scholarly journals 742 Multi-armed myxoma virus induces potent anti-tumor responses in vitro and in vivo

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A773-A773
Author(s):  
Wazir Abdullahi ◽  
Lina Franco ◽  
Christopher Fraser ◽  
Heather Hrach ◽  
Nicole Grigaitis ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Transgene Expression ◽  
Caspase 3 ◽  
Cellular Responses ◽  
Myxoma Virus ◽  
Mouse Tumor ◽  
Tgf Beta ◽  
Oncolytic Activity

BackgroundMyxoma virus (MYXV) has been shown to selectively infect cancer cells in humans in vitro and inhibit tumor growth in mice. The genome of MYXV is large and amenable to engineering for expression of multiple transgenes. We armed MYXV with mouse or human IL-12 and human decorin. IL-12 is an immune modulator. Cellular responses to decorin include tumor cell intrinsic signaling effects, tumor matrix remodeling, and inhibition of the TGF-beta pathway. We hypothesized that MYXV armed with decorin and IL-12 would be an effective anti-tumor therapy. The current work describes the oncolytic activity and transgene expression, following exposure to armed MYXV in human cancer cell lines in vitro and efficacy in in vivo in murine models, as single agents and in combination with immune checkpoint inhibition.MethodsCytotoxicity was measured by a cell viability assay. ELISAs were used to detect transgene expression, Caspase-3 activation, and TGF-beta induced SMAD phosphorylation. Mouse tumor models were treated with vehicle control or the indicated virus.ResultsMYXV carrying payloads of decorin and mouse IL-12 (vMYX-mIL-12/Dec) or human IL-12 (vMYX-hIL-12/Dec) were tested. Human tumor cell lines infected with vMYX-hIL-12/Dec in vitro showed independent effects when levels of transgene expression and cytotoxicity were compared, suggesting that oncolytic activity and transgene expression differentially contribute to MYXV activity. Virus-free supernatants derived from infected cells suggested a decorin specific response in caspase-3 activation, and inhibition of TGF-beta signaling. Human IL-12 is not active on mouse immune cells giving the opportunity to evaluate the role of decorin in tumor regression. B16-F10 murine melanoma mice treated with vMYX-mIL-12/Dec showed a robust response while vMYX-hIL-12/Dec showed an intermediate anti-tumor response suggesting decorin has cancer inhibitory activity and synergized with IL-12. We tested anti-PD-1 and vMYX-mIL-12/Dec in the colon adenocarcinoma model MC38. We observed that the combination for multi-armed MYXV with an immune checkpoint inhibitor showed dramatically reduced tumor growth and improved survival.ConclusionsOur data demonstrates that MYXV with IL-12 and decorin payloads have cytotoxic activity in vitro and inhibit tumor growth in vivo. Cellular responses to decorin in vitro included inhibition of processes intrinsic to tumor progression. In mouse tumor models decorin played a role in inhibiting tumor progression and synergized with IL-12 implying the combination has immune-modulatory activity. Interestingly, MYXV with IL-12 and decorin payloads significantly synergized with anti-PD-1 in preventing tumor growth, suggesting a potentially new approach towards anti-cancer therapy.Ethics ApprovalAll studies and procedures involving animals were carried out under the institutional guidelines of Translational Drug Development Institutional Animal Care and Use Committee

AVIDIO as a novel oncolytic immunotherapy platform for the treatment of colorectal cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15210-e15210
Author(s):  
Bijan Almassian ◽  
Bhaskara R Madina ◽  
Ju Chen ◽  
Xiaoyang Ye ◽  
Marie M Krady ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
Tumor Growth ◽  
Semliki Forest Virus ◽  
Tumor Model ◽  
Oncolytic Viruses ◽  
Immunomodulatory Agents ◽  
Oncolytic Activity

e15210 Background: Colorectal cancer is the third deadliest of all cancers causing more than 50,000 deaths per year in the U.S. Oncolytic viruses have seen limited use for the treatment of cancers, and further improvement of these methods with immune-modulating activities may prove crucial for the effectiveness of these agents in the treatment of human malignancies. To this end, we developed an artificial virus for infectious diseases and immuno-oncology (AVIDIO) platform that employs virus-like vesicles (VLV) for both the delivery of immunomodulatory agents to tumors and oncolytic activity. Methods: The AVIDIO platform is comprised of in vitro evolved RNA-dependent RNA polymerase from an alphavirus, Semliki forest virus, and envelope glycoproteins from vesicular stomatitis virus, which together form VLVs. Both unarmed VLVs and VLVs armed with the p35 subunit of IL-12 (VLV-IL12p35), an immunomodulatory cytokine that can induce Th1-mediated immunity, were tested for oncolytic activity against various cancer cell lines, including MC38 colorectal cancer cells, in vitro. Using the MC38 syngeneic murine tumor model, we evaluated the antitumor activity of VLV-IL-12p35 in vivo. We used tumor growth measurements and analyses of tumor-infiltrating cells after consecutive treatments with VLV-IL-12p35 to monitor its antitumor and immunomodulatory activities, respectively. Results: VLV-IL-12p35 showed robust oncolytic activity against MC38 cells in vitro, killing over 80% of cells within 24 h. Treatment of intradermal MC38 tumors by intra-tumoral delivery of VLV-IL-12p35 resulted in more than 65% suppression of tumor growth within 2 weeks ( p< 0.05). VLV-IL-12p35-treated tumors also harbored significantly more CD8+ T cells, IFN-gamma-producing CD4+ T cells, and reduced numbers of Foxp3+ regulatory T cells. Conclusions: Our results show that VLV-IL-12p35 derived from the AVIDIO platform has oncolytic activity in vitro and antitumor and immunomodulatory activities in vivo. Therefore, AVIDIO is a promising platform for the delivery of immunomodulatory agents to tumors. Further optimization of the platform, including the addition of other immunomodulatory agents, is in progress to advance the AVIDIO platform to clinical applications for colorectal cancer.

Indole-3-Carbinol Inhibits Nasopharyngeal Carcinoma

2010 ◽  
Vol 29 (2) ◽  
pp. 185-192 ◽  
Author(s):  
Wei Zhu ◽  
Wenxue Li ◽  
Guangyu Yang ◽  
Quanxin Zhang ◽  
Ming Li ◽  
...  
Keyword(s):  
Superoxide Dismutase ◽  
Nasopharyngeal Carcinoma ◽  
Glutathione Peroxidase ◽  
Tumor Growth ◽  
Caspase 3 ◽  
Caspase 9 ◽  
Human Nasopharyngeal Carcinoma ◽  
Induced Apoptosis

This study explored the effects of indole-3-carbinol on the proliferation of human nasopharyngeal carcinoma, both in vitro and in vivo, and the underlying mechanisms in inducing apoptosis of CNE1 cells. Proliferation, apoptosis, malondialdehyde, superoxide dismutase, glutathione peroxidase, expressions of caspase-9, and caspase-3 in human nasopharyngeal carcinoma cells CNE1 were examined. Indole-3-carbinol suppressed proliferation, induced apoptosis, decreased malondialdehyde level, increased the activity of superoxide dismutase and glutathione peroxidase, and up-regulated the expression of active fragments of caspase-9 and caspase-3 both in vitro and in vivo. It was concluded that indole-3-carbinol could inhibit proliferation and induce apoptosis of CNE1 cells and inhibit tumor growth in mice. Increased activity of superoxide dismutase and glutathione peroxidase and activated expression of caspase-9 and caspase-3 were also observed in indole-3-carbinol–treated tumors or tumor cells, suggesting that stress- and apoptosis-related molecules are involved in the indole-3-carbinol–induced apoptosis and inhibition of tumor growth.

scholarly journals Transgene codon usage drives viral fitness and therapeutic efficacy in oncolytic adenoviruses

NAR Cancer ◽  
2021 ◽  
Vol 3 (2) ◽  
Author(s):  
Estela Núñez-Manchón ◽  
Martí Farrera-Sal ◽  
Marc Otero-Mateo ◽  
Giancarlo Castellano ◽  
Rafael Moreno ◽  
...  
Keyword(s):  
Viral Replication ◽  
Codon Usage ◽  
Transgene Expression ◽  
Rational Design ◽  
Viral Fitness ◽  
Fine Tuning ◽  
Oncolytic Adenoviruses ◽  
Oncolytic Activity

Abstract Arming oncolytic adenoviruses with therapeutic transgenes is a well-established strategy for multimodal tumour attack. However, this strategy sometimes leads to unexpected attenuated viral replication and a loss of oncolytic effects, preventing these viruses from reaching the clinic. Previous work has shown that altering codon usage in viral genes can hamper viral fitness. Here, we have analysed how transgene codon usage impacts viral replication and oncolytic activity. We observe that, although transgenes with optimized codons show high expression levels at the first round of infection, they impair viral fitness and are therefore not expressed in a sustained manner. Conversely, transgenes encoded by suboptimal codons do not compromise viral replication and are thus stably expressed over time, allowing a greater oncolytic activity both in vitro and in vivo. Altogether, our work shows that fine-tuning codon usage leads to a concerted optimization of transgene expression and viral replication paving the way for the rational design of more efficacious oncolytic therapies.

scholarly journals Cystathionine β-synthase mediated PRRX2/IL-6/STAT3 inactivation suppresses Tregs infiltration and induces apoptosis to inhibit HCC carcinogenesis

2021 ◽  
Vol 9 (8) ◽  
pp. e003031
Author(s):  
Yu-Fu Zhou ◽  
Shu-Shu Song ◽  
Meng-Xin Tian ◽  
Zheng Tang ◽  
Han Wang ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Tumor Cells ◽  
Immune Evasion ◽  
Knockout Mice ◽  
Caspase 3 ◽  
Severe Combined Immunodeficiency ◽  
Foxp3 Expression ◽  
Stat3 Pathway

BackgroundHepatocellular carcinoma (HCC) is characterized by inflammation and immunopathogenesis. Accumulating evidence has shown that the cystathionine β-synthase/hydrogen sulfide (CBS/H2S) axis is involved in the regulation of inflammation. However, roles of CBS in HCC development and immune evasion have not been systematically investigated, and their underlying mechanisms remain elusive. Here, we investigated the roles of CBS in tumor cells and tumor microenvironment of HCC.Methods236 HCC samples were collected to detect the expression of CBS, cleaved Caspase-3 and paired related homeobox 2 (PRRX2) and the number of immune cells. HCC cell lines were employed to examine the effects of CBS on cellular viability, apoptosis and signaling in vitro. Cbs heterozygous knockout mice, C57BL/6 mice, nude mice and non-obese diabetic severe combined immunodeficiency mice were used to investigate the in vivo functions of CBS.ResultsDownregulation of CBS was observed in HCC, and low expression of CBS predicted poor prognosis in HCC patients. CBS overexpression dramatically promoted cellular apoptosis in vitro and inhibited tumor growth in vivo. Activation of the Cbs/H2S axis also reduced the abundance of tumor-infiltrating Tregs, while Cbs deficiency promoted Tregs-mediated immune evasion and boosted tumor growth in Cbs heterozygous knockout mice. Mechanistically, CBS facilitated the expression cleaved Caspase-3 in tumor cells, and on the other hand, suppressed Foxp3 expression in Tregs via inactivating IL-6/STAT3 pathway. As a transcription factor of IL-6, PRRX2 was reduced by CBS. Additionally, miR-24-3p was proven to be an upstream suppressor of CBS in HCC.ConclusionsOur results indicate the antitumor function of CBS in HCC by inactivation of the PRRX2/IL-6/STAT3 pathway, which may serve as a potential target for HCC clinical immunotherapy.

scholarly journals Searching for Promoters to Drive Stable and Long-Term Transgene Expression in Fibroblasts for Syngeneic Mouse Tumor Models

2020 ◽  
Vol 21 (17) ◽  
pp. 6098
Author(s):  
Dina V. Antonova ◽  
Irina V. Alekseenko ◽  
Anastasiia K. Siniushina ◽  
Alexey I. Kuzmich ◽  
Victor V. Pleshkan
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Transgene Expression ◽  
Close Contact ◽  
Mouse Tumor ◽  
Cancer Associated Fibroblasts

Tumor is a complex system of interactions between cancer cells and other cells of the tumor microenvironment. The cancer-associated fibroblasts (CAFs) of the tumor microenvironment remain in close contact with the cancer cells and play an important role in cancer progression. Genetically, CAFs are more stable than cancer cells, making them an attractive target for genetic modification in gene therapy. However, the efficiency of various promoters for transgene expression in fibroblasts is scarcely studied. We performed a comparative analysis of transgene long-term expression under the control of strong cytomegalovirus promoter (pCMV), constitutive cell promoter of the PCNA gene (pPCNA), and the potentially fibroblast-specific promoter of the IGFBP2 gene (pIGFBP2). In vitro expression of the transgene under the control of pCMV in fibroblasts was decreased soon after transduction, whereas the expression was more stable under the control of pIGFBP2 and pPCNA. The efficiency of transgene expression was higher under pPCNA than that under pIGFBP2. Additionally, in a mouse model, pPCNA provided more stable and increased transgene expression in fibroblasts as compared to that under pCMV. We conclude that PCNA promoter is the most efficient for long-term expression of transgenes in fibroblasts both in vitro and in vivo.

scholarly journals A Targeted-Covalent Inhibitor of 17β-HSD1 Blocks Two Estrogen-Biosynthesis Pathways: In Vitro (Metabolism) and In Vivo (Xenograft) Studies in T-47D Breast Cancer Models

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1841
Author(s):  
Donald Poirier ◽  
Jenny Roy ◽  
René Maltais
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Therapeutic Potential ◽  
Tumor Model ◽  
Growth Effect ◽  
Mouse Tumor ◽  
Cancer Models ◽  
Model Cell

17β-Hydroxysteroid dehydrogenase type 1 (17β-HSD1) plays an important role in estrogen-dependent breast tumor growth. In addition to being involved in the production of estradiol (E2), the most potent estrogen in women, 17β-HSD1 is also responsible for the production of 5-androsten-3β,17β-diol (5-diol), a weaker estrogen than E2, but whose importance increases after menopause. 17β-HSD1 is therefore a target of choice for the treatment of estrogen-dependent diseases such as breast cancer and endometriosis. After we developed the first targeted-covalent (irreversible) and non-estrogenic inhibitor of 17β-HSD1, a molecule named PBRM, our goal was to demonstrate its therapeutic potential. Enzymatic assays demonstrated that estrone (E1) and dehydroepiandrosterone (DHEA) were transformed into E2 and 5-diol in T-47D human breast cancer cells, and that PBRM was able to block these transformations. Thereafter, we tested PBRM in a mouse tumor model (cell-derived T-47D xenografts). After treatment of ovariectomized (OVX) mice receiving E1 or DHEA, PBRM given orally was able to reduce the tumor growth at the control (OVX) level without any observed toxic effects. Thanks to its irreversible type of inhibition, PBRM retained its anti-tumor growth effect, even after reducing its frequency of administration to only once a week, a clear advantage over reversible inhibitors.

scholarly journals 446 Immunopeptidome changes mediated by a novel ERAP1 inhibitor leads to tumor growth inhibition

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A472-A472
Author(s):  
Peter Joyce ◽  
Lesley Young ◽  
Martin Quibell ◽  
Jason Shiers ◽  
Carmen Tong ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Growth ◽  
Growth Inhibition ◽  
Hla Class I ◽  
Class I ◽  
Tumor Growth Inhibition ◽  
Mouse Tumor ◽  
Cell Repertoire

BackgroundClinical data demonstrates increased antigen presentation diversity is a key factor in determining response rates to checkpoint inhibitors.1 In addition to tumour mutational burden/microsatellite instability, increased HLA heterozygosity and HLA evolutionary diversity are non-overlapping factors recently identified to further diversify the immunopeptidome and improve clinical response to checkpoint therapies.2 3 Endoplasmic reticulum aminopeptidase 1 (ERAP1) is an enzyme that trims peptides loaded into classical and nonclassical class I MHC molecules.4 5 Ablation of mouse ERAAP modifies the immunopeptidome, resulting in improved immunogenicity, generation of CD8 T cell responses and tumor growth inhibition.6 7 Recently identified selective small molecules potently inhibit ERAP1 across key species and haplotypes.8 We report the further profiling of lead candidate ERAP1 inhibitors in human primary T cell in vitro assays and in vivo tumor models in mice.MethodsHuman cancer cell lines treated with ERAP1 inhibitors in vitro or in vivo in xenograft mouse models were assessed by immunopeptidomics9 to profile peptide repertoire changes. Novel or upregulated peptides were also tested in human immunogenicity assays. FACS analysis of T cells stimulated with Tyrosinase mRNA transfected human dendritic cells ± ERAP1 inhibition was to assess T cell repertoire changes. ERAP1 inhibitor and anti PD-1 mAb combination was assessed in syngeneic mouse tumor models to investigate tumour growth inhibition and PD end-points (e.g. IHC).ResultsAnalysis of human cervical, lung, colorectal and melanoma cell lines carrying distinct HLA haplotypes demonstrates a consistent and profound effect of ERAP1 inhibition on the immunopeptidome. Novel and upregulated cancer associated antigens identified in association with multiple different HLA-A and B alleles stimulate IFNγ production in primary naïve human T cell immunogenicity assays. The impact of ERAP1 inhibition on the T cell repertoire to the melanoma antigen tyrosinase is ongoing. The combination of ERAP1 inhibitor and anti PD-1 mAb led to significant tumor growth inhibition in the CT26 syngeneic mouse tumor model that correlated with increased infiltration of T cells to the tumor. Further PD end-points to be analysed include immune gene array and TCR Vbeta repertoire.ConclusionsGrey Wolf ERAP1 inhibitors significantly modify the immunopeptidome both in vitro and in vivo across a broad range of HLA and tumor types. Combination of these inhibitors with anti PD-1 leads to significant T cell infiltration and tumor growth inhibition. Thus, ERAP1 mediated modulation of the immunopeptidome has the potential to drive anti tumor T cell responses and be a transformative immunotherapy.ReferencesRizvi N, Hellmann MD, Snyder A, et al. Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer. Science. 2015;348(6230):124–128.Chowell D, Morris LGT, Grigg CM, et al. Patient HLA class I genotype influences cancer response to checkpoint blockade immunotherapy. Science 2018;359 (6375):582–587.Chowell D, Krishna C, Pierini F, et al. Evolutionary divergence of HLA class I genotype impacts efficacy of cancer immunotherapy. Nature Medicine 2019;25(11):1715–1720.Shastri N, Nagarajan N, Lind KC, et al. Monitoring peptide processing for MHC class I molecules in the endoplasmic reticulum. Curr Opin Immunol 2014; 26:123–127.Mpakali A, Maben Z, Stern LJ, et al. Molecular pathways for antigenic peptide generation by ER aminopeptidase 1. Mol Immunol 2018; 13:50–57.James E, Bailey I, Sugiyarto G, et al. Induction of protective antitumor immunity through attenuation of ERAAP function. J Immunol 2013;190(11):5839–5846.Manguso RT, Pope HW, Zimmer MD, et al. In vivo CRISPR screening identifies Ptpn2 as a cancer immunotherapy target. Nature 2017;547(7664):413–418.Leonard, H Remtulla A, Poynton F, et al. AACR Annual Meeting 2020.Purcell AW, Ramarathinam SH, Ternette N. Mass spectrometry–based identification of MHC-bound peptides for immunopeptidomics. Nat Protoc 2019;14(6):1687–1707.

scholarly journals Single Amino Acid Differences between Closely Related Reovirus T3D Lab Strains Alter Oncolytic Potency In Vitro and In Vivo

2019 ◽  
Vol 94 (4) ◽  
Author(s):  
Adil Mohamed ◽  
Derek R. Clements ◽  
Shashi A. Gujar ◽  
Patrick W. Lee ◽  
James R. Smiley ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Amino Acid ◽  
Cancer Therapy ◽  
Murine Model ◽  
Single Amino Acid ◽  
Mouse Tumor ◽  
Plaque Size ◽  
Oncolytic Activity

ABSTRACT Little is known about how genetic variations in viruses affect their success as therapeutic agents. The type 3 Dearing strain of Mammalian orthoreovirus (T3D) is undergoing clinical trials as an oncolytic virotherapy. Worldwide, studies on reovirus oncolysis use T3D stocks propagated in different laboratories. Here, we report that genetic diversification among T3D stocks from various sources extensively impacts oncolytic activity. The T3D strain from the Patrick Lee laboratory strain (TD3PL) showed significantly stronger oncolytic activities in a murine model of melanoma than the strain from the Terence Dermody laboratory (T3DTD). Overall in vitro replication and cytolytic properties of T3D laboratory strains were assessed by measuring virus plaque size on a panel of human and mouse tumor cells, and results were found to correlate with in vivo oncolytic potency in a melanoma model. T3DPL produced larger plaques than T3DTD and than the T3D strain from the ATCC (T3DATCC) and from the Kevin Coombs laboratory (T3DKC). Reassortant and reverse genetics analyses were used to decipher key genes and polymorphisms that govern enhanced plaque size of T3DPL. Five single amino acid changes in the S4, M1, and L3 genome segments of reovirus were each partially correlated with plaque size and when combined were able to fully account for differences between T3DPL and T3DTD. Moreover, polymorphisms were discovered in T3DTD that promoted virus replication and spread in tumors, and a new T3DPL/T3DTD hybrid was generated with enhanced plaque size compared to that of T3DPL. Altogether, single amino acid changes acquired during laboratory virus propagation can have a large impact on reovirus therapeutic potency and warrant consideration as possible confounding variables between studies. IMPORTANCE The reovirus serotype 3 Dearing (T3D) strain is in clinical trials for cancer therapy. We find that closely related laboratory strains of T3D exhibit large differences in their abilities to replicate in cancer cells in vitro, which correlates with oncolytic activity in a in a murine model of melanoma. The study reveals that five single amino acid changes among three reovirus genes strongly impact reovirus therapeutic potency. In general, the findings suggest that attention should be given to genomic divergence of virus strains during research and optimization for cancer therapy.

scholarly journals Cysteinyl leukotriene 2 receptor promotes endothelial permeability, tumor angiogenesis, and metastasis

2018 ◽  
Vol 116 (1) ◽  
pp. 199-204 ◽  
Author(s):  
Ernest Duah ◽  
Lakshminarayan Reddy Teegala ◽  
Vinay Kondeti ◽  
Ravi K. Adapala ◽  
Venkateshwar G. Keshamouni ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Ex Vivo ◽  
Endothelial Permeability ◽  
Tumor Vasculature ◽  
In Vivo Model ◽  
Mouse Tumor ◽  
Proinflammatory Mediators ◽  
Myosin Light Chain 2

Cysteinyl leukotrienes (cys-LTs) are proinflammatory mediators that enhance vascular permeability through distinct receptors (CysLTRs). We found that CysLT2R regulates angiogenesis in isolated mouse endothelial cells (ECs) and in Matrigel implants in WT mice and enhances EC contraction and permeability via the Rho-dependent myosin light chain 2 and vascular endothelial (VE)-cadherin axis. Since solid tumors utilize aberrant angiogenesis for their growth and metastasis and their vessels exhibit vascular hyperpermeability, we hypothesized that CysLT2R, via its actions on the endothelium, might regulate tumor growth. Both tumor growth and metastases of adoptively transferred syngeneic Lewis lung carcinoma (LLC) cells are significantly reduced in CysLT2R-null mice (Cysltr2−/−) compared with WT and CysLT1R-null mice (Cysltr1−/−). In WT recipients of LLC cells, CysLT2R expression is significantly increased in the tumor vasculature, compared with CysLT1R. Further, the tumor vasculature in Cysltr2−/− recipients exhibited significantly improved integrity, as revealed by increased pericyte coverage and decreased leakage of i.v.-administered Texas Red-conjugated dextran. Administration of a selective CysLT2R antagonist significantly reduced LLC tumor volume, vessel density, dextran leakage, and metastases in WT mice, highlighting CysLT2R as a VEGF-independent regulator of the vasculature promoting risk of metastasis. Thus, both genetic and pharmacological findings establish CysLT2R as a gateway for angiogenesis and EC dysregulation in vitro and ex vivo and in an in vivo model with a mouse tumor. Our data suggest CysLT2R as a possible target for intervention.

scholarly journals Transgene codon usage drives viral fitness and therapeutic efficacy in oncolytic adenoviruses

2020 ◽  
Author(s):  
Estela Núñez-Manchón ◽  
Martí Farrera-Sal ◽  
Giancarlo Castellano ◽  
David Medel ◽  
Ramon Alemany ◽  
...  
Keyword(s):  
Viral Replication ◽  
Codon Usage ◽  
Transgene Expression ◽  
Rational Design ◽  
Viral Fitness ◽  
Fine Tuning ◽  
Oncolytic Adenoviruses ◽  
Oncolytic Activity

AbstractArming oncolytic adenoviruses with therapeutic transgenes is a well-established strategy for multimodal tumour attack. However, this strategy sometimes leads to unexpected attenuated viral replication and a loss of oncolytic effects, preventing these viruses from reaching the clinic. Previous work has shown that altering codon usage in viral genes can hamper viral fitness. Here, we have analysed how transgene codon usage impacts viral replication and oncolytic activity. We observe that, although transgenes with optimised codons show high expression levels at a first round of infection, they impair viral fitness and are therefore not expressed in a sustained manner. Conversely, transgenes encoded by suboptimal codons do not compromise viral replication and are thus stably expressed over time allowing a greater oncolytic activity both in vitro and in vivo. Altogether, our work shows that fine-tuning codon usage leads to a concerted optimisation of transgene expression and viral replication paving the way for the rational design of more efficacious oncolytic therapies.

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