Oncolytic HSV-1 Virotherapy: Clinical Experience and Opportunities for Progress

Kaur, Balveen; Chiocca, E. Antonio; Cripe, Timothy P.

doi:10.2174/138920112800958814

Cited by 62 publications

(57 citation statements)

References 101 publications

(119 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…have been tested pre-clinically and in patients both as single agent and as combination strategies. Evaluation of changes in tumor microenvironment after oHSV therapy have uncovered changes in vascularization post therapy inciting several studies combining virotherapy with vascular disrupting agents and angiogenesis inhibitors (37). We have previously demonstrated increased anti-tumor effects when arming oHSV with Vstat120, a 120 kDa cleaved secreted fragment of BAI1, against a variety of preclinical cancer models, including glioblastoma, ovarian cancer, and head and neck cancer (6, 32, 38, 39).…”

Section: Discussionmentioning

confidence: 99%

BAI1 Orchestrates Macrophage Inflammatory Response to HSV Infection—Implications for Oncolytic Viral Therapy

Bolyard

Meisen

Banasavadi-Siddegowda

et al. 2017

Clinical Cancer Research

Self Cite

View full text Add to dashboard Cite

Purpose Brain Angiogenesis Inhibitor (BAI1) facilitates phagocytosis, and bacterial pathogen clearance by macrophages; however, its role in viral infections is unknown. Here we examined the role of BAI1, and its N-terminal cleavage fragment (Vstat120) in antiviral macrophage responses to oncolytic herpes simplex virus (oHSV). Experimental Design Changes in infiltration and activation of monocytic and microglial cells after treatment of glioma-bearing mice brains with a control (rHSVQ1) or Vstat120-expressing (RAMBO) oHSV was analyzed using flow cytometry. Co-culture of infected glioma cells with macrophages or microglia was used to examine antiviral signaling. Cytokine array gene expression and ingenuity pathway analysis (IPA) helped evaluate changes in macrophage signaling in response to viral infection. TNFα blocking antibodies and macrophages derived from Bai1−/− mice were used. Results RAMBO treatment of mice reduced recruitment and activation of macrophages/microglia in mice with brain tumors, and showed increased virus replication compared to rHSVQ1. Cytokine gene expression array revealed that RAMBO significantly altered the macrophage inflammatory response to infected glioma cells via altered secretion of TNFα. Further we showed that BAI1 mediated macrophage TNFα induction in response to oHSV therapy. Intracranial inoculation of wild type/RAMBO virus in Bai1−/− or wild type non-tumor-bearing mice revealed the safety of this approach. Conclusions We have uncovered a new role for BAI1 in facilitating macrophage anti-viral responses. We show that arming oHSV with antiangiogenic Vstat120 also shields them from inflammatory macrophage antiviral response, without reducing safety.

show abstract

Section: Discussionmentioning

confidence: 99%

BAI1 Orchestrates Macrophage Inflammatory Response to HSV Infection—Implications for Oncolytic Viral Therapy

Bolyard

Meisen

Banasavadi-Siddegowda

et al. 2017

Clinical Cancer Research

Self Cite

View full text Add to dashboard Cite

show abstract

“…Imlygic and similar oncolytic viruses have displayed remarkable specificity for infecting and destroying neoplastic cells while leaving the normal surrounding tissue undamaged 20, 21, 22. No dose-limiting toxicities have been reported for oHSVs that have advanced to clinical trials, and adverse events, if present, have typically been limited to mild to moderate flu-like symptoms 20, 22, 23. As such, these therapies may have considerable potential for pediatric brain tumor patients, because many tumors are refractory to conventional treatment modalities (i.e., surgical resection, chemotherapy, and radiation) that are associated with devastating and often permanent neurocognitive defects.…”

Section: Discussionmentioning

confidence: 99%

Oncolytic Herpes Virus rRp450 Shows Efficacy in Orthotopic Xenograft Group 3/4 Medulloblastomas and Atypical Teratoid/Rhabdoid Tumors

Studebaker

Hutzen

Pierson

et al. 2017

Molecular Therapy - Oncolytics

View full text Add to dashboard Cite

Pediatric brain tumors including medulloblastoma and atypical teratoid/rhabdoid tumor are associated with significant mortality and treatment-associated morbidity. While medulloblastoma tumors within molecular subgroups 3 and 4 have a propensity to metastasize, atypical teratoid/rhabdoid tumors frequently afflict a very young patient population. Adjuvant treatment options for children suffering with these tumors are not only sub-optimal but also associated with many neurocognitive obstacles. A potentially novel treatment approach is oncolytic virotherapy, a developing therapeutic platform currently in early-phase clinical trials for pediatric brain tumors and recently US Food and Drug Administration (FDA)-approved to treat melanoma in adults. We evaluated the therapeutic potential of the clinically available oncolytic herpes simplex vector rRp450 in cell lines derived from medulloblastoma and atypical teratoid/rhabdoid tumor. Cells of both tumor types were supportive of virus replication and virus-mediated cytotoxicity. Orthotopic xenograft models of medulloblastoma and atypical teratoid/rhabdoid tumors displayed significantly prolonged survival following a single, stereotactic intratumoral injection of rRp450. Furthermore, addition of the chemotherapeutic prodrug cyclophosphamide (CPA) enhanced rRp450’s in vivo efficacy. In conclusion, oncolytic herpes viruses with the ability to bioactivate the prodrug CPA within the tumor microenvironment warrant further investigation as a potential therapy for pediatric brain tumors.

show abstract

“…Currently, numerous viruses, in their natural or modified form, have been shown to possess oncolytic properties, and thus are being studied for their potential use as anticancer agents. Some prominent examples of these OVs include reovirus, [4] Newcastle disease, [5] vesicular stomatitis, [6] vaccinia, [7] measles, [8] poliovirus, [9] herpessimplex, [10] adenovirus, [11] Maraba, [12] [13] and Coxsackie. [14 Although the use of reovirus in cancer therapy stems from the oncolytic capabilities of the virus, recent studies have illustrated that reovirus additionally invokes a sequence of immunological events that ultimately overturn various tumor-induced immunosuppressive mechanisms and promotes the development of an antitumor immune response.…”

Section: Introductionmentioning

confidence: 99%