Enhancement of replication of genetically engineered herpes simplex viruses by ionizing radiation: a new paradigm for destruction of therapeutically intractable tumors

Advani, SJ; Sibley, GS; Song, PY; Hallahan, DE; Kataoka, Yuki; Roizman, Bernard; Weichselbaum, R.R.

doi:10.1038/sj.gt.3300546

Cited by 140 publications

(101 citation statements)

References 18 publications

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“…4 Thus, combination treatment has great potential for translation into effective clinic therapy in the immediate future. [14][15][16] In the case of CG7870, the alterations in vector design (relative to earlier adenovirus-based therapeutic agents) presented an unknown material impact on the efficacy of a treatment regimen combining the vector and radiation. Namely, CG7870 is transcriptionally regulated by dual, heterologous promoters and retains the Ad5, wild-type E3 region.…”

Section: Discussionmentioning

confidence: 99%

Oncolytic adenovirus CG7870 in combination with radiation demonstrates synergistic enhancements of antitumor efficacy without loss of specificity

Dilley

Reddy

et al. 2005

Cancer Gene Ther

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Conditionally replicating adenoviruses that selectively replicate in tumor cells, but not in normal cells, are being explored as virotherapeutic agents for cancer. A prostate-specific oncolytic adenovirus, CG7870 is currently being evaluated in phase 1/2 clinical trials for the treatment of prostate cancer. To decrease the effective dose and further increase the therapeutic efficacy of CG7870, the combination of virotherapy with radiation therapy was explored in this study. CG7870 is an oncolytic adenovirus in which tumor-specific promoters are driving the expression of E1A and E1B proteins. The effects of combined treatment with CG7870 and radiation on cultured cells were determined in cytotoxicity and virus yield assays. The antitumor efficacy of CG7870 (1 Â 10 7 particles/mm 3 of tumor), 10 Gy of local radiation or both was evaluated in established subcutaneous LNCaP xenografts in nude mice. In vitro, the dual agent treatment resulted in synergistically enhanced potency at suboptimal doses of radiation and virus. Virus yield in irradiated cells increased relative to yield in nonirradiated cells without compromising the specificity of the vector for its target cell types. In vivo, CG7870 treatment alone suppressed tumor growth and extended tumor nonprogression time. The average tumor-volume of the groups treated with CG7870 only and radiation only was 121 and 126% of baseline, respectively, 39 days after treatment. The average tumor-volume of the combination group was 34% of baseline 39 days after a single dose of treatment. No significant body weight loss was observed in any treatment group. There was a significant drop in serum level of prostate-specific antigen (PSA) in the combination group compared to the group treated with either agent alone. In mice treated with CG7870 only or radiation only, serum PSA levels changed to 26 and 383% of baseline, respectively, by study day 46. In contrast, PSA levels in mice treated with CG7870 plus radiation decreased to less than 11% of baseline by study day 46. Histological analysis of tumor sections collected from the combination group revealed enhanced necrosis and more apoptotic cells. Combination of CG7870 with radiotherapy significantly increased antitumor efficacy compared to either agent alone. These results suggest that CG7870 in combination with radiation has improved antitumor efficacy at lower doses and with no additional side effects.

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Section: Discussionmentioning

confidence: 99%

Oncolytic adenovirus CG7870 in combination with radiation demonstrates synergistic enhancements of antitumor efficacy without loss of specificity

Dilley

Reddy

et al. 2005

Cancer Gene Ther

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“…Andreansky et al 11 and Toda et al 29 have shown that coexpression of interleukin-4 or interleukin-12 can augment the efficacy of HSV-based oncolytic therapy for the treatment of gliomas or colorectal carcinoma, respectively. Advani et al 30 have shown that adjuvant radiation therapy can augment the efficacy of HSV-R3616 oncolytic therapy. We are pursuing a cell carrier system to augment the delivery of HSV mutants to tumors, thereby increasing the effective dose.…”

Section: Discussionmentioning

confidence: 99%

Multi-attenuated herpes simplex virus-1 mutant G207 exerts cytotoxicity against epithelial ovarian cancer but not normal mesothelium and is suitable for intraperitoneal oncolytic therapy

et al. 2000

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Recombinant strains of herpes simplex virus-1 (HSV-1) harboring mutations in the infected cell product (ICP)34.5 region lose their neurovirulence and replicate more efficiently in dividing tumor cells than stationary cells, becoming replication-selective oncolytic agents. Additional mutation of the ICP6 gene, which encodes ribonucleotide reductase, further impairs the ability of HSV-1 mutants to replicate in normal cells, enhancing tumor selectivity. The present study investigated the effect of HSV-G207, a recombinant HSV-1 lacking ICP34.5 and ICP6, against epithelial ovarian cancer (EOC) in vitro and in vivo in a mouse xenograft model. To assess the selectivity of multimutated HSV-G207 against malignant cells, HSV-G207 and wild-type HSV-F were comparatively tested against normal human peritoneal mesothelial cells and EOC cells in vitro. HSV-G207 infected both EOC cells and mesothelial cells; however, unlike EOC cells, mesothelial cells provided a poor substrate for replication of HSV-G207. In contrast to wild-type HSV-F, HSV-G207 exerted a potent oncolytic effect on EOC cells but spared normal mesothelial cells in vitro. Primary EOC cells were more sensitive to the virus than established EOC cell lines. A single intraperitoneal injection of HSV-G207 resulted in a significant reduction in tumor volume and tumor spread in vivo. HSV-G207 was shown to penetrate deeply within tumor nodules and caused no apparent intraperitoneal toxicity. Oncolytic therapy with multimutated replication-restricted HSV may offer a novel approach in the treatment of EOC. Cancer Gene Therapy (2000) 7, 275-283 Key words: Viral oncolytic therapy; herpes simplex virus; ovarian cancer; intraperitoneal therapy.V iral-based oncolytic therapy has gained renewed interest due to recent advances in molecular virology allowing for manipulation of the viral particles and enhancement of their tumor specificity. 1,2 Replicationselective herpes simplex virus-1 (HSV-1) mutants have been engineered by deletions of both copies of the RL1 gene. 3 Its product, infected cell product (ICP)34.5 protein, plays a major role in neurovirulence 4 and in prevention of the premature shutoff of protein synthesis in infected cells. 5 ICP34.5-null HSV-1 mutants such as HSV-1716 and HSV-R3616 have been shown to replicate preferentially in tumor cells, causing a direct oncolytic effect. 2,6 HSV-G207 was further attenuated by inserting the Escherichia coli lacZ gene into the HSV ICP6 gene, which encodes ribonucleotide reductase (RR), on the ICP34.5 Ϫ backbone of HSV-R3616. 7 HSV-G207 was shown to be hypersensitive to the antiherpetic drug ganciclovir 7 and to display no detectable neurovirulence. 7,8 Replication-selective HSV-1 mutants have been demonstrated to be efficacious antitumor agents in experimental models of various central nervous system (CNS) tumors. 3,4,8 -17 Based on promising preclinical results in experimental CNS tumors, dose escalation phase I clinical trials have begun using stereotactic application of HSV-G207 and HSV-1716 for the treatment of malignan...

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“…[107][108][109][110][111][112] Additionally, combination of HSV mutants with chemotherapy or radiotherapy has demonstrated enhanced antitumor activity. 80,101,[113][114][115][116][117][118] Radiation increased the anticancer activity of HSV when used in pancreatic, glioblastoma and cervical cancer models 119 but did not alter the antitumor effect of HSV in prostate cancer. However, high-dose radiation combined with oncolytic HSV virus did improve efficacy in other prostate cancer models.…”

Section: Herpes Simplex Virus (Hsv)mentioning

confidence: 99%

“…However, high-dose radiation combined with oncolytic HSV virus did improve efficacy in other prostate cancer models. 102,115,116 Low-dose irradiation also improved efficacy of HSV viral therapy in a cervical cancer model. 118 In chemotherapy combination studies, interestingly, both chemotherapy-resistant and -sensitive tumors were equally responsive.…”

Section: Herpes Simplex Virus (Hsv)mentioning

confidence: 99%

Clinical development directions in oncolytic viral therapy

Eager

Nemunaitis

2011

Cancer Gene Ther

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Oncolytic virotherapy is an emerging experimental treatment platform for cancer therapy. Oncolytic viruses are replicativecompetent viruses that are engineered to replicate selectively in cancer cells with specified oncogenic phenotypes. Multiple DNA and RNA viruses have been clinically tested in a variety of tumors. This review will provide a brief description of these novel anticancer biologics and will summarize the results of clinical investigation. To date oncolytic virotherapy has shown to be safe, and has generated clinical responses in tumors that are resistant to chemotherapy or radiotherapy. The major challenge for researchers is to maximize the efficacy of these viral therapeutics, and to establish stable systemic delivery mechanisms.

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Enhancement of replication of genetically engineered herpes simplex viruses by ionizing radiation: a new paradigm for destruction of therapeutically intractable tumors

Cited by 140 publications

References 18 publications

Oncolytic adenovirus CG7870 in combination with radiation demonstrates synergistic enhancements of antitumor efficacy without loss of specificity

Oncolytic adenovirus CG7870 in combination with radiation demonstrates synergistic enhancements of antitumor efficacy without loss of specificity

Multi-attenuated herpes simplex virus-1 mutant G207 exerts cytotoxicity against epithelial ovarian cancer but not normal mesothelium and is suitable for intraperitoneal oncolytic therapy

Clinical development directions in oncolytic viral therapy

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