Efficacy of HER2 retargeted herpes simplex virus as therapy for high-grade glioma in immunocompetent mice

Reisoli, Elisa; Gambini, Eleonora; Appolloni, Irene; Gatta, Valentina; Barilari, Manuela; Menotti, Laura; Malatesta, Paolo

doi:10.1038/cgt.2012.62

Cited by 27 publications

(23 citation statements)

References 40 publications

(46 reference statements)

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“…Repeated injections of R-LM249 doses higher than 10 6 pfu left 60% of mice tumor-free, and dramatically reduced the tumor size in the remaining 40%. Recently, a HSV retargeted to HER-2 showed efficient antitumor activity in an intracranial model of high-grade glioma in immunosuppressed and immunocompetent mice [7], [9]. Overall, these findings demonstrated that R-LM249 is effective in killing HER-2+ tumors in vivo, when administered locally [6].…”

Section: Introductionmentioning

confidence: 88%

“…The strategy pursued in our laboratories is to modify HSV-1 tropism, and efficiently retarget the virus to cancer-associated cell-surface molecules, such as the human epithelial growth factor receptor 2 (HER-2), a member of the tyrosine kinase receptors [4]–[9]. The clinical impact of the HER-2 oncogene stems from the fact that it is overexpressed in human breast and ovary carcinomas (>200,000 new cancer cases each year in the U.S.), and correlates with worsened prognosis.…”

Section: Introductionmentioning

confidence: 99%

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Preclinical Therapy of Disseminated HER-2+ Ovarian and Breast Carcinomas with a HER-2-Retargeted Oncolytic Herpesvirus

et al. 2013

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Oncolytic viruses aim to specifically kill tumor cells. A major challenge is the effective targeting of disseminated tumors in vivo. We retargeted herpes simplex virus (HSV) tropism to HER-2 oncoprotein p185, overexpressed in ovary and breast cancers. The HER-2-retargeted R-LM249 exclusively infects and kills tumor cells expressing high levels of human HER-2. Here, we assessed the efficacy of systemically i.p. delivered R-LM249 against disseminated tumors in mouse models that recapitulate tumor spread to the peritoneum in women. The human ovarian carcinoma SK-OV-3 cells implanted intraperitoneally (i.p.) in immunodeficient Rag2−/−;Il2rg−/− mice gave rise to a progressive peritoneal carcinomatosis which mimics the fatal condition in advanced human patients. I.p. administration of R-LM249 strongly inhibited carcinomatosis, resulting in 60% of mice free from peritoneal diffusion, and 95% reduction in the total weight of neoplastic nodules. Intraperitoneal metastases are a common outcome in breast cancer: i.p. administration of R-LM249 strongly inhibited the growth of ovarian metastases of HER-2+ MDA-MB-453 breast cells. Brain metastases were also reduced. Cumulatively, upon i.p. administration the HER-2-redirected oncolytic HSV effectively reduced the growth of ovarian and breast carcinoma disseminated to the peritoneal cavity.

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Section: Introductionmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Preclinical Therapy of Disseminated HER-2+ Ovarian and Breast Carcinomas with a HER-2-Retargeted Oncolytic Herpesvirus

et al. 2013

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“…The deleted portions of gD were amino acids (aa) 6 to 38 in the recombinant HSV construct named R-LM113 and the entire gD core (aa 61 to 218) in the recombinant HSV construct named R-LM249 (14, 15). In preclinical studies, R-LM113 and R-LM249 exerted antitumor activities against HER2-positive breast and ovarian cancers and against glioblastoma (14, 16, 21–23). Recently, we showed that not only gD but also gH can be a retargeting tool.…”

Section: Introductionmentioning

confidence: 99%

A Strategy for Cultivation of Retargeted Oncolytic Herpes Simplex Viruses in Non-cancer Cells

Leoni

Gatta

Casiraghi

et al. 2017

J Virol

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The oncolytic herpes simplex virus (HSV) that has been approved for clinical practice and those HSVs in clinical trials are attenuated viruses, often with the neurovirulence gene γ134.5 and additional genes deleted. One strategy to engineer nonattenuated oncolytic HSVs consists of retargeting the viral tropism to a cancer-specific receptor of choice, exemplified by HER2 (human epidermal growth factor receptor 2), which is present in breast, ovary, and other cancers, and in detargeting from the natural receptors. Because the HER2-retargeted HSVs strictly depend on this receptor for infection, the viruses employed in preclinical studies were cultivated in HER2-positive cancer cells. The production of clinical-grade viruses destined for humans should avoid the use of cancer cells. Here, we engineered the R-213 recombinant, by insertion of a 20-amino-acid (aa) short peptide (named GCN4) in the gH of R-LM113; this recombinant was retargeted to HER2 through insertion in gD of a single-chain antibody (scFv) to HER2. Next, we generated a Vero cell line expressing an artificial receptor (GCN4R) whose N terminus consists of an scFv to GCN4 and therefore is capable of interacting with GCN4 present in gH of R-213. R-213 replicated as well as R-LM113 in SK-OV-3 cells, implying that addition of the GCN4 peptide was not detrimental to gH. R-213 grew to relatively high titers in Vero-GCN4R cells, efficiently spread from cell to cell, and killed both Vero-GCN4R and SK-OV-3 cells, as expected for an oncolytic virus. Altogether, Vero-GCN4R cells represent an efficient system for cultivation of retargeted oncolytic HSVs in non-cancer cells.IMPORTANCE There is growing interest in viruses as oncolytic agents, which can be administered in combination with immunotherapeutic compounds, including immune checkpoint inhibitors. The oncolytic HSV approved for clinical practice and those in clinical trials are attenuated viruses. An alternative to attenuation is a cancer specificity achieved by tropism retargeting to selected cancer receptors. However, the retargeted oncolytic HSVs strictly depend on cancer receptors for infection. Here, we devised a strategy for in vitro cultivation of retargeted HSVs in non-cancer cells. The strategy envisions a double-retargeting approach: one retargeting is via gD to the cancer receptor, and the second retargeting is via gH to an artificial receptor expressed in Vero cells. The double-retargeted HSV uses alternatively the two receptors to infect cancer cells or producer cells. A universal non-cancer cell line for growth of clinical-grade retargeted HSVs represents a step forward in the translational phase.

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“…The Campadelli-Fiume group has employed recombinant oHSV containing an anti-HER2 scFv in gD to target HER2-expressing tumor cells [7,55–60] in culture and in vivo . Early studies employed gD recombinants that could still enter cells by binding to the canonical gD receptor nectin-1 [55–57,60] and although they displayed good efficacies in ovarian and glioma tumor models in mice [55,57,60], exclusive targeting of the HER2 tumor receptor was not achieved. Subsequent reports from this group [7,58,59] employed oHSV that were mutationally inactivated for binding to nectin-1 and HVEM, resulting in sole entry into HER2-bearing tumor cells.…”

Section: Retargeting Of Hsv Attachment/entrymentioning

confidence: 99%

Retargeting of herpes simplex virus (HSV) vectors

Goins

Hall

Cohen

et al. 2016

Current Opinion in Virology

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Gene therapy applications depend on vector delivery and gene expression in the appropriate target cell. Vector infection relies on the distribution of natural virus receptors that may either not be present on the desired target cell or distributed in a manner to give off-target gene expression. Some viruses display a very limited host range, while others, including herpes simplex virus (HSV), can infect almost every cell within the human body. It is often an advantage to retarget virus infectivity to achieve selective target cell infection. Retargeting can be achieved by (i) the inclusion of glycoproteins from other viruses that have a different host-range, (ii) modification of existing viral glycoproteins or coat proteins to incorporate peptide ligands or single-chain antibodies (scFvs) that bind to the desired receptor, or (iii) employing soluble adapters that recognize both the virus and a specific receptor on the target cell. This review summarizes efforts to target HSV using these three strategies.

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Efficacy of HER2 retargeted herpes simplex virus as therapy for high-grade glioma in immunocompetent mice

Cited by 27 publications

References 40 publications

Preclinical Therapy of Disseminated HER-2+ Ovarian and Breast Carcinomas with a HER-2-Retargeted Oncolytic Herpesvirus

Preclinical Therapy of Disseminated HER-2+ Ovarian and Breast Carcinomas with a HER-2-Retargeted Oncolytic Herpesvirus

A Strategy for Cultivation of Retargeted Oncolytic Herpes Simplex Viruses in Non-cancer Cells

Retargeting of herpes simplex virus (HSV) vectors

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