In vivo evaluation of a cancer therapy strategy combining HSV1716-mediated oncolysis with gene transfer and targeted radiotherapy

Annette Sorensen, R.J. Mairs, Lynne Braidwood, Craig Joyce, Joe Conner, S.L. Pimlott, Moira Brown, Marie Boyd

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Oncolytic herpes viruses show promise for cancer treatment. However, it is unlikely that they will fulfill their therapeutic potential when used as monotherapies. An alternative strategy is to use these viruses not only as oncolytic agents but also as a delivery mechanism of therapeutic transgenes to enhance tumor cell killing. The herpes simplex virus 1 deletion mutant HSV1716 is a conditionally replicating oncolytic virus that selectively replicates in and lyses dividing tumor cells. It has a proven safety profile in clinical trials and has demonstrated efficacy as a gene-delivery vehicle. To enhance its therapeutic potential, we have engineered HSV1716 to convey the noradrenaline transporter (NAT) gene (HSV1716/NAT), whose expression endows infected cells with the capacity to accumulate the noradrenaline analog metaiodobenzylguanidine (MIBG). Thus, the NAT gene-infected cells are susceptible to targeted radiotherapy using radiolabeled I-131-MIBG, a strategy that has already shown promise for combined targeted radiotherapy-gene therapy in cancer cells after plasmid-mediated transfection. Methods: We used HSV1716/NAT as a dual cell lysis-gene delivery vehicle for targeting the NAT transgene to human tumor xenografts in vivo. Results: In tumor xenografts that did not express NAT, intratumoral or intravenous injection of HSV1716/NAT induced the capacity for active uptake of I-131-MIBG. Administration of HSV1716/NAT and I-131-MIBG resulted in decreased tumor growth and enhanced survival relative to injection of either agent alone. Efficacy was dependent on the scheduling of delivery of the 2 agents. Conclusion: These findings support a role for combination radiotherapy-gene therapy for cancer using HSV1716 expressing the NAT transgene and targeted radionuclide therapy.
LanguageEnglish
Pages647-654
Number of pages8
JournalThe Journal of Nuclear Medicine
Volume53
Issue number4
Early online date13 Mar 2012
DOIs
Publication statusPublished - 1 Apr 2012

Fingerprint

Norepinephrine Plasma Membrane Transport Proteins
Radiotherapy
Genes
Neoplasms
Transgenes
Oncolytic Viruses
Therapeutics
Heterografts
Genetic Therapy
Human Herpesvirus 1
Intravenous Injections
Radioisotopes
Transfection
Norepinephrine
Plasmids
Clinical Trials
Viruses
Safety

Keywords

  • cancer therapy strategy
  • gene transfer
  • radiotherapy
  • in vivo evaluation
  • hsv1716-mediated oncolysis
  • gene transfer
  • targeted radiotherapy

Cite this

Sorensen, Annette ; Mairs, R.J. ; Braidwood, Lynne ; Joyce, Craig ; Conner, Joe ; Pimlott, S.L. ; Brown, Moira ; Boyd, Marie. / In vivo evaluation of a cancer therapy strategy combining HSV1716-mediated oncolysis with gene transfer and targeted radiotherapy. In: The Journal of Nuclear Medicine. 2012 ; Vol. 53, No. 4. pp. 647-654.
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In vivo evaluation of a cancer therapy strategy combining HSV1716-mediated oncolysis with gene transfer and targeted radiotherapy. / Sorensen, Annette; Mairs, R.J.; Braidwood, Lynne; Joyce, Craig; Conner, Joe ; Pimlott, S.L.; Brown, Moira; Boyd, Marie.

In: The Journal of Nuclear Medicine, Vol. 53, No. 4, 01.04.2012, p. 647-654.

Research output: Contribution to journalArticle

TY - JOUR

T1 - In vivo evaluation of a cancer therapy strategy combining HSV1716-mediated oncolysis with gene transfer and targeted radiotherapy

AU - Sorensen, Annette

AU - Mairs, R.J.

AU - Braidwood, Lynne

AU - Joyce, Craig

AU - Conner, Joe

AU - Pimlott, S.L.

AU - Brown, Moira

AU - Boyd, Marie

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N2 - Oncolytic herpes viruses show promise for cancer treatment. However, it is unlikely that they will fulfill their therapeutic potential when used as monotherapies. An alternative strategy is to use these viruses not only as oncolytic agents but also as a delivery mechanism of therapeutic transgenes to enhance tumor cell killing. The herpes simplex virus 1 deletion mutant HSV1716 is a conditionally replicating oncolytic virus that selectively replicates in and lyses dividing tumor cells. It has a proven safety profile in clinical trials and has demonstrated efficacy as a gene-delivery vehicle. To enhance its therapeutic potential, we have engineered HSV1716 to convey the noradrenaline transporter (NAT) gene (HSV1716/NAT), whose expression endows infected cells with the capacity to accumulate the noradrenaline analog metaiodobenzylguanidine (MIBG). Thus, the NAT gene-infected cells are susceptible to targeted radiotherapy using radiolabeled I-131-MIBG, a strategy that has already shown promise for combined targeted radiotherapy-gene therapy in cancer cells after plasmid-mediated transfection. Methods: We used HSV1716/NAT as a dual cell lysis-gene delivery vehicle for targeting the NAT transgene to human tumor xenografts in vivo. Results: In tumor xenografts that did not express NAT, intratumoral or intravenous injection of HSV1716/NAT induced the capacity for active uptake of I-131-MIBG. Administration of HSV1716/NAT and I-131-MIBG resulted in decreased tumor growth and enhanced survival relative to injection of either agent alone. Efficacy was dependent on the scheduling of delivery of the 2 agents. Conclusion: These findings support a role for combination radiotherapy-gene therapy for cancer using HSV1716 expressing the NAT transgene and targeted radionuclide therapy.

AB - Oncolytic herpes viruses show promise for cancer treatment. However, it is unlikely that they will fulfill their therapeutic potential when used as monotherapies. An alternative strategy is to use these viruses not only as oncolytic agents but also as a delivery mechanism of therapeutic transgenes to enhance tumor cell killing. The herpes simplex virus 1 deletion mutant HSV1716 is a conditionally replicating oncolytic virus that selectively replicates in and lyses dividing tumor cells. It has a proven safety profile in clinical trials and has demonstrated efficacy as a gene-delivery vehicle. To enhance its therapeutic potential, we have engineered HSV1716 to convey the noradrenaline transporter (NAT) gene (HSV1716/NAT), whose expression endows infected cells with the capacity to accumulate the noradrenaline analog metaiodobenzylguanidine (MIBG). Thus, the NAT gene-infected cells are susceptible to targeted radiotherapy using radiolabeled I-131-MIBG, a strategy that has already shown promise for combined targeted radiotherapy-gene therapy in cancer cells after plasmid-mediated transfection. Methods: We used HSV1716/NAT as a dual cell lysis-gene delivery vehicle for targeting the NAT transgene to human tumor xenografts in vivo. Results: In tumor xenografts that did not express NAT, intratumoral or intravenous injection of HSV1716/NAT induced the capacity for active uptake of I-131-MIBG. Administration of HSV1716/NAT and I-131-MIBG resulted in decreased tumor growth and enhanced survival relative to injection of either agent alone. Efficacy was dependent on the scheduling of delivery of the 2 agents. Conclusion: These findings support a role for combination radiotherapy-gene therapy for cancer using HSV1716 expressing the NAT transgene and targeted radionuclide therapy.

KW - cancer therapy strategy

KW - gene transfer

KW - radiotherapy

KW - in vivo evaluation

KW - hsv1716-mediated oncolysis

KW - gene transfer

KW - targeted radiotherapy

U2 - 10.2967/jnumed.111.090886

DO - 10.2967/jnumed.111.090886

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JF - The Journal of Nuclear Medicine

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