In Vivo Behavior of Genetically Engineered Herpes Simplex Viruses R7017 and R7020. II. Studies in Immunocompetent and Immunosuppressed Owl Monkeys (Aotus trivirgatus)

Meignier, Bernard; Martin, Bruno; Whitley, Richard J.; Roizman, Bernard

doi:10.1093/infdis/162.2.313

Cited by 149 publications

(82 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Determined by the onset of severe symptoms, the survival time in our study is, however, comparable to the 6-8 days reported by Melendez et al 10 as well as to the 6-19 days reported by Meingier et al after intradermal or vaginal infection at titers of wildtype HSV-1 and HSV-2 as low as 10 2 -10 3 PFU. 12,13 The common marmosets succumbed much sooner than the owl monkey, showing severe symptoms usually around 6 days post-injection, and their brains also displayed marked infection with HSV, with far more extensive HSV immunopositivity than seen in the owl monkeys. This survival time corresponds with the findings of Cho et al, 4 who reported an average survival time of 8 days after injecting 10 5 PFU HSV-1 intracerebrally into two marmosets.…”

Section: Discussionmentioning

confidence: 99%

Development of a novel non-human primate model for preclinical gene vector safety studies. Determining the effects of intracerebral HSV-1 inoculation in the common marmoset: a comparative study

et al. 2003

View full text Add to dashboard Cite

The owl monkey (Aotus trivirgatus) has served as the standard non-human primate model of herpes simplex virus-1 (HSV-1) infection because it is highly susceptible to HSV-1 encephalitis. Owl monkeys, however, are expensive, difficult to obtain, and difficult to maintain in captivity, thus greatly hampering the efficiency of preclinical gene therapy trials for brain tumors using HSV-1-based vectors. We have therefore compared the susceptibility of the common marmoset (Callithrix jacchus) with the owl monkey in a model of intracerebral inoculation of wildtype HSV-1 F-strain at increasing titers. The common marmosets consistently succumbed earlier to viral encephalitis than the owl monkeys.The histological evaluation of the common marmoset revealed extensive HSV-1 infection with a concomitant yet less marked inflammatory response compared to the owl monkeys. PCR for HSV-1 demonstrated a similar extra-CNS shedding route in both experimental models. Our findings show that the common marmoset is at least as susceptible to intracerebral HSV-infection as the owl monkey and that it can therefore serve as a valid and reliable experimental model for the important preclinical safety tests of HSV-based therapeutic viral vector constructs in the brain.

show abstract

Section: Discussionmentioning

confidence: 99%

Development of a novel non-human primate model for preclinical gene vector safety studies. Determining the effects of intracerebral HSV-1 inoculation in the common marmoset: a comparative study

et al. 2003

View full text Add to dashboard Cite

show abstract

“…These viruses were derived from NV1020, a nonselected clonal derivative of R7020 obtained from B Roizman. 36,37 NV1021 and NV1022 are precursors of NV1023 and NV1042 and derived from NV1020. NV1021 contains the E. coli lacZ gene under control of the ICP47 (US12) promoter.…”

Section: Virusesmentioning

confidence: 99%

Neoadjuvant treatment of hepatic malignancy: an oncolytic herpes simplex virus expressing IL-12 effectively treats the parent tumor and protects against recurrence-after resection

et al. 2003

View full text Add to dashboard Cite

The objective of the study was to evaluate the utility of NV1042, a replication competent, oncolytic herpes simplex virus (HSV) containing the interleukin-12 (IL-12) gene, as primary treatment for hepatic tumors and to further assess its ability to reduce tumor recurrence following resection. Resection is the most effective therapy for hepatic malignancies, but is not possible in the majority of the patients. Furthermore, recurrence is common after resection, most often in the remnant liver and likely because of microscopic residual disease in the setting of postoperative host cellular immune dysfunction. We hypothesize that, unlike other gene transfer approaches, direct injection of liver tumors with replication competent, oncolytic HSV expressing IL-12 will not only provide effective control of the parent tumor, but will also elicit an immune response directed at residual tumor cells, thus decreasing the risk of cancer recurrence after resection. Solitary Morris hepatomas, established in Buffalo rat livers, were injected directly with 10 7 particles of NV1042, NV1023, an oncolytic HSV identical to NV1042 but without the IL-12 gene, or with saline. Following tumor injection, the parent tumors were resected and measured and the animals were challenged with an intraportal injection of 10 5 tumor cells, recreating the clinical scenario of residual microscopic cancer. In vitro cytotoxicity against Morris hepatoma cells was similar for both viruses at a multiplicity of infection of 1 (MOI, ratio of viral particles to target cells), with 490% tumor cell kill by day 6. NV1042 induced high-level expression of IL-12 in vitro, peaking after 4 days in culture. Furthermore, a single intratumoral injection of NV1042, but not NV1023, induced marked IL-12 and interferon-g (IFN-g) expression. Both viruses induced a significant local immune response as evidenced by an increase in the number of intratumoral CD4(+) and CD8(+) lymphocytes, although the peak of CD8(+) infiltration was later with NV1042 compared with NV1023. NV1042 and NV1023 reduced parent tumor volume by 74% (Po.003) and 52% (Po.03), respectively, compared to control animals. Treatment of established tumors with NV1042, but not with NV1023, significantly reduced the number of hepatic tumors after resection of the parent tumor and rechallenge (16.8711 (median ¼ 4) vs. 65.9715 (median ¼ 66) in control animals, Po.025). In conclusion, oncolytic HSV therapy combined with local immune stimulation with IL-12 offers effective control of parent hepatic tumors and also protects against microscopic residual disease after resection. The ease of use of this combined modality approach, which appears to be superior to either approach alone, suggests that it may have clinical relevance, both as primary treatment for patients with unresectable tumors and also as a neoadjuvant strategy for reducing recurrence after resection.

show abstract

“…[8][9][10][11] The first attenuated HSV virus to be constructed and analyzed as a viral vaccine in humans was the NV1020 (formerly R7020) strain. 12,13 This virus, based on HSV-1 strain F, has a portion of the unique short region of the viral genome encoding glycoproteins G, D, I and E, replaced by the homologous region from HSV-2, and possesses one copy of ICP4. This virus was very strongly attenuated in rodents and primates.…”

Section: Live Viral Anti-hsv Vaccinementioning

confidence: 99%

“…41 In many of these studies, the efficacy of G207 has been compared with that of the above mentioned NV1020, which was shown to be too attenuated to work as a live viral vaccine. 12,13 Moreover, NV1020 is currently being investigated in Phase I clinical trials for patients with colon cancer that has metastasized to the liver and has proven recalcitrant to chemotherapy. This is also the first trial to investigate administration via intravascular delivery.…”

Section: Oncolytic Hsv Attenuated Virusesmentioning

confidence: 99%

“…These mutations give the virus the attenuated phenotype that leads to replication only in permissive cells such as dividing tumor cells or cells with defects in specific cancer pathways. 13,23,30,66 However, a limitation of this strategy is that many normal tissues also have high mitotic indices, and such viruses may not discriminate between rapidly proliferating normal and cancer cells.…”

Section: Targeting Hsv Attenuated Vectorsmentioning

confidence: 99%

See 1 more Smart Citation

Replication-competent herpes simplex vectors: design and applications

et al. 2005

View full text Add to dashboard Cite

In Vivo Behavior of Genetically Engineered Herpes Simplex Viruses R7017 and R7020. II. Studies in Immunocompetent and Immunosuppressed Owl Monkeys (Aotus trivirgatus)

Cited by 149 publications

References 10 publications

Development of a novel non-human primate model for preclinical gene vector safety studies. Determining the effects of intracerebral HSV-1 inoculation in the common marmoset: a comparative study

Development of a novel non-human primate model for preclinical gene vector safety studies. Determining the effects of intracerebral HSV-1 inoculation in the common marmoset: a comparative study

Neoadjuvant treatment of hepatic malignancy: an oncolytic herpes simplex virus expressing IL-12 effectively treats the parent tumor and protects against recurrence-after resection

Replication-competent herpes simplex vectors: design and applications

Contact Info

Product

Resources

About