Inhibition of human tumor growth in mice by an oncolytic herpes simplex virus designed to target solely HER-2-positive cells

Laura Menotti, Giordano Nicoletti, Valentina Gatta, Stefania Croci, Lorena Landuzzi, Carla De Giovanni, Patrizia Nanni, Pier Luigi Lollini, Gabriella Campadelli-Fiume

Research output: Contribution to journalArticle

Abstract

Oncolytic virotherapy exploits the ability of viruses to infect, replicate into, and kill tumor cells. Among the viruses that entered clinical trials are HSVs. HSVs can be engineered to become tumor-specific by deletion of selected genes or retargeting to tumor-specific receptors. A clinically relevant surface molecule is HER-2, hyperexpressed in one fourth of mammary and ovary carcinomas, and associated with high metastatic ability. As a previously undescribed strategy to generate HSV recombinants retargeted to HER-2 and detargeted from natural receptors, we replaced the Ig-folded core in the receptor-binding virion glycoprotein gD with anti-HER-2 single-chain antibody. The recombinant entered cells solely via HER-2 and lysed HER-2-positive cancer cells. Because of the high specificity, its safety profile in i.p. injected mice was very high, with a LD50 >5 × 108 pfu, a figure at least 10,000-fold higher than that of corresponding WT-gD carrying virus (LD50 ≈ 5 × 104 pfu). When administered intratumorally to nude mice bearing HER-2-hyperexpressing human tumors, it strongly inhibited progressive tumor growth. The results provide a generally applicable strategy to engineer HSV recombinants retargeted to a wide range of receptors for which a single-chain antibody is available, and show the potential for retargeted HSV to exert target-specific inhibition of human tumor growth. Therapy with HER-2-retargeted oncolytic HSV could be effective in combined or sequential protocols with monoclonal antibodies and small inhibitors, particularly in patients resistant to HER-2-targeted therapy because of alterations in HER-2 signaling pathway, or against brain metastases inaccessible to anti-HER-2 antibodies.

Original languageEnglish
Pages (from-to)9039-9044
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number22
DOIs
Publication statusPublished - Jun 2 2009

Fingerprint

Oncolytic Viruses
Simplexvirus
Growth
Neoplasms
Single-Chain Antibodies
Lethal Dose 50
Viruses
Oncolytic Virotherapy
Gene Deletion
Nude Mice
Virion
Ovary
Glycoproteins
Monoclonal Antibodies
Clinical Trials
Breast Neoplasms
Neoplasm Metastasis
Safety
Antibodies
Brain

Keywords

  • Mammary carcinoma
  • Ovary carcinoma
  • Retarget
  • Tropism

ASJC Scopus subject areas

  • General

Cite this

Inhibition of human tumor growth in mice by an oncolytic herpes simplex virus designed to target solely HER-2-positive cells. / Menotti, Laura; Nicoletti, Giordano; Gatta, Valentina; Croci, Stefania; Landuzzi, Lorena; De Giovanni, Carla; Nanni, Patrizia; Lollini, Pier Luigi; Campadelli-Fiume, Gabriella.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 106, No. 22, 02.06.2009, p. 9039-9044.

Research output: Contribution to journalArticle

Menotti, Laura ; Nicoletti, Giordano ; Gatta, Valentina ; Croci, Stefania ; Landuzzi, Lorena ; De Giovanni, Carla ; Nanni, Patrizia ; Lollini, Pier Luigi ; Campadelli-Fiume, Gabriella. / Inhibition of human tumor growth in mice by an oncolytic herpes simplex virus designed to target solely HER-2-positive cells. In: Proceedings of the National Academy of Sciences of the United States of America. 2009 ; Vol. 106, No. 22. pp. 9039-9044.
@article{0875cdd58d3a41348b5270ef8bf465d8,
title = "Inhibition of human tumor growth in mice by an oncolytic herpes simplex virus designed to target solely HER-2-positive cells",
abstract = "Oncolytic virotherapy exploits the ability of viruses to infect, replicate into, and kill tumor cells. Among the viruses that entered clinical trials are HSVs. HSVs can be engineered to become tumor-specific by deletion of selected genes or retargeting to tumor-specific receptors. A clinically relevant surface molecule is HER-2, hyperexpressed in one fourth of mammary and ovary carcinomas, and associated with high metastatic ability. As a previously undescribed strategy to generate HSV recombinants retargeted to HER-2 and detargeted from natural receptors, we replaced the Ig-folded core in the receptor-binding virion glycoprotein gD with anti-HER-2 single-chain antibody. The recombinant entered cells solely via HER-2 and lysed HER-2-positive cancer cells. Because of the high specificity, its safety profile in i.p. injected mice was very high, with a LD50 >5 × 108 pfu, a figure at least 10,000-fold higher than that of corresponding WT-gD carrying virus (LD50 ≈ 5 × 104 pfu). When administered intratumorally to nude mice bearing HER-2-hyperexpressing human tumors, it strongly inhibited progressive tumor growth. The results provide a generally applicable strategy to engineer HSV recombinants retargeted to a wide range of receptors for which a single-chain antibody is available, and show the potential for retargeted HSV to exert target-specific inhibition of human tumor growth. Therapy with HER-2-retargeted oncolytic HSV could be effective in combined or sequential protocols with monoclonal antibodies and small inhibitors, particularly in patients resistant to HER-2-targeted therapy because of alterations in HER-2 signaling pathway, or against brain metastases inaccessible to anti-HER-2 antibodies.",
keywords = "Mammary carcinoma, Ovary carcinoma, Retarget, Tropism",
author = "Laura Menotti and Giordano Nicoletti and Valentina Gatta and Stefania Croci and Lorena Landuzzi and {De Giovanni}, Carla and Patrizia Nanni and Lollini, {Pier Luigi} and Gabriella Campadelli-Fiume",
year = "2009",
month = "6",
day = "2",
doi = "10.1073/pnas.0812268106",
language = "English",
volume = "106",
pages = "9039--9044",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "22",

}

TY - JOUR

T1 - Inhibition of human tumor growth in mice by an oncolytic herpes simplex virus designed to target solely HER-2-positive cells

AU - Menotti, Laura

AU - Nicoletti, Giordano

AU - Gatta, Valentina

AU - Croci, Stefania

AU - Landuzzi, Lorena

AU - De Giovanni, Carla

AU - Nanni, Patrizia

AU - Lollini, Pier Luigi

AU - Campadelli-Fiume, Gabriella

PY - 2009/6/2

Y1 - 2009/6/2

N2 - Oncolytic virotherapy exploits the ability of viruses to infect, replicate into, and kill tumor cells. Among the viruses that entered clinical trials are HSVs. HSVs can be engineered to become tumor-specific by deletion of selected genes or retargeting to tumor-specific receptors. A clinically relevant surface molecule is HER-2, hyperexpressed in one fourth of mammary and ovary carcinomas, and associated with high metastatic ability. As a previously undescribed strategy to generate HSV recombinants retargeted to HER-2 and detargeted from natural receptors, we replaced the Ig-folded core in the receptor-binding virion glycoprotein gD with anti-HER-2 single-chain antibody. The recombinant entered cells solely via HER-2 and lysed HER-2-positive cancer cells. Because of the high specificity, its safety profile in i.p. injected mice was very high, with a LD50 >5 × 108 pfu, a figure at least 10,000-fold higher than that of corresponding WT-gD carrying virus (LD50 ≈ 5 × 104 pfu). When administered intratumorally to nude mice bearing HER-2-hyperexpressing human tumors, it strongly inhibited progressive tumor growth. The results provide a generally applicable strategy to engineer HSV recombinants retargeted to a wide range of receptors for which a single-chain antibody is available, and show the potential for retargeted HSV to exert target-specific inhibition of human tumor growth. Therapy with HER-2-retargeted oncolytic HSV could be effective in combined or sequential protocols with monoclonal antibodies and small inhibitors, particularly in patients resistant to HER-2-targeted therapy because of alterations in HER-2 signaling pathway, or against brain metastases inaccessible to anti-HER-2 antibodies.

AB - Oncolytic virotherapy exploits the ability of viruses to infect, replicate into, and kill tumor cells. Among the viruses that entered clinical trials are HSVs. HSVs can be engineered to become tumor-specific by deletion of selected genes or retargeting to tumor-specific receptors. A clinically relevant surface molecule is HER-2, hyperexpressed in one fourth of mammary and ovary carcinomas, and associated with high metastatic ability. As a previously undescribed strategy to generate HSV recombinants retargeted to HER-2 and detargeted from natural receptors, we replaced the Ig-folded core in the receptor-binding virion glycoprotein gD with anti-HER-2 single-chain antibody. The recombinant entered cells solely via HER-2 and lysed HER-2-positive cancer cells. Because of the high specificity, its safety profile in i.p. injected mice was very high, with a LD50 >5 × 108 pfu, a figure at least 10,000-fold higher than that of corresponding WT-gD carrying virus (LD50 ≈ 5 × 104 pfu). When administered intratumorally to nude mice bearing HER-2-hyperexpressing human tumors, it strongly inhibited progressive tumor growth. The results provide a generally applicable strategy to engineer HSV recombinants retargeted to a wide range of receptors for which a single-chain antibody is available, and show the potential for retargeted HSV to exert target-specific inhibition of human tumor growth. Therapy with HER-2-retargeted oncolytic HSV could be effective in combined or sequential protocols with monoclonal antibodies and small inhibitors, particularly in patients resistant to HER-2-targeted therapy because of alterations in HER-2 signaling pathway, or against brain metastases inaccessible to anti-HER-2 antibodies.

KW - Mammary carcinoma

KW - Ovary carcinoma

KW - Retarget

KW - Tropism

UR - http://www.scopus.com/inward/record.url?scp=67049100254&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=67049100254&partnerID=8YFLogxK

U2 - 10.1073/pnas.0812268106

DO - 10.1073/pnas.0812268106

M3 - Article

C2 - 19458262

AN - SCOPUS:67049100254

VL - 106

SP - 9039

EP - 9044

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 22

ER -