…”

Section: Discussionmentioning

confidence: 99%

Morphology of Immunomodulation in Breast Cancer Tumor Draining Lymph Nodes Depends on Stage and Intrinsic Subtype

Seidl

Bader

Vaihinger

et al. 2018

Sci Rep

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Cancer research of immune-modulating mechanisms mainly addresses the role of tumor-infiltrating immune cells. Mechanisms modulating the adaptive immune system at the primary activation site – the draining lymph node (LN) – are less investigated. Here we present tumor-caused histomorphological changes in tumor draining LNs of breast cancer patients, dependent on the localization (sentinel LN vs. non-sentinel LN), the tumor size, the intrinsic subtype and nodal metastatic status. The quantitative morphological study was conducted in breast cancer patients with at least one sentinel LN and no neoadjuvant therapy. All LNs were annotated considering to their topographical location, stained for IgD/H&E, digitized and quantitatively analyzed. In 206 patients, 394 sentinels and 940 non-sentinel LNs were categorized, comprising 40758 follicles and 7074 germinal centers. Subtype specific immunomorphological patterns were detectable: Follicular density was higher in LNs of Her2 enriched hormone receptor positive and triple-negative breast cancers whereas hormone receptor positive breast cancers showed more macrophage infiltrations in the LN cortex. Follicles are rounder in metastatic LNs and non-sentinel LNs. The identified immunomorphological changes reflect different underlying immunomodulations taking place in the tumor-draining LNs and should therefore be considered as possible prognostic and predictive markers for LN metastasis and therapy associated immunomodulation.

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Sequential administration of a MVA-based MUC1 cancer vaccine and the TLR9 ligand Litenimod (Li28) improves local immune defense against tumors

Cited by 17 publications

References 24 publications

Vaccinia virus-mediated cancer immunotherapy: cancer vaccines and oncolytics

Vaccinia virus-mediated cancer immunotherapy: cancer vaccines and oncolytics

NAB2 is a novel immune stimulator of MDA-5 that promotes a strong type I interferon response

Morphology of Immunomodulation in Breast Cancer Tumor Draining Lymph Nodes Depends on Stage and Intrinsic Subtype

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