Evidence of Anti-tumoral Efficacy in an Immune Competent Setting with an iRGD-Modified Hyaluronidase-Armed Oncolytic Adenovirus

Al-Zaher, Ahmed Abdullah; Moreno, Rafael; Fajardo, Carlos Alberto; Arias-Badia, Marcel; Farrera, M.; Sostoa, Jana de; Rojas, Luis A.; Alemany, Ramón

doi:10.1016/j.omto.2018.01.003

Cited by 16 publications

(14 citation statements)

References 22 publications

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“…The intratumoral administration of VCN-01 did not show any antitumor activity, as previously published. 30 In contrast, ICO15K-E1aPH20 delayed tumor growth. Elevated immune responses against the virus (anti-E1B) correlated with a greater antitumor response (anti- Itgav ), suggesting that the two immune responses are associated, as previously indicated by pre-clinical 31 , 32 and clinical data.…”

Section: Discussionmentioning

confidence: 99%

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Hyaluronidase expression within tumors increases virotherapy efficacy and T cell accumulation

Farrera-Sal

Moreno

Mato-Berciano

et al. 2021

Molecular Therapy - Oncolytics

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Oncolytic viruses (OVs) preferentially infect and selectively replicate in cancer cells. OVs have been tested in clinical trials as monotherapy or in combination with chemotherapy, radiotherapy, and immunotherapy. However, the dense extracellular matrix hampers the intratumoral spreading and efficacy of OVs. Previously we described VCN-01, an oncolytic adenovirus expressing a soluble version of human sperm hyaluronidase (hyal) PH20, which exhibited enhanced intratumoral distribution and antitumor activity in different models. Here, we present two oncolytic adenoviruses designed to increase the secretion of PH20 compared to VCN-01. ICO15K-40SAPH20, encoding PH20 under an Ad40 splice acceptor, and ICO15K-E1aPH20 expressing PH20 fused to the E1A gene by P2A peptide. We demonstrate that increased hyal activity improves antitumor efficacy in both a sensitive immunodeficient model and an immunocompetent model. Moreover, we show that hyal activity impacts T cell accumulation in tumors, highlighting the value of a hyaluronidase-expressing virus for combinations with other immunotherapies in cancers involving dense stroma.

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Section: Discussionmentioning

confidence: 99%

“… 42 For CMT64.6 neoepitopes the peptides of Nduf1s (AAVSNMVQKI), Arghef10a.2 , (AAVKRGRSFI), and Cep192A (QIINNSVTL) were used based on previous publications. 30 , 43 The Itgav (SSILYVKSL) was predicted in silico by NetMHCcons v1.0. For antiviral response, E1b 192 (VNIRNCCYI) was used.…”

Section: Methodsmentioning

confidence: 99%

Hyaluronidase expression within tumors increases virotherapy efficacy and T cell accumulation

Farrera-Sal

Moreno

Mato-Berciano

et al. 2021

Molecular Therapy - Oncolytics

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“…This increased ECM density decreases immune cell infiltration and stymies cell-to-cell spread of the vector. To address this issue, several groups have armed their vectors with hyaluronidase [80][81][82][83]. VCN01 is a variant of the ICOVIR adenovirus (Ad-DM-E2F-K-∆24RGD) with Ad-E1A under the E2F promoter control, instead of the myotonic dystrophy locus in the parental ICOVIR vector.…”

Section: Vectors Expressing Transgenes Which Do Not Directly Interact With Immune Cellsmentioning

confidence: 99%

Immunomodulatory Arming Factors—The Current Paradigm for Oncolytic Vectors Relies on Immune Stimulating Molecules

Peters

Nigim

2021

IJMS

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The dogma of engineering oncolytic viral vectors has shifted from emphasizing the viral lysis of individual cancer cells to the recruitment and coordination of the adaptive immune system to clear the tumor. To accomplish this, researchers have been adding several classes of transgenes to their preferred viral platforms. The most prevalent of these include antibodies and targeting moieties, interleukins and cytokines, and genes which rely on small molecule co-administration for tumor killing. Most current vectors rely exclusively on one of these types of transgenes to elicit the desired immune response to clear tumors, but are not mutually exclusive, with several larger OVs armed with several of these factors. The common theme of emerging armed vectors is to simply initiate or enhance infiltration of effector CD8+ T cells to clear the tumor locally at OV infection sites, and systemically throughout the body where the OV has not infected tumor cells. The precision of oncolytic vectors to target a cell type or tissue remains its key advantage over small-molecule drugs. Unlike chemo- and other drug therapies, viral vectors can be made to specifically infect and grow within tumor cells. This ensures localized expression of the therapeutic transgene to the diseased tissue, thereby limiting systemic toxicity. This review will examine the immunomodulating transgenes of current OVs, describe their general effect on the immune system, and provide the rationale for each vector’s use in clearing its targeted tumor.

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“…For this reason, a number of approaches have been explored to improve HAdV dispersion in a tumor, including the expression of extracellular matrix-degrading enzymes, junction-opening peptides, and proteins intended to improve cytolysis 18, 19, 20, 21. Alternatively, several research groups have evaluated the ability of fusogenic proteins, such as those encoded by the gibbon ape leukemia virus (GALV) or measles virus, to enhance spread of virus-associated cell death through the tumor mass through direct cell-cell fusion 22, 23, 24, 25.…”

Section: Introductionmentioning

confidence: 99%

An Oncolytic Adenovirus Vector Expressing p14 FAST Protein Induces Widespread Syncytium Formation and Reduces Tumor Growth Rate In Vivo

Papa

Petryk

Bell

et al. 2019

Molecular Therapy - Oncolytics

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Intratumoral injection of oncolytic viruses provides a direct means of tumor cell destruction for inoperable tumors. Unfortunately, oncolytic vectors based on human adenovirus (HAdV) typically do not spread efficiently throughout the tumor mass, reducing the efficacy of treatment. In this study, we explore the efficacy of a conditionally replicating HAdV vector expressing the p14 Fusion-Associated Small Transmembrane (FAST) protein (CRAdFAST) in both immunocompetent and immunodeficient mouse models of cancer. The p14 FAST protein mediates cell-cell fusion, which may enhance spread of the virus-mediated, tumor cell-killing effect. In the murine 4T1 model of cancer, treatment with CRAdFAST resulted in enhanced cell death compared to vector lacking the p14 FAST gene, but it did not reduce the tumor growth rate in vivo . In the human A549 lung adenocarcinoma model of cancer, CRAdFAST showed significantly improved oncolytic efficacy in vitro and in vivo . In an A549 xenograft tumor model in vivo , CRAdFAST induced tumor cell fusion, which led to the formation of large acellular regions within the tumor and significantly reduced the tumor growth rate compared to control vector. Our results indicate that expression of p14 FAST from an oncolytic HAdV can improve vector efficacy for the treatment of cancer.

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Evidence of Anti-tumoral Efficacy in an Immune Competent Setting with an iRGD-Modified Hyaluronidase-Armed Oncolytic Adenovirus

Cited by 16 publications

References 22 publications

Hyaluronidase expression within tumors increases virotherapy efficacy and T cell accumulation

Hyaluronidase expression within tumors increases virotherapy efficacy and T cell accumulation

Immunomodulatory Arming Factors—The Current Paradigm for Oncolytic Vectors Relies on Immune Stimulating Molecules

An Oncolytic Adenovirus Vector Expressing p14 FAST Protein Induces Widespread Syncytium Formation and Reduces Tumor Growth Rate In Vivo

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