Systemic Armed Oncolytic and Immunologic Therapy for Cancer with JX-594, a Targeted Poxvirus Expressing GM-CSF

Kim, J.H.; Oh, Joe; Park, B.H.; Lee, D.E.; Kim, J.S.; Park, H.E.; Roh, Mee‐Sook; Je, Ji Eun; Yoon, Jihyun; Thorne, Steve H.; Kirn, David H.; Hwang, Tae-Ho

doi:10.1016/j.ymthe.2006.05.008

Cited by 274 publications

(240 citation statements)

References 40 publications

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“…15); this virus was designated JX-963. Because human GM-CSF is not active in rodents but is active in rabbits (16), and in order to assess the activity against much larger primary tumors that reproducibly metastasize, JX-963 was used in a rabbit model with primary (VX2) liver tumors and lung metastases (17). At the time of dosing, multiple 1-to 2-mm tumor metastases were already evident on histopathology of the lungs of control rabbits.…”

Section: Jx-963 (Vvdd-gm-csf) Final Product Engineering and Evaluatiomentioning

confidence: 99%

Rational strain selection and engineering creates a broad-spectrum, systemically effective oncolytic poxvirus, JX-963

Thorne¹,

Hwang²,

O’Gorman³

et al. 2007

J. Clin. Invest.

180

172

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Replication-selective oncolytic viruses (virotherapeutics) are being developed as novel cancer therapies with unique mechanisms of action, but limitations in i.v. delivery to tumors and systemic efficacy have highlighted the need for improved agents for this therapeutic class to realize its potential. Here we describe the rational, stepwise design and evaluation of a systemically effective virotherapeutic (JX-963). We first identified a highly potent poxvirus strain that also trafficked efficiently to human tumors after i.v. administration. This strain was then engineered to target cancer cells with activation of the transcription factor E2F and the EGFR pathway by deletion of the thymidine kinase and vaccinia growth factor genes. For induction of tumor-specific cytotoxic T lymphocytes, we further engineered the virus to express human GM-CSF. JX-963 was more potent than the previously used virotherapeutic Onyx-015 adenovirus and as potent as wild-type vaccinia in all cancer cell lines tested. Significant cancer selectivity of JX-963 was demonstrated in vitro in human tumor cell lines, in vivo in tumor-bearing rabbits, and in primary human surgical samples ex vivo. Intravenous administration led to systemic efficacy against both primary carcinomas and widespread organ-based metastases in immunocompetent mice and rabbits. JX-963 therefore holds promise as a rationally designed, targeted virotherapeutic for the systemic treatment of cancer in humans and warrants clinical testing.

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Section: Jx-963 (Vvdd-gm-csf) Final Product Engineering and Evaluatiomentioning

confidence: 99%

Rational strain selection and engineering creates a broad-spectrum, systemically effective oncolytic poxvirus, JX-963

Thorne¹,

Hwang²,

O’Gorman³

et al. 2007

J. Clin. Invest.

180

172

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“…18) expressed from vaccinia virus or GM-CSF (19) expressed from herpes simplex virus] has shown great promise in clinical trials. In addition, preclinical reports of other viruses modified to express cytokines were able to confer an increase in their therapeutic efficacy in several tumor models (20)(21)(22)(23)(24)(25)(26)(27). In this regard, we developed several NDV vectors carrying GM-CSF, tumor necrosis factor (TNF)-a, IFN-g, or IL-2 and tested them for increased therapeutic efficacy.…”

Section: Introductionmentioning

confidence: 99%

Use of Reverse Genetics to Enhance the Oncolytic Properties of Newcastle Disease Virus

Vigil¹,

Park²,

Martinez³

et al. 2007

Cancer Research

150

153

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Naturally occurring strains of Newcastle disease virus (NDV) have shown oncolytic therapeutic efficacy in preclinical studies and are currently in clinical trials. Here, we have evaluated the possibility to enhance the cancer therapeutic potential of NDV by means of reverse genetics. Mice bearing s.c. implanted CT26 tumors were treated with intratumoral (i.t.) injections of a recombinant NDV modified to contain a highly fusogenic F protein. These treated mice exhibited significant reduction in tumor development compared with mice treated with the unmodified virus. Furthermore, mice in a CT26 metastatic tumor model treated with an i.v. injection of the genetically engineered NDV exhibited prolonged survival compared with wild-type control virus. In addition, we examined whether the oncolytic properties of NDV could be improved by expression of immunostimulatory molecules. In this regard, we engineered several NDVs to express granulocyte macrophage colony-stimulating factor, IFN-;, interleukin 2 (IL-2), or tumor necrosis factor A, and evaluated their therapeutic potential in an immunocompetent colon carcinoma tumor model. Mice bearing s.c. CT26 tumors treated with i.t. injections of recombinant NDV expressing IL-2 showed dramatic reductions in tumor growth, with a majority of the mice undergoing complete and long-lasting remission. Our data show the use of reverse genetics to develop enhanced recombinant NDV vectors as effective therapeutic agents for cancer treatment. [Cancer Res 2007;67(17):8285-92]

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“…This study documented tumor-specific virus replication and gene expression, GM-CSF detection, and tumor-infiltrating cytotoxic T-lymphocytes. 59 The effect of JX-594 on the tumor-associated vasculature was tested; the results showed a significant regression in the tumor-associated vasculature in xenograft models as well as in patients. This study demonstrated that a biologic agent can be used for infection and selective replication in endothelial cells.…”

Section: Wyeth Strainsmentioning

confidence: 99%

Viruses as nanomedicine for cancer

Badrinath

Heo²,

Yoo

2016

IJN

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Oncolytic virotherapy, a type of nanomedicine in which oncolytic viruses (OVs) are used to selectively infect and lyse cancer cells, is an emerging field in cancer therapy. Some OVs exhibit a specific tropism for cancer cells, whereas others require genetic modification to enhance their binding with and entry into cancer cells. OVs both kill tumor cells and induce the host’s immune response against tumor cells. Armed with antitumor cellular molecules, antibodies, and/or in combination with anticancer drugs, OVs can accelerate the lysis of cancer cells. Among the OVs, vaccinia virus has been the focus of preclinical and clinical research because of its many favorable properties. In this review, the basic mechanisms of action of OVs are presented, including their entry, survival, tumor lysis, and immune activation, and the latest research in vaccinia virus-based virotherapy and its status as an anticancer nanomedicine in prospective clinical trials are discussed.

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Systemic Armed Oncolytic and Immunologic Therapy for Cancer with JX-594, a Targeted Poxvirus Expressing GM-CSF

Cited by 274 publications

References 40 publications

Rational strain selection and engineering creates a broad-spectrum, systemically effective oncolytic poxvirus, JX-963

Rational strain selection and engineering creates a broad-spectrum, systemically effective oncolytic poxvirus, JX-963

Use of Reverse Genetics to Enhance the Oncolytic Properties of Newcastle Disease Virus

Viruses as nanomedicine for cancer

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