Phase I/II Study of Oncolytic HSVGM-CSF in Combination with Radiotherapy and Cisplatin in Untreated Stage III/IV Squamous Cell Cancer of the Head and Neck

Harrington, Kevin; Hingorani, Mohan; Tanay, Mary Anne; Hickey, Jennifer; Bhide, Shreerang A.; Clarke, Peter; Renouf, Louise C.; Thway, Khin; Sibtain, Amen; McNeish, Iain A.; Newbold, Kate; Goldsweig, Howard; Coffin, Robert S.; Nutting, Christopher M.

doi:10.1158/1078-0432.ccr-10-0196

Cited by 226 publications

(180 citation statements)

References 23 publications

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“…28 Phase I clinical trials have already begun to explore the feasibility of combining oncolytic viruses with radiotherapy. [29][30][31] A clinical trial has also been undertaken to demonstrate the safety and feasibility of combining IR (single 5 Gy fraction) and oncolytic HSV-1 (JM Markert, personal communication). The data from the current study in part provided the basis for this trial in which radiotherapy is rationally integrated into the viral replicative cycle.…”

Section: Discussionmentioning

confidence: 99%

Increased oncolytic efficacy for high-grade gliomas by optimal integration of ionizing radiation into the replicative cycle of HSV-1

et al. 2011

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Oncolytic viruses have been combined with standard cancer therapies to increase therapeutic efficacy. Given the sequential activation of herpes viral genes (herpes simplex virus-1, HSV-1) and the temporal cellular changes induced by ionizing radiation, we hypothesized an optimal temporal sequence existed in combining oncolytic HSV-1 with ionizing radiation. Murine U-87 glioma xenografts were injected with luciferase encoding HSV-1, and ionizing radiation (IR) was given at times before or after viral injection. HSV-1 replication and tumor-volume response were followed. Radiation given 6-9 h after HSV-1 injection resulted in maximal viral luciferase expression and infectious viral production in tumor xenografts. The greatest xenograft regression was also seen with radiation given 6 h after viral injection. We then tested if HSV-1 replication had a dose response to ionizing radiation. HSV-1 luciferase expression exhibited a dose response as xenografts were irradiated from 0 to 5 Gy. There was no difference in viral luciferase expression as IR dose increased from 5 Gy up to 20 Gy. These results suggest that the interaction of IR with the HSV-1 lytic cycle can be manipulated for therapeutic gain by delivering IR at a specific time within viral replicative cycle.

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Section: Discussionmentioning

confidence: 99%

Increased oncolytic efficacy for high-grade gliomas by optimal integration of ionizing radiation into the replicative cycle of HSV-1

et al. 2011

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“…A number of preclinical studies have shown that oncolytic herpes viruses induce cytotoxic T lymphocyte-mediated antitumor immunity, which can inhibit tumor regrowth upon rechallenge. [33][34][35][36] Consistent with this, efforts have been made to arm oncolytic herpes viruses with cytokines such as interleukin-12 37 and granulocyte-macrophage colony-stimulating factor 10,38 in order to intensify antitumor immunity. From this perspective, it might be said that the potency of a virus relies on its capacity to induce antitumor immunity.…”

Section: Introductionmentioning

confidence: 92%

“…A growing body of preclinical and clinical data suggests that oncolytic viral therapy could be an effective therapeutic modality in the treatment of advanced cancer. [5][6][7][8][9][10][11] Various strains of viruses, such as adenovirus, 12 herpes simplex virus, 13 Newcastle disease virus, measles virus, vesicular stomatitis virus and vaccinia virus 14 are being analyzed for their oncolytic capacity; some of these viruses have progressed to the clinical trial phase. Herpes simplex virus type 1 (HSV 1) is an ideal candidate for oncolytic viral therapy because of the following reasons: (a) it infects a broad range of hosts; (b) it causes lyses of the host cell at the end of viral replication; (c) it has a very large genome and therefore harbors many non-essential genes, mostly related to neuroinvasiveness that are expendable and can be replaced during the recombinant engineering process; (d) it can be controlled by antiviral drugs in the event of uncontrolled replication; and (e) its genome remains as an episome and does not incorporate in to the host genome, avoiding the risk of introducing mutations.…”

Section: Introductionmentioning

confidence: 99%

Impact of novel oncolytic virus HF10 on cellular components of the tumor microenviroment in patients with recurrent breast cancer

et al. 2011

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Oncolytic viruses are a promising method of cancer therapy, even for advanced malignancies. HF10, a spontaneously mutated herpes simplex type 1, is a potent oncolytic agent. The interaction of oncolytic herpes viruses with the tumor microenvironment has not been well characterized. We injected HF10 into tumors of patients with recurrent breast carcinoma, and sought to determine its effects on the tumor microenvironment. Six patients with recurrent breast cancer were recruited to the study. Tumors were divided into two groups: saline-injected (control) and HF10-injected (treatment). We investigated several parameters including neovascularization (CD31) and tumor lymphocyte infiltration (CD8, CD4), determined by immunohistochemistry, and apoptosis, determined by terminal deoxynucleotidyl transferase dUTP nick end labeling assay. Median apoptotic cell count was lower in the treatment group (P ¼ 0.016). Angiogenesis was significantly higher in treatment group (P ¼ 0.032). Count of CD8-positive lymphocytes infiltrating the tumors was higher in the treatment group (P ¼ 0.008). We were unable to determine CD4-positive lymphocyte infiltration. An effective oncolytic viral agent must replicate efficiently in tumor cells, leading to higher viral counts, in order to aid viral penetration. HF10 seems to meet this criterion; furthermore, it induces potent antitumor immunity. The increase in angiogenesis may be due to either viral replication or the inflammatory response.

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“…This has been attempted through the use of combination with other agents, such as chemotherapy, radiotherapy and/or adjuvant therapeutic genes. The second-generation HSV-1 mutant G207 has been combined with cisplatin for head and neck cancer, 8,14 vincristine to treat rhabdomyosarcoma 15 and paclitaxel to combat anaplastic thyroid cancer. 16 All of these combination therapies were more effective than HSV-1 treatment alone.…”

Section: Introductionmentioning

confidence: 99%

“…Finally, a recent phase I clinical trial with oncolytic HSV-1 virus, JS1/34.5-/47-/(granulocyte-macrophage-colony-stimulating factor), in combination with cisplatin-based chemotherapy demonstrated an optimal tolerated dose of HSV-1, and improved rates in relapse-free survival in squamous cell cancer of the head and neck. 14 Although these combinatory studies are all promising, they do not address a major weakness of HSV-1, which is its limited capability to replicate within a tumor. Indeed, although the main appeal of oncolytic herpes viruses is their potential for exponential increases in titer with passing time, in quantitative studies we have documented their gradual loss from animal tumors.…”

Section: Introductionmentioning

confidence: 99%

Effect of a caspase inhibitor, zVADfmk, on the inhibition of breast cancer cells by herpes simplex virus type 1

Wood

Shillitoe

2011

Cancer Gene Ther

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The oncolytic effects of herpes simplex virus-1 (HSV-1) are limited, possibly because of premature death of infected cells by apoptosis, which limits the amount of progeny virus that is produced. It has been proposed that inhibition of apoptosis in infected tumor cells would allow increased viral persistence, replication and therapeutic effect. To test this hypothesis, we infected monocyte chemoattractant factor-7 (MCF-7) and MDA-MB-231 breast cancer cells with HSV-1 strain 17 þ and 17Dg34.5 in the presence or absence of N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVADfmk), a pan-caspase inhibitor. At low doses of HSV-1 strain 17 þ and 17Dg34.5, the growth of MCF-7 cells was reduced to 37% or 42%, respectively, of uninfected cells. However, when cells were infected in the presence of zVADfmk, cell growth was further reduced to 24 and 33%. Similar results were seen in MDA-MB-231 cells. Cells treated with zVADfmk contained roughly 10 times more infectious viral particles than cells infected without zVADfmk, as shown by both plaque-forming and quantitative polymerase chain reaction assays. To model the situation within an infected tumor, supernatant fluids were collected from infected and non-infected cell cultures and then passed to non-infected cells. In the presence of zVADfmk, the cell growth inhibitory effect became stronger with repeated passages and was attributed to viral replication, because it could be prevented by anti-HSV antibody. These results suggest that caspases represent a novel target for drugs that increase the therapeutic efficacy of oncolytic herpes viruses against breast cancer.

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Phase I/II Study of Oncolytic HSVGM-CSF in Combination with Radiotherapy and Cisplatin in Untreated Stage III/IV Squamous Cell Cancer of the Head and Neck

Cited by 226 publications

References 23 publications

Increased oncolytic efficacy for high-grade gliomas by optimal integration of ionizing radiation into the replicative cycle of HSV-1

Increased oncolytic efficacy for high-grade gliomas by optimal integration of ionizing radiation into the replicative cycle of HSV-1

Impact of novel oncolytic virus HF10 on cellular components of the tumor microenviroment in patients with recurrent breast cancer

Effect of a caspase inhibitor, zVADfmk, on the inhibition of breast cancer cells by herpes simplex virus type 1

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