Effective Intravenous Therapy of Murine Pulmonary Metastases with an Oncolytic Herpes Virus Expressing Interleukin 12

Wong, Richard J.; Chan, M; Yu, Zhenkun; Kim, Teresa H.; Bhargava, Amit; Stiles, Brendon M.; Horsburgh, Brian C.; Shah, Jatin P.; Ghossein, Ronald; Singh, Bhuvanesh; Fong, Yuman

doi:10.1158/1078-0432.ccr-0197-3

Cited by 57 publications

(41 citation statements)

References 31 publications

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“…given NV1042 for the treatment of metastatic lung tumors of squamous cell carcinoma has been previously reported (32); however, in that study, treatment was initiated 1 day after tumor cell inoculation, at which time it is unlikely that tumor nodules were established. Here, we have studied animals with established tumor nodules, which better reflects the clinical situation, where there is an initial increase in prostate-specific antigen but still small or radiologically nondetectable metastases.…”

Section: Discussionmentioning

confidence: 94%

Systemic Oncolytic Herpes Virus Therapy of Poorly Immunogenic Prostate Cancer Metastatic to Lung

Varghese

Rabkin

Nielsen

et al. 2006

Clinical Cancer Research

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Purpose: Our goal was to evaluate whether systemic administration of NV1042, an interleukin-12 (IL-12)^expressing oncolytic herpes simplex virus, and its noncytokine parental vector NV1023 are effective against preexisting metastatic prostate cancer in an immunocompetent mice model. Experimental Design: MetastaticTRAMP-C2 lung tumors established in C57Bl/6 or nude mice were treated on day 21with four i.v. administrations of NV1042 or NV1023 and sacrificed on day 42 to assess virus efficacy and the potential mechanism of efficacy. Results: NV1042 or NV1023 treatment was similarly effective in eliminating extrapleural and hemorrhagic tumors present in mock-treated mice. However, NV1042 was further effective compared with NV1023 in controlling the growth of lung tumors (as determined by mean surface tumor nodule number, lung weights, and surface tumor burden) and in extending survival. NV1042-treated mice exhibited a transient increase of serum IL-12 1 day posttreatment, whereas IL-12 levels in tumor bearing lungs persisted a further 2 days at least. Only splenocytes from NV1042-treated mice secreted IFN-g in response to TRAMP-C2 stimulation and displayed natural killer activity. The IL-12-mediated enhancement observed with NV1042 in the syngeneic model was abrogated in athymic mice treated in a similar manner, thus indicating a role forTcells in the augmented efficacy of NV1042 virus. Conclusions: Systemic administration of the IL-12-expressing NV1042 virus is more effective than its noncytokine parent, NV1023, against preestablished metastatic lung tumors. Given the clinical safety profile of NV1020, the parental vector of NV1023, and NV1042's enhanced efficacy and ability to activate the host immune system, NV1042 merits clinical consideration for treating metastatic prostate cancers.Prostate cancer is the most commonly diagnosed cancer in men in the United States, accounting for 33% of all cancers and claiming the life of one in eight men with this diagnosis (1). Early diagnosis facilitated by screening high-risk populations using prostate-specific antigen and imaging techniques have aided in lowering the mortality rates of patients with localized, early-stage cancer. However, about one third will bear regional or metastatic tumors at the time of diagnosis with another 25% progressively developing metastatic disease during the course of the disease (2). Bone is the primary site of metastasis in 85% of cases followed by lymph nodes, lung, liver, and adrenals, in f45% of cases.Currently, there are no curative treatment options available for patients with advanced prostate cancer. Although organconfined cancer responds well to surgery and radiation therapy, with 5-year survival rates for such patients being 89%, the survival rates for patients with metastatic cancer decreases to 31% (2). Hormonal therapy (androgen ablation) has been the primary treatment of choice since the 1960s for patients with advanced disease. Unfortunately, the effectiveness of hormonal therapy is limited by the inevitable developme...

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Section: Discussionmentioning

confidence: 94%

Systemic Oncolytic Herpes Virus Therapy of Poorly Immunogenic Prostate Cancer Metastatic to Lung

Varghese

Rabkin

Nielsen

et al. 2006

Clinical Cancer Research

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“…Preclinical and clinical studies argue that prior immunity to HSV does not represent an obstacle. Thus, intravenously administered ␥ 1 34.5-deleted HSV was effective in prostate and pulmonary tumor models, irrespective of whether mice were previously immunized with HSV (35,36). In phase I clinical trials, ␥ 1 34.5-deleted HSV was administered i.t.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of human tumor growth in mice by an oncolytic herpes simplex virus designed to target solely HER-2-positive cells

Menotti

Nicoletti

Gatta

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

126

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Oncolytic virotherapy exploits the ability of viruses to infect, replicate into, and kill tumor cells. Among the viruses that entered clinical trials are HSVs. HSVs can be engineered to become tumorspecific by deletion of selected genes or retargeting to tumorspecific receptors. A clinically relevant surface molecule is HER-2, hyperexpressed in one fourth of mammary and ovary carcinomas, and associated with high metastatic ability. As a previously undescribed strategy to generate HSV recombinants retargeted to HER-2 and detargeted from natural receptors, we replaced the Ig-folded core in the receptor-binding virion glycoprotein gD with anti-HER-2 single-chain antibody. The recombinant entered cells solely via HER-2 and lysed HER-2-positive cancer cells. Because of the high specificity, its safety profile in i.p. injected mice was very high, with a LD 50 >5 ؋ 10 8 pfu, a figure at least 10,000-fold higher than that of corresponding WT-gD carrying virus (LD 50 Ϸ 5 ؋ 10 4 pfu). When administered intratumorally to nude mice bearing HER-2-hyperexpressing human tumors, it strongly inhibited progressive tumor growth. The results provide a generally applicable strategy to engineer HSV recombinants retargeted to a wide range of receptors for which a single-chain antibody is available, and show the potential for retargeted HSV to exert target-specific inhibition of human tumor growth. Therapy with HER-2-retargeted oncolytic HSV could be effective in combined or sequential protocols with monoclonal antibodies and small inhibitors, particularly in patients resistant to HER-2-targeted therapy because of alterations in HER-2 signaling pathway, or against brain metastases inaccessible to anti-HER-2 antibodies. mammary carcinoma ͉ ovary carcinoma ͉ retarget ͉ tropism

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“…HSV armed with IL-12 showed enhanced oncolytic effects on squamous cell carcinoma. In a murine model of squamous cell carcinoma or micro-metastatic liver disease, NV1042 expressing IL-12 displayed significantly stronger anti-tumor in comparison with its non-IL-12-expressing analog, NV1023 [71][72][73]. Moreover, NV1042 also exhibited more efficacious effects than GM-CSF-expressing NV1034 [74].…”

Section: Arming Hsv With Therapeutic Genesmentioning

confidence: 96%

Advance in herpes simplex viruses for cancer therapy

Liu

Dai

You

et al. 2013

Sci. China Life Sci.

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Oncolytic virotherapy is an attractive approach that uses live viruses to selectively kill cancer cells. Oncolytic viruses can be genetically engineered to induce cell lyses through virus replication and cytotoxic protein expression. Herpes simplex virus (HSV) has become one of the most widely clinically used oncolytic agent. Various types of HSV have been studied in basic or clinical research. Combining oncolytic virotherapy with chemotherapy or radiotherapy generally produces synergic action with unclear molecular mechanisms. Arming HSV with therapeutic transgenes is a promising strategy and can be used to complement conventional therapies. As an efficient gene delivery system, HSV has been successfully used to deliver various immunomodulatory molecules. Arming HSV with therapeutic genes merits further investigation for potential clinical application.

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Effective Intravenous Therapy of Murine Pulmonary Metastases with an Oncolytic Herpes Virus Expressing Interleukin 12

Cited by 57 publications

References 31 publications

Systemic Oncolytic Herpes Virus Therapy of Poorly Immunogenic Prostate Cancer Metastatic to Lung

Systemic Oncolytic Herpes Virus Therapy of Poorly Immunogenic Prostate Cancer Metastatic to Lung

Inhibition of human tumor growth in mice by an oncolytic herpes simplex virus designed to target solely HER-2-positive cells

Advance in herpes simplex viruses for cancer therapy

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