Development of a second‐generation oncolytic Herpes simplex virus expressing TNFα for cancer therapy

Han, Z.; Assenberg, M.; Liu, Binlei; Wang, Y. B.; Simpson, Guy R.; Thomas, Stuart; Coffin, Robert S.

doi:10.1002/jgm.999

Cited by 48 publications

(29 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To overcome this problem, OVs were armed with inflammatory cytokines or delivered together with anti-tumour factors. Adenovirus-and HSVbased OVs armed with TNF-a were shown to have enhanced anti-tumour activity (Han et al, 2007;Hirvinen et al, 2015), as were HSV or vaccinia-based OVs armed with GM-CSF (Kaufman et al, 2014;Parviainen et al, 2015) and an oncolytic Newcastle disease delivered in combination with systemic cytotoxic T-lymphocyte antigen 4 (CTLA-4) blockade (Zamarin et al, 2014). However, individual cytokines deliver immunostimulatory signals in a relatively non-specific manner and they may even contribute to the establishment of immune tolerance, as shown for exogenously delivered GM-CSF (Mortha et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

ΔPK oncolytic activity includes modulation of the tumour cell milieu

Bollino

Nghiem

et al. 2016

Journal of General Virology

View full text Add to dashboard Cite

Oncolytic virotherapy is a unique cancer therapeutic that encompasses tumour cell lysis through both virus replication and programmed cell death (PCD) pathways. Nonetheless, clinical efficacy is relatively modest, likely related to the immunosuppressive tumour milieu. Our studies use the herpes simplex virus type 2 (HSV-2)-based oncolytic virus D PK that has documented anti-tumour activity associated with virus replication, PCD and cancer stem cell lysis. They are designed to examine whether D PK-mediated oncolysis includes the ability to reverse the immunosuppressive tumour microenvironment by altering the balance of cytokines directly secreted by the melanoma cells and to define its mechanism. Here, we show that melanoma cells secreted the immunosuppressive cytokine IL-10, and that secretion was inhibited by D PK through virus replication and c-Jun N-terminal kinase/c-Jun activation. D PK-induced IL-10 inhibition upregulated surface expression of MHC class I chain-related protein A, the ligand for the activating NKG2D receptor expressed on NK-and cytotoxic T-cells. Concomitantly, D PK also upregulated the secretion of inflammatory cytokines TNF-a, granulocyte macrophage colony-stimulating factor and IL-1b through autophagy-mediated activation of Toll-like receptor 2 pathways and pyroptosis, and it inhibited the expression of the negative immune checkpoint regulator cytotoxic T-lymphocyte antigen 4. Pharmacologic inhibition of these processes significantly reduces the oncolytic activity of D PK.

show abstract

Section: Discussionmentioning

confidence: 99%

ΔPK oncolytic activity includes modulation of the tumour cell milieu

Bollino

Nghiem

et al. 2016

Journal of General Virology

View full text Add to dashboard Cite

show abstract

“…A range of transgene inserts have been evaluated, including suicide genes (Chase et al, 1998;Aghi et al, 1999;Nakamura et al, 2001;Guffey et al, 2007), or those expressing antiangiogenic (Liu et al, 2006;Goodwin et al, 2012;Yoo et al, 2012), apoptotic (Han et al, 2007;Prabhakar et al, 2010), fusogenic (Nakamori et al, 2004;Simpson et al, 2009;Takaoka et al, 2011), and immunomodulatory proteins (Andreansky et al, 1998;Liu et al, 2003;Parker et al, 2005;Walker et al, 2011). Our group has focused on oHSV that express immunostimulatory cytokines (Andreansky et al, 1998;Parker et al, 2000;Hellums et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the Safety and Biodistribution of M032, an Attenuated Herpes Simplex Virus Type 1 Expressing hIL-12, After Intracerebral Administration toAotusNonhuman Primates

Roth

Cassady

Cody

et al. 2014

Human Gene Therapy Clinical Development

View full text Add to dashboard Cite

Herpes simplex virus type 1 (HSV-1) mutants lacking the c 1 34.5 neurovirulence loci are promising agents for treating malignant glioma. Arming oncolytic HSV-1 to express immunostimulatory genes may potentiate therapeutic efficacy. We have previously demonstrated improved preclinical efficacy, biodistribution, and safety of M002, a c 1 34.5-deleted HSV-1 engineered to express murine IL-12. Herein, we describe the safety and biodistribution of M032, a c 1 34.5-deleted HSV-1 virus that expresses human IL-12 after intracerebral administration to nonhuman primates, Aotus nancymae. Cohorts were administered vehicle, 10 6 , or 10 8 pfu of M032 on day 1 and subjected to detailed clinical observations performed serially over a 92-day trial. Animals were sacrificed on days 3, 31, and 91 for detailed histopathologic assessments of all organs and to isolate and quantify virus in all organs. With the possible exception of one animal euthanized on day 16, neither adverse clinical signs nor sex-or dose-related differences were attributed to M032. Elevated white blood cell and neutrophil counts were observed in virus-injected groups on day 3, but no other significant changes were noted in clinical chemistry or coagulation parameters. Minimal to mild inflammation and fibrosis detected, primarily in meningeal tissues, in M032-injected animals on days 3 and 31 had mostly resolved by day 91. The highest viral DNA levels were detected at the injection site and motor cortex on day 3 but decreased in central nervous system tissues over time. These data demonstrate the requisite safety of intracerebral M032 administration for consideration as a therapeutic for treating malignant brain tumors.

show abstract

“…The most frequently used are adenoviruses, adeno-associated viruses, retroviruses, lentiviruses and herpes simplex viruses. 10,15,23,31 Autonomous parvoviruses are small, nonintegrating single-stranded DNA viruses that replicate without the assistance of a helper virus. 32 Certain rodent parvoviruses, hereafter referred to as parvoviruses, replicate preferentially in tumor-derived and oncogene-transformed human and rodent cells and show oncosuppressive activity in laboratory animals.…”

Section: Introductionmentioning

confidence: 99%

TNF-α and the IFN-γ-inducible protein 10 (IP-10/CXCL-10) delivered by parvoviral vectors act in synergy to induce antitumor effects in mouse glioblastoma

et al. 2008

View full text Add to dashboard Cite

Interferon-g-inducible protein 10 is a potent chemoattractant for natural killer cells and activated T lymphocytes. It also displays angiostatic properties and some antitumor activity. Tumor necrosis factor-a (TNF-a) is a powerful immunomodulating cytokine with demonstrated tumoricidal activity in various tumor models and the ability to induce strong immune responses. This prompted us to evaluate the antitumor effects of recombinant parvoviruses designed to deliver IP-10 or TNF-a into a glioblastoma. When Gl261 murine glioma cells were infected in vitro with an IP-10-or TNF-a-transducing parvoviral vector and were subcutaneously implanted in mice, tumor growth was significantly delayed. Complete tumor regression was observed when the glioma cells were coinfected with both the vectors, demonstrating synergistic antitumor activity. In an established in vivo glioma model, however, repeated simultaneous peritumoral injection of the IP-10-and TNF-a-delivering parvoviruses failed to improve the therapeutic effect as compared with the use of a single cytokine-delivering vector. In this tumor model, cytokine-mediated immunostimulation, rather than inhibition of vascularization, is likely responsible for the therapeutic efficacy.

show abstract

Development of a second‐generation oncolytic Herpes simplex virus expressing TNFα for cancer therapy

Cited by 48 publications

References 26 publications

ΔPK oncolytic activity includes modulation of the tumour cell milieu

ΔPK oncolytic activity includes modulation of the tumour cell milieu

Evaluation of the Safety and Biodistribution of M032, an Attenuated Herpes Simplex Virus Type 1 Expressing hIL-12, After Intracerebral Administration toAotusNonhuman Primates

TNF-α and the IFN-γ-inducible protein 10 (IP-10/CXCL-10) delivered by parvoviral vectors act in synergy to induce antitumor effects in mouse glioblastoma

Contact Info

Product

Resources

About