Safe and Effective Treatment of Experimental Neuroblastoma and Glioblastoma Using Systemically Delivered Triple MicroRNA-Detargeted Oncolytic Semliki Forest Virus

Ramachandran, Mohanraj; Yu, Di; Dyczynski, Matheus; Baskaran, Sathishkumar; Zhang, Lei; Lulla, Aleksei; Lulla, Valeria; Saul, Sirle; Nelander, Sven; Dimberg, Anna; Merits, Andres; Leja-Jarblad, Justyna; Essand, Magnus

doi:10.1158/1078-0432.ccr-16-0925

Cited by 47 publications

(52 citation statements)

References 42 publications

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“…Wild-type human Adenovirus serotype 5 (Ad) was obtained from ATCC and was amplified and purified as described previously 11 . Semliki Forest virus (SFV) strain 4 was obtained from Andres Merits, University of Tartu, Tartu, Estonia and was amplified and purified as previously described 15 . Vaccinia virus (VV) Western Reserve stain was obtained from Bernard Moss, National Institute for Allergy and Infectious Diseases, and was amplified and purified as described previously 52 .…”

Section: Virusesmentioning

confidence: 99%

“…Adenovirus is a non-enveloped virus, containing a linear double-stranded DNA genome and Adenoviruses are some of the most commonly used OVs in pre-clinical and clinical research 14 . SFV4 is a neurotropic enveloped virus, with a positive-sense singlestranded RNA genome 15 . SFVs have been engineered as OV for treatment of glioblastoma 15,16 but is yet to be evaluated in clinical trials.…”

Section: Introductionmentioning

confidence: 99%

“…SFV4 is a neurotropic enveloped virus, with a positive-sense singlestranded RNA genome 15 . SFVs have been engineered as OV for treatment of glioblastoma 15,16 but is yet to be evaluated in clinical trials. VV is an enveloped virus, containing a large linear, double-stranded DNA genome.…”

Section: Introductionmentioning

confidence: 99%

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Characterization of virus-mediated immunogenic cancer cell death and the consequences for oncolytic virus-based immunotherapy of cancer

et al. 2020

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Oncolytic viruses have the potential to induce immunogenic cell death (ICD) that may provoke potent and longlasting anti-cancer immunity. Here we aimed to characterize the ICD-inducing ability of wild-type Adenovirus (Ad), Semliki Forest virus (SFV) and Vaccinia virus (VV). We did so by investigating the cell death and immune-activating properties of virus-killed tumor cells. Ad-infection of tumor cells primarily activates autophagy, but also activate events of necroptotic and pyroptotic cell death. SFV infection on the other hand primarily activates immunogenic apoptosis while VV activates necroptosis. All viruses mediated lysis of tumor cells leading to the release of danger-associated molecular patterns, triggering of phagocytosis and maturation of dendritic cells (DCs). However, only SFV-infected tumor cells triggered significant T helper type 1 (Th1)-cytokine release by DCs and induced antigen-specific T-cell activation. Our results elucidate cell death processes activated upon Ad, SFV, and VV infection and their potential to induce T cell-mediated anti-tumor immune responses. This knowledge provides important insight for the choice and design of therapeutically successful virus-based immunotherapies.

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Section: Virusesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Characterization of virus-mediated immunogenic cancer cell death and the consequences for oncolytic virus-based immunotherapy of cancer

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“…Many alphaviruses, such as Semliki Forest virus (SFV) [67,68], Sindbis virus (SINV) [69], and M1, exhibit antitumor activity. M1 is a recently identified Getah-like alphavirus from culicine mosquitoes [70,71].…”

Section: Wild-type Ovs In Oncolytic Virotherapymentioning

confidence: 99%

Development of oncolytic virotherapy: from genetic modification to combination therapy

et al. 2020

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Oncolytic virotherapy (OVT) is a novel form of immunotherapy using natural or genetically modified viruses to selectively replicate in and kill malignant cells. Many genetically modified oncolytic viruses (OVs) with enhanced tumor targeting, antitumor efficacy, and safety have been generated, and some of which have been assessed in clinical trials. Combining OVT with other immunotherapies can remarkably enhance the antitumor efficacy. In this work, we review the use of wild-type viruses in OVT and the strategies for OV genetic modification. We also review and discuss the combinations of OVT with other immunotherapies.

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“…Patient-derived xenograft (PDX) models of GBM are routinely employed to evaluate complex interactions between the human tumor cells and a CNS microenvironment [4,5,6]. These PDX models also serve as an invaluable preclinical model to evaluate the efficacy of candidate therapeutics [7,8 ]. The Mayo Clinic Glioma PDX National Resource comprises 96 well-characterized GBM lines that collectively capture much of the clinical and molecular breadth of human GBM [9].…”

Section: Introductionmentioning

confidence: 99%

Impact of the radiated brain microenvironment on a panel of human patient-derived xenografts

Zhang

Olson

Carlstrom

et al. 2020

Preprint

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ObjectiveRadiotherapy, combined with surgical resection and chemotherapy, remains a first-line treatment for infiltrative gliomas. However, these tumor are not surgically curable, and often recur, even within the prior radiation field, and may demonstrate a more aggressive phenotype. We recently demonstrated that the radiated brain tumor microenvironment promotes tumor aggressiveness in an orthotopic patient-derived xenograft (PDX) model of glioblastoma (Mayo GBM 143). Importantly, high grade gliomas display diverse molecular phenotypes, and whether this genetic variability leads to divergent behaviour in the radiated tumor microenvironment is unknown. Herein, we characterize the effects of the irradiated brain microenvinroment on nine additional unique GBM cell lines to better understand the nuances of how tumor molecular phenotypes influence cellular dynamics. MethodsFemale athymic nude mice were randomly divided into cranial radiation (15 Gy) and non-radiated groups. Mice then underwent intracranial implantation with one of the selected PDX GBM cell lines (GBM 6,10,12, 39, 46, 76, 123, 164, 196; per group, per line). GBM 6 cells were additionally implanted 6 months after completion of fractionated radiation (4Gy x 10 fractions or 2Gy x 30 fractions) vs sham radiation.Kaplan-Meyer (K-M) and log-rank tests were performed to compare the survival between irradiated and non-irradiated groups. ResultOf nine previously untested human GBM lines, we found that five demonstrated shorter survival in the pre-radiated brain (GBM 6, 46, 76, 164, 196); similar to previous observations with GBM 143. GBM 6 was also evaluated 6 months after fractionated radiation yielding similar results. However, two lines yielded prolonged survival in the 4 pre-radiated brain (GBM 10, 12); GBM12 and 10 demonstrated the fastest baseline growth in the non-radiated brain; GBM 39, 123 whose rate of growth was not impacted by the radiated brain, demonstrated a an intermediate baseline growth rate between that of those positively and negatively impacted by the radiated brain microenvironment. No other clinical or molecular phenotype was found to consistently correlate with response to the radiated microenvironment. ConclusionAmong a total of 10 total human GBM lines evaluated to date, 60% induce faster mortality in a radiated microenvironment, and 20% induce slower mortality. These results highlight the likely critical impact of the irradiated microenvironment on tumor behaviour, yet illustrate that different tumors may exhibit opposing responses. Although further evaluation will be needed to understand mechanisms of divergent behavior, our data suggest the increased rate of growth in the radiated microenvironment may not apply to the fastest-growing tumor lines, which could instead demonstrate a paradoxical response.

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Safe and Effective Treatment of Experimental Neuroblastoma and Glioblastoma Using Systemically Delivered Triple MicroRNA-Detargeted Oncolytic Semliki Forest Virus

Cited by 47 publications

References 42 publications

Characterization of virus-mediated immunogenic cancer cell death and the consequences for oncolytic virus-based immunotherapy of cancer

Characterization of virus-mediated immunogenic cancer cell death and the consequences for oncolytic virus-based immunotherapy of cancer

Development of oncolytic virotherapy: from genetic modification to combination therapy

Impact of the radiated brain microenvironment on a panel of human patient-derived xenografts

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