Local and Distant Immunity Induced by Intralesional Vaccination with an Oncolytic Herpes Virus Encoding GM-CSF in Patients with Stage IIIc and IV Melanoma

Kaufman, Howard L.; Kim, Dae Won; DeRaffele, Gail; Mitcham, Josephine; Rs, Coffin; Kim‐Schulze, Seunghee

doi:10.1245/s10434-009-0809-6

Cited by 469 publications

(366 citation statements)

References 38 publications

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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: 91%

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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Section: Introductionmentioning

confidence: 91%

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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“…The most promising immunotherapy strategies for melanoma so far have included the combination of the adjuvant GM-CSF with ipilimumab (32), which is an anti-CTLA-4 antibody, and the recombinant viral vector-based vaccine OncoVex GM-CSF , now known as T-VEC (talimogene laherparepvec; refs. [33][34][35][36].…”

Section: Discussionmentioning

confidence: 99%

Assessing the Effects of Concurrent versus Sequential Cisplatin/Radiotherapy on Immune Status in Lung Tumor–Bearing C57BL/6 Mice

Kao

Wurz

Lin

et al. 2015

Cancer Immunology Research

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Concurrent and sequential cisplatin-based chemoradiotherapy regimens are standard therapeutic approaches in cancer treatment. Recent clinical data suggest that these different dosing schedules may adversely affect antigen-specific immunotherapy. The goal of the present preclinical study was to explore the effects of concurrent and sequential cisplatin/radiotherapy on immune status in a lung cancer mouse model. A total of 150 C57BL/6 mice were randomized into six treatment groups: control; 8 Gy thoracic radiotherapy (dose schedules 1 and 2); cisplatin 2.5 mg/ kg i.p.; cisplatin þ radiotherapy (concurrent); and cisplatin þ radiotherapy (sequential; n ¼ 25, all groups). At the end of the study (week 41), serum cytokines were assessed by multiplex immunoassay, surface markers of spleen-derived lymphocytes were assessed by immunostaining and flow cytometry, lung tumor expression of programmed death ligands 1 and 2 (PD-L1/2) was evaluated by immunohistochemistry, and miRNA profiling was performed in serum and lymphocytes by quantitative real-time PCR. Lung whole mounts were prepared to assess treatment effects on lung tumor foci formation. The results showed that sequential chemoradiotherapy (two cycles of cisplatin followed by 8 Gy radiotherapy) had equivalent antitumor activity as concurrent therapy. However, sequential cisplatin/ radiotherapy resulted in significant differences in several immune response biomarkers, including regulatory T cells, miR-29c, expression of costimulatory molecule CD28, and serum IFNg. PD-L1 and PD-L2 were strongly expressed in tumor foci, but no trend was seen between groups. These results suggest that monitoring immune status may be necessary when designing treatment regimens combining immunotherapy with chemoradiotherapy.

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“…On the other hand, it has been demonstrated that the oncolytic efficacy of an attenuated HSV vector may be increased by the virally induced antitumor immunity, 32 either locally by the recruitment of immune effector cells, which may increase oncolytic activity and improve tumor clearance, or at distant sites by cross-priming the immune response to the tumor. 33 With this respect, in some instances HSVs have been armed in order to achieve a better immune-mediated tumor killing. 34,35 Syngeneic models for gliomas have been developed in rats and mice.…”

Section: Discussionmentioning

confidence: 99%

Efficacy of HER2 retargeted herpes simplex virus as therapy for high-grade glioma in immunocompetent mice

et al. 2012

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Replication-competent oncolytic herpes simplex viruses (HSVs) are considered a promising therapeutic approach for treatment of high-grade gliomas (HGGs), which are usually resistant to all the available treatments. We previously demonstrated that R-LM113, a recombinant HSV-1 fully retargeted to the human epidermal growth factor receptor 2 (HER2), is safe and prolongs survival of immunodeficient NOD/SCID mice in an intracranial model of HGG. However, because the treatment is designed to be employed on immunocompetent patients, it is necessary to test whether the host immune system impairs the viral efficacy or triggers a potentially fatal reaction. Here we confirmed the safety of R-LM113 in the immunocompetent mouse strain BALB/c, where it does not trigger encephalitis when intracranially inoculated. Then, we set up a syngeneic HGG model expressing HER2 in adult BALB/c mice and evaluated R-LM113 therapeutic efficacy. We found that R-LM113 leads to a significant improvement in animal survival when administered at the time of tumor inoculation, as well as when injected into an already established tumor. This study suggests that the host immune defenses do not curtail the oncolytic antitumor activity of replication-competent HSV R-LM113, which results effective in counteracting tumor growth.

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Local and Distant Immunity Induced by Intralesional Vaccination with an Oncolytic Herpes Virus Encoding GM-CSF in Patients with Stage IIIc and IV Melanoma

Abstract: Melanoma patients present with elevated levels of Tregs, Ts, and MDSC within established tumors. Direct injection of Oncovex(GM-CSF) induces local and systemic antigen-specific T cell responses and decreases Treg, Ts, and MDSC in patients exhibiting therapeutic responses.

Cited by 469 publications

References 38 publications

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

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

Assessing the Effects of Concurrent versus Sequential Cisplatin/Radiotherapy on Immune Status in Lung Tumor–Bearing C57BL/6 Mice

Efficacy of HER2 retargeted herpes simplex virus as therapy for high-grade glioma in immunocompetent mice

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