Axitinib increases the infiltration of immune cells and reduces the suppressive capacity of monocytic MDSCs in an intracranial mouse melanoma model

Four, Stephanie Du; Maenhout, Sarah; Pierre, Kari De; Renmans, Dries; Niclou, Simone P.; Thielemans, Kris; Neyns, Bart; Aerts, Joeri L.

doi:10.1080/2162402x.2014.998107

Cited by 65 publications

(52 citation statements)

References 47 publications

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“…Axitinib (AG-013736) is an FDA approved, orally administered potent small molecule tyrosine kinase inhibitor (TKI), which inhibits VEGF receptor (VEGFR) 1-3, platelet-derived growth factor receptor beta (PDGFR-β) and receptor tyrosine kinase c-KIT (CD117) [115], and shows promising anti-vascular and anti-tumor activity in a variety of advanced stage cancers, including GBM [116][117][118]. In addition to anti-vascular effects, it also induces anti-tumor immune effects [119,120]. Therefore, anti-vascular/immune axitinib was tested in combination with anti-angiogenic/immune stimulatory G47∆-IL12 in highly angiogenic patient and mouse GSC-derived GBM models [76].…”

Section: Inhibition Of Tumor Angiogenesis Enhances Anti-tumor Potentimentioning

confidence: 99%

Oncolytic Virus Encoding a Master Pro-Inflammatory Cytokine Interleukin 12 in Cancer Immunotherapy

Nguyen

Guz-Montgomery

Saha

2020

Cells

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Oncolytic viruses (OVs) are genetically modified or naturally occurring viruses, which preferentially replicate in and kill cancer cells while sparing healthy cells, and induce anti-tumor immunity. OV-induced tumor immunity can be enhanced through viral expression of anti-tumor cytokines such as interleukin 12 (IL-12). IL-12 is a potent anti-cancer agent that promotes T-helper 1 (Th1) differentiation, facilitates T-cell-mediated killing of cancer cells, and inhibits tumor angiogenesis. Despite success in preclinical models, systemic IL-12 therapy is associated with significant toxicity in humans. Therefore, to utilize the therapeutic potential of IL-12 in OV-based cancer therapy, 25 different IL-12 expressing OVs (OV-IL12s) have been genetically engineered for local IL-12 production and tested preclinically in various cancer models. Among OV-IL12s, oncolytic herpes simplex virus encoding IL-12 (OHSV-IL12) is the furthest along in the clinic. IL-12 expression locally in the tumors avoids systemic toxicity while inducing an efficient anti-tumor immunity and synergizes with anti-angiogenic drugs or immunomodulators without compromising safety. Despite the rapidly rising interest, there are no current reviews on OV-IL12s that exploit their potential efficacy and safety to translate into human subjects. In this article, we will discuss safety, tumor-specificity, and anti-tumor immune/anti-angiogenic effects of OHSV-IL12 as mono-and combination-therapies. In addition to OHSV-IL12 viruses, we will also review other IL-12-expressing OVs and their application in cancer therapy.

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Section: Inhibition Of Tumor Angiogenesis Enhances Anti-tumor Potentimentioning

confidence: 99%

Oncolytic Virus Encoding a Master Pro-Inflammatory Cytokine Interleukin 12 in Cancer Immunotherapy

Nguyen

Guz-Montgomery

Saha

2020

Cells

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“…Our results also indicate that, irrespective of tumor administration approach, but more profoundly in the traditional approach, tumor burden was lower in the brain compared to the rest of the head tissue, in both the 24 hours tumor retention index and the 14 days bioluminescence index. This observation has crucial implications for in vivo bioluminescent imaging of brain metastases (Chung et al, 2009; Du Four et al, 2015; Song et al, 2009; Wolff et al, 2015), which cannot distinguish between cerebral and extra-cerebral signaling. It implies that ex-vivo analyses of separated tissues, as conducted herein, have a significant added value.…”

Section: Discussionmentioning

confidence: 99%

Maintaining unperturbed cerebral blood flow is key in the study of brain metastasis and its interactions with stress and inflammatory responses

Benbenishty

Segev-Amzaleg

Shaashua

et al. 2017

Brain, Behavior, and Immunity

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Blood-borne brain metastases are associated with poor prognosis, but little is known about the interplay between cerebral blood flow, surgical stress responses, and the metastatic process. The intra-carotid inoculation approach, traditionally used in animal studies, involves permanent occlusion of the common carotid artery (CCA). Herein we introduce a novel intra-carotid inoculation approach that avoids CCA ligation, namely – assisted external carotid artery inoculation (aECAi) – and compared it to the traditional approach in C57/BL6 mice, assessing cerebral blood flow; particle distribution; blood-brain barrier (BBB) integrity; stress, inflammatory and immune responses; and tumor brain retention and growth. Doppler flowmetry and two-photon imaging confirmed that only in the traditional approach regional and capillary cerebral blood flux were significantly reduced. Corticosterone and plasma IL-6 levels were higher in the traditional approach, splenic numbers of NK, CD3+, granulocytes, and dendritic cells were lower, and many of these indices were more profoundly affected by surgical stress in the traditional approach. BBB integrity was unaffected. Administration of spherical beads indicated that CCA ligation significantly limited brain distribution of injected particles, and inoculation of D122-LLC syngeneic tumor cells resulted in 10-fold lower brain tumor-cell retention in the traditional approach. Last, while most of the injected tumor cells were arrested in extra-cranial head areas, our method improved targeting of brain-tissue by 7-fold. This head versus brain distribution difference, commonly overlooked, cannot be detected using in vivo bioluminescent imaging. Overall, it is crucial to maintain unperturbed cerebral blood flow while studying brain metastasis and interactions with stress and inflammatory responses.

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“…(B): Immunomodulatory targets for tyrosine kinase inhibitors (TKIs)—rationale for combination with checkpoint inhibitors in RCC. TKIs have been shown, generally in ex vivo or non‐VHL tumor models, to modulate (suppress [red line] or stimulate [green arrow]) the activity of immune cells (e.g., activation, migration, proliferation, expansion, recruitment) involved in the tumor‐immune response, including CD8+ T cells , CD4+ T cells , T reg cells , APC , tumor‐associated macrophages , MDSC , and NK cells . Abbreviations: APC, antigen‐presenting cell; CD, cluster of differentiation; CTLA‐4, cytotoxic T‐lymphocyte‐associated protein 4; FGF, fibroblast growth factor; FGFR, fibroblast growth factor receptor; GAS6, AXL receptor tyrosine kinase ligand; HGF, hepatocyte growth factor; HIFα, hypoxia‐inducible factor alpha; IL‐10, interleukin 10; MDSC, myeloid‐derived suppressor cell; MHC, major histocompatibility complex; mTOR, mechanistic target of rapamycin; NK, natural killer; PD‐1, programmed cell death receptor 1; PDGF, platelet‐derived growth factor; PDGFR, platelet‐derived growth factor receptor; PD‐L1/L2, programmed cell death‐ligand 1 or 2; TCR, T‐cell receptor; T eff , effector T cell; TGF‐β, transforming growth factor‐β; T reg cell, regulatory T cell; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptors; VHL, von Hippel‐Lindau.…”

Section: Treatment Characteristicsmentioning

confidence: 99%

Second-Line Treatment Landscape for Renal Cell Carcinoma: A Comprehensive Review

Tannir

Pal

Atkins³

2018

The Oncologist

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This review article provides the reader with a comprehensive overview of current treatment options for patients with advanced clear-cell renal cell carcinoma (RCC) whose disease has progressed after their first therapy. As many patients with RCC experience disease progression with initial treatments, effective second-line therapies are critical. Nivolumab, cabozantinib, and lenvatinib plus everolimus have recently been approved as second-line treatments. The new agents discussed in this review increase the therapeutic options available and provide physicians with opportunities to individualize treatments for their patients, with a view to improving disease control and survival outcomes.

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Axitinib increases the infiltration of immune cells and reduces the suppressive capacity of monocytic MDSCs in an intracranial mouse melanoma model

Abstract: Aerts (2015) Axitinib increases the infiltration of immune cells and reduces the suppressive capacity of monocytic MDSCs in an intracranial mouse melanoma model , OncoImmunology, 4:4, e998107,

Cited by 65 publications

References 47 publications

Oncolytic Virus Encoding a Master Pro-Inflammatory Cytokine Interleukin 12 in Cancer Immunotherapy

Oncolytic Virus Encoding a Master Pro-Inflammatory Cytokine Interleukin 12 in Cancer Immunotherapy

Maintaining unperturbed cerebral blood flow is key in the study of brain metastasis and its interactions with stress and inflammatory responses

Second-Line Treatment Landscape for Renal Cell Carcinoma: A Comprehensive Review

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