Tumor vasculature-targeted delivery of tumor necrosis factor-α

Anita Tandle, Engy Hanna, Dominique Lorang, Amin Hajitou, Catherine A. Moya, Renata Pasqualini, Wadih Arap, Asha Adem, Elizabeth Starker, Stephen Hewitt, Steven K. Libutti

Research output: Contribution to journalArticle

64 Citations (Scopus)

Abstract

BACKGROUND: Recently, considerable efforts have been directed toward antivascular therapy as a new modality to treat human cancers. However, targeting a therapeutic gene of interest to the tumor vasculature with minimal toxicity to other tissues remains the objective of antivascular gene therapy. Tumor necrosis factor-α (TNF-α) is a potent antivascular agent but has limited clinical utility because of significant systemic toxicity. At the maximum tolerated doses of systemic TNF-α, there is no meaningful antitumor activity. Hence, the objective of this study was to deliver TNF-α targeted to tumor vasculature by systemic delivery to examine its antitumor activity. METHODS: A hybrid adeno-associated virus phage vector (AAVP) was used that targets tumor endothelium to express TNF-α (AAVP-TNF-α). The activity of AAVP-TNF-α was analyzed in various in vitro and in vivo settings using a human melanoma tumor model. RESULTS: In vitro, AAVP-TNF-α infection of human melanoma cells resulted in high levels of TNF-α expression. Systemic administration of targeted AAVP-TNF-α to melanoma xenografts in mice produced the specific delivery of virus to tumor vasculature. In contrast, the nontargeted vector did not target to tumor vasculature. Targeted AAVP delivery resulted in expression of TNF-α, induction of apoptosis in tumor vessels, and significant inhibition of tumor growth. No systemic toxicity to normal organs was observed. CONCLUSIONS: Targeted AAVP vectors can be used to deliver TNF-α specifically to tumor vasculature, potentially reducing its systemic toxicity. Because TNF-α is a promising antivascular agent that currently is limited by its toxicity, the current results suggest the potential for clinical translation of this strategy.

Original languageEnglish (US)
Pages (from-to)128-139
Number of pages12
JournalCancer
Volume115
Issue number1
DOIs
StatePublished - Jan 1 2009
Externally publishedYes

Fingerprint

Dependovirus
Tumor Necrosis Factor-alpha
Bacteriophages
Neoplasms
Melanoma
Oncogenic Viruses
Maximum Tolerated Dose
Heterografts
Genetic Therapy
Endothelium
Apoptosis
Therapeutics
Growth
Infection
Genes

Keywords

  • Adeno-associated virus phage vector
  • Antivascular
  • Human melanoma
  • Targeted gene therapy
  • Tumor necrosis factor α

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Tandle, A., Hanna, E., Lorang, D., Hajitou, A., Moya, C. A., Pasqualini, R., ... Libutti, S. K. (2009). Tumor vasculature-targeted delivery of tumor necrosis factor-α. Cancer, 115(1), 128-139. https://doi.org/10.1002/cncr.24001

Tumor vasculature-targeted delivery of tumor necrosis factor-α. / Tandle, Anita; Hanna, Engy; Lorang, Dominique; Hajitou, Amin; Moya, Catherine A.; Pasqualini, Renata; Arap, Wadih; Adem, Asha; Starker, Elizabeth; Hewitt, Stephen; Libutti, Steven K.

In: Cancer, Vol. 115, No. 1, 01.01.2009, p. 128-139.

Research output: Contribution to journalArticle

Tandle, A, Hanna, E, Lorang, D, Hajitou, A, Moya, CA, Pasqualini, R, Arap, W, Adem, A, Starker, E, Hewitt, S & Libutti, SK 2009, 'Tumor vasculature-targeted delivery of tumor necrosis factor-α', Cancer, vol. 115, no. 1, pp. 128-139. https://doi.org/10.1002/cncr.24001
Tandle A, Hanna E, Lorang D, Hajitou A, Moya CA, Pasqualini R et al. Tumor vasculature-targeted delivery of tumor necrosis factor-α. Cancer. 2009 Jan 1;115(1):128-139. https://doi.org/10.1002/cncr.24001
Tandle, Anita ; Hanna, Engy ; Lorang, Dominique ; Hajitou, Amin ; Moya, Catherine A. ; Pasqualini, Renata ; Arap, Wadih ; Adem, Asha ; Starker, Elizabeth ; Hewitt, Stephen ; Libutti, Steven K. / Tumor vasculature-targeted delivery of tumor necrosis factor-α. In: Cancer. 2009 ; Vol. 115, No. 1. pp. 128-139.
@article{aad516ab72df419a9b299dd670f92fb9,
title = "Tumor vasculature-targeted delivery of tumor necrosis factor-α",
abstract = "BACKGROUND: Recently, considerable efforts have been directed toward antivascular therapy as a new modality to treat human cancers. However, targeting a therapeutic gene of interest to the tumor vasculature with minimal toxicity to other tissues remains the objective of antivascular gene therapy. Tumor necrosis factor-α (TNF-α) is a potent antivascular agent but has limited clinical utility because of significant systemic toxicity. At the maximum tolerated doses of systemic TNF-α, there is no meaningful antitumor activity. Hence, the objective of this study was to deliver TNF-α targeted to tumor vasculature by systemic delivery to examine its antitumor activity. METHODS: A hybrid adeno-associated virus phage vector (AAVP) was used that targets tumor endothelium to express TNF-α (AAVP-TNF-α). The activity of AAVP-TNF-α was analyzed in various in vitro and in vivo settings using a human melanoma tumor model. RESULTS: In vitro, AAVP-TNF-α infection of human melanoma cells resulted in high levels of TNF-α expression. Systemic administration of targeted AAVP-TNF-α to melanoma xenografts in mice produced the specific delivery of virus to tumor vasculature. In contrast, the nontargeted vector did not target to tumor vasculature. Targeted AAVP delivery resulted in expression of TNF-α, induction of apoptosis in tumor vessels, and significant inhibition of tumor growth. No systemic toxicity to normal organs was observed. CONCLUSIONS: Targeted AAVP vectors can be used to deliver TNF-α specifically to tumor vasculature, potentially reducing its systemic toxicity. Because TNF-α is a promising antivascular agent that currently is limited by its toxicity, the current results suggest the potential for clinical translation of this strategy.",
keywords = "Adeno-associated virus phage vector, Antivascular, Human melanoma, Targeted gene therapy, Tumor necrosis factor α",
author = "Anita Tandle and Engy Hanna and Dominique Lorang and Amin Hajitou and Moya, {Catherine A.} and Renata Pasqualini and Wadih Arap and Asha Adem and Elizabeth Starker and Stephen Hewitt and Libutti, {Steven K.}",
year = "2009",
month = "1",
day = "1",
doi = "10.1002/cncr.24001",
language = "English (US)",
volume = "115",
pages = "128--139",
journal = "Cancer",
issn = "0008-543X",
publisher = "John Wiley and Sons Inc.",
number = "1",

}

TY - JOUR

T1 - Tumor vasculature-targeted delivery of tumor necrosis factor-α

AU - Tandle, Anita

AU - Hanna, Engy

AU - Lorang, Dominique

AU - Hajitou, Amin

AU - Moya, Catherine A.

AU - Pasqualini, Renata

AU - Arap, Wadih

AU - Adem, Asha

AU - Starker, Elizabeth

AU - Hewitt, Stephen

AU - Libutti, Steven K.

PY - 2009/1/1

Y1 - 2009/1/1

N2 - BACKGROUND: Recently, considerable efforts have been directed toward antivascular therapy as a new modality to treat human cancers. However, targeting a therapeutic gene of interest to the tumor vasculature with minimal toxicity to other tissues remains the objective of antivascular gene therapy. Tumor necrosis factor-α (TNF-α) is a potent antivascular agent but has limited clinical utility because of significant systemic toxicity. At the maximum tolerated doses of systemic TNF-α, there is no meaningful antitumor activity. Hence, the objective of this study was to deliver TNF-α targeted to tumor vasculature by systemic delivery to examine its antitumor activity. METHODS: A hybrid adeno-associated virus phage vector (AAVP) was used that targets tumor endothelium to express TNF-α (AAVP-TNF-α). The activity of AAVP-TNF-α was analyzed in various in vitro and in vivo settings using a human melanoma tumor model. RESULTS: In vitro, AAVP-TNF-α infection of human melanoma cells resulted in high levels of TNF-α expression. Systemic administration of targeted AAVP-TNF-α to melanoma xenografts in mice produced the specific delivery of virus to tumor vasculature. In contrast, the nontargeted vector did not target to tumor vasculature. Targeted AAVP delivery resulted in expression of TNF-α, induction of apoptosis in tumor vessels, and significant inhibition of tumor growth. No systemic toxicity to normal organs was observed. CONCLUSIONS: Targeted AAVP vectors can be used to deliver TNF-α specifically to tumor vasculature, potentially reducing its systemic toxicity. Because TNF-α is a promising antivascular agent that currently is limited by its toxicity, the current results suggest the potential for clinical translation of this strategy.

AB - BACKGROUND: Recently, considerable efforts have been directed toward antivascular therapy as a new modality to treat human cancers. However, targeting a therapeutic gene of interest to the tumor vasculature with minimal toxicity to other tissues remains the objective of antivascular gene therapy. Tumor necrosis factor-α (TNF-α) is a potent antivascular agent but has limited clinical utility because of significant systemic toxicity. At the maximum tolerated doses of systemic TNF-α, there is no meaningful antitumor activity. Hence, the objective of this study was to deliver TNF-α targeted to tumor vasculature by systemic delivery to examine its antitumor activity. METHODS: A hybrid adeno-associated virus phage vector (AAVP) was used that targets tumor endothelium to express TNF-α (AAVP-TNF-α). The activity of AAVP-TNF-α was analyzed in various in vitro and in vivo settings using a human melanoma tumor model. RESULTS: In vitro, AAVP-TNF-α infection of human melanoma cells resulted in high levels of TNF-α expression. Systemic administration of targeted AAVP-TNF-α to melanoma xenografts in mice produced the specific delivery of virus to tumor vasculature. In contrast, the nontargeted vector did not target to tumor vasculature. Targeted AAVP delivery resulted in expression of TNF-α, induction of apoptosis in tumor vessels, and significant inhibition of tumor growth. No systemic toxicity to normal organs was observed. CONCLUSIONS: Targeted AAVP vectors can be used to deliver TNF-α specifically to tumor vasculature, potentially reducing its systemic toxicity. Because TNF-α is a promising antivascular agent that currently is limited by its toxicity, the current results suggest the potential for clinical translation of this strategy.

KW - Adeno-associated virus phage vector

KW - Antivascular

KW - Human melanoma

KW - Targeted gene therapy

KW - Tumor necrosis factor α

UR - http://www.scopus.com/inward/record.url?scp=58949090367&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=58949090367&partnerID=8YFLogxK

U2 - 10.1002/cncr.24001

DO - 10.1002/cncr.24001

M3 - Article

C2 - 19090007

AN - SCOPUS:58949090367

VL - 115

SP - 128

EP - 139

JO - Cancer

JF - Cancer

SN - 0008-543X

IS - 1

ER -