Unshackling the links between reovirus oncolysis, Ras signaling, translational control and cancer

Shmulevitz, Maya; Marcato, Paola; Lee, Patrick W.K.

doi:10.1038/sj.onc.1209041

Cited by 87 publications

(75 citation statements)

References 89 publications

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“…8,9,44 The detailed relationship between the cell's Ras status and the various consequences of infection has not been fully elucidated yet. 5,44 While our data suggests components of the Ras/ RalGEF/p38 pathway 6 (particularly p38 and in some cell lines PI3K, but not MEK 1/2) are implicated in the reovirus-induced killing of melanoma (Figure 4), for clinical application the key findings of this study are the sensitivity of melanoma (both cell lines and primary tumours) to reovirus killing and replication, together with the relative resistance of Melan-A normal melanocytes. Sequencing to date of our lines has shown that they are all mutant in the Ras/BRAF pathway (as expected for melanomas 45 ), while Melan-A is normal.…”

Section: Discussionmentioning

confidence: 99%

Inflammatory tumour cell killing by oncolytic reovirus for the treatment of melanoma

et al. 2008

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Reovirus is a promising unmodified double-stranded RNA (dsRNA) anti-cancer oncolytic virus, which is thought to specifically target cells with activated Ras. Although reovirus has been tested in a wide range of preclinical models and has entered early clinical trials, it has not previously been tested for the treatment of human melanoma. Here, we show that reovirus effectively kills and replicates in both human melanoma cell lines and freshly resected tumour; intratumoural injection also causes regression of melanoma in a xenograft in vivo model. Reovirus-induced melanoma death is blocked by caspase inhibition and is dependent on constituents of the Ras/RalGEF/p38 pathway. Reovirus melanoma killing is more potent than, and distinct from, chemotherapy or radiotherapy-induced cell death; a range of inflammatory cytokines and chemokines are released by infected tumour cells, while IL-10 secretion is abrogated. Furthermore, the inflammatory response generated by reovirus-infected tumour cells causes bystander toxicity against reovirus-resistant tumour cells and activates human myeloid dendritic cells (DC) in vitro. Hence, reovirus is suitable for clinical testing in melanoma, and may provide a useful danger signal to reverse the immunologically suppressive environment characteristic of this tumour.

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Section: Discussionmentioning

confidence: 99%

Inflammatory tumour cell killing by oncolytic reovirus for the treatment of melanoma

et al. 2008

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“…Reovirus, a naturally occurring benign human pathogen, preferentially targets cancerous cells of many origins and is currently under clinical trials as a novel anticancer therapeutic agent (23,24). Reovirus efficiently destroys local as well as distant metastatic tumors in immunocompromised animals even after a single injection administered through intravenous, intraperitoneal, or intratumoral routes (25)(26)(27)(28).…”

Section: Introductionmentioning

confidence: 99%

Reovirus Virotherapy Overrides Tumor Antigen Presentation Evasion and Promotes Protective Antitumor Immunity

Gujar

Marcato

Pan

et al. 2010

Molecular Cancer Therapeutics

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105

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Tumor-associated immunosuppressive strategies, such as lack of tumor antigen recognition and failure of lymphocyte activation and homing, resist the development of tumor-specific immunity and hamper the immune response-mediated elimination of cancerous cells. In this report, we show that reovirus virotherapy overrides such a tumor immune evasion and establishes clinically meaningful antitumor immunity capable of protecting against subsequent tumor challenge. Reovirus-mediated destruction of tumor cells facilitates the recognition of tumor antigens by promoting the display of otherwise inaccessible tumorspecific immunogenic peptides on the surface of dendritic cells (DC). Furthermore, on exposure to reovirus, DCs produce IL-1α, IL-1β, IL-6, IL-12p40/70, IL-17, CD30L, eotaxin, GM-CSF, KC, MCP-1, MCP-5, M-CSF, MIG, MIP-1α, RANTES, TNF-α, VCAM-1, VSGF, CXCL-16, AXL, and MCP-2; undergo maturation; and migrate into the tumor microenvironment along with CD8 T cells. These reovirus-activated DCs also acquire the capacity to prime tumor antigen-specific transgenic T cells in vitro and intrinsic antitumor T-cell response in vivo. Further, reovirus virotherapy augments the efficacy of DC-or T cell-based anticancer immunotherapies and synergistically enhances the survival in tumor-bearing mice. Most importantly, antitumor cellular immune responses initiated during reovirus oncotherapy protect the host against subsequent tumor challenge in a reovirus-independent but antigen-dependent manner. These reovirus oncotherapy-initiated antitumor immune responses represent an anticancer therapeutic entity that can maintain a long-term cancer-free health even after discontinuation of therapy.

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“…To date, only wild-type T3D has been used in clinical trials. 1,6,41 The results of this approach are encouraging and the procedure is welltolerated. However, the scarcity or inaccessibility of reovirus receptors on the surface of tumor cells may limit the efficacy of wild-type reoviruses as oncolytic agents.…”

Section: Discussionmentioning

confidence: 92%

A strategy for genetic modification of the spike-encoding segment of human reovirus T3D for reovirus targeting

et al. 2008

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Human Orthoreovirus Type 3 Dearing is not pathogenic to humans and has been evaluated clinically as an oncolytic agent. Its transduction efficiency and the tumor cell selectivity may be enhanced by incorporating ligands for alternative receptors. However, the genetic modification of reoviruses has been difficult, and genetic targeting of reoviruses has not been reported so far. Here we describe a technique for generating genetically targeted reoviruses. The propagation of wild-type reoviruses on cells expressing a modified s1-encoding segment embedded in a conventional RNA polymerase II transcript leads to substitution of the wild-type genome segment by the modified version. This technique was used for generating reoviruses that are genetically targeted to an artificial receptor expressed on U118MG cells. These cells lack the junction adhesion molecule-1 and therefore resist infection by wild-type reoviruses. The targeted reoviruses were engineered to carry the ligand for this receptor at the C terminus of the s1 spike protein. This demonstrates that the C terminus of the s1 protein is a suitable locale for the insertion of oligopeptide ligands and that targeting of reoviruses is feasible. The genetically targeted viruses can be propagated using the modified U118MG cells as helper cells. This technique may be applicable for the improvement of human reoviruses as oncolytic agents.

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Unshackling the links between reovirus oncolysis, Ras signaling, translational control and cancer

Cited by 87 publications

References 89 publications

Inflammatory tumour cell killing by oncolytic reovirus for the treatment of melanoma

Inflammatory tumour cell killing by oncolytic reovirus for the treatment of melanoma

Reovirus Virotherapy Overrides Tumor Antigen Presentation Evasion and Promotes Protective Antitumor Immunity

A strategy for genetic modification of the spike-encoding segment of human reovirus T3D for reovirus targeting

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