Cytokine Gene Transfer Enhances Herpes Oncolytic Therapy in Murine Squamous Cell Carcinoma

Wong, Richard J.; Patel, Snehal G.; Kim, Se‐Heon; DeMatteo, Ronald P.; Malhotra, Sandeep K.; Bennett, Joseph; St‐Louis, Maryse; Shah, Jatin P.; Johnson, Paul A.; Fong, Yuman

doi:10.1089/10430340150218396

Cited by 126 publications

(152 citation statements)

References 43 publications

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“…While a number of cytokines have been considered for use in anti-tumour therapy (including the use of GM-CSF or IL12 in oncolytic HSV vectors [39][40][41][42][43] ), GM-CSF has generally, and most reliably, given the best results when tested in comparison to other cytokines in pre-clinical models. Clinically, for cancer treatment, indications of efficacy have also been seen when GM-CSF has been delivered by a number of means (eg using engineered, re-injected primary tumour cells -'GVAX'; eg reference 44).…”

Section: Discussionmentioning

confidence: 99%

ICP34.5 deleted herpes simplex virus with enhanced oncolytic, immune stimulating, and anti-tumour properties

Liu¹,

Robinson²,

Han³

et al. 2003

Gene Ther

678

624

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Section: Discussionmentioning

confidence: 99%

ICP34.5 deleted herpes simplex virus with enhanced oncolytic, immune stimulating, and anti-tumour properties

Liu¹,

Robinson²,

Han³

et al. 2003

Gene Ther

678

624

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“…Given the significant lack of systemic activity of viral-induced oncolysis following local-regional treatment in the clinic, several new vectors carrying immunestimulating transgenes have been developed (GM-CSF, IL-2, IL-12, B7.1). [263][264][265][266][267][268] In addition, combination of HSV mutants with chemotherapy or radiotherapy has demonstrated enhancement in antitumor activity. 222,243,[269][270][271][272][273][274] Radiation enhanced anticancer activity of HSV when used in pancreatic, glioblastoma, and cervical cancer models, 275 but did not alter the antitumor effect of HSV in prostate cancer.…”

Section: Ongoing Trialmentioning

confidence: 99%

Oncolytic viral therapies

2004

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Molecular research has vastly advanced our understanding of the mechanism of cancer growth and spread. Targeted approaches utilizing molecular science have yielded provocative results in the treatment of cancer. Oncolytic viruses genetically programmed to replicate within cancer cells and directly induce toxic effect via cell lysis or apoptosis are currently being explored in the clinic. Safety has been confirmed and despite variable efficacy results several dramatic responses have been observed with some oncolytic viruses. This review summarizes results of clinical trials with oncolytic viruses in cancer.

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“…The construction of these viruses has previously been described. 33,38 The viruses NV1020, NV1023, and NV1042 were propagated on Vero cells and titers measured by standard plaque assay.…”

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

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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.

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Cytokine Gene Transfer Enhances Herpes Oncolytic Therapy in Murine Squamous Cell Carcinoma

Cited by 126 publications

References 43 publications

ICP34.5 deleted herpes simplex virus with enhanced oncolytic, immune stimulating, and anti-tumour properties

ICP34.5 deleted herpes simplex virus with enhanced oncolytic, immune stimulating, and anti-tumour properties

Oncolytic viral therapies

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

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