Reovirus therapy of lymphoid malignancies

Alain, Tommy; Hirasawa, Kensuke; Pon, Kelly J; Nishikawa, Sandra; Urbanski, Stefan J.; Auer, Yvonna; Luider, Joanne; Martin, Anita; Johnston, Randal N.; Janowska‐Wieczorek, Anna; Lee, Patrick W.K.; Kossakowska, Anna E.

doi:10.1182/blood-2002-02-0503

Cited by 106 publications

(80 citation statements)

References 40 publications

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“…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). Tumor regression achieved during reovirus anticancer therapy is thought to be primarily mediated by direct destruction of cancer cells.…”

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

106

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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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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

106

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“…12,[15][16][17]58,59 Further to this promising in vitro data, positive in vivo data highlights the potential of reovirus as a future cancer therapy. Initially, reovirus oncolytic activity was tested in the hind flank tumor xenograft of severe combined immunodeficient (SCID) mouse model.…”

Section: Reovirus As a Cancer Therapymentioning

confidence: 99%

“…Reovirus injections were also effective in tumor regression and survival of SCID or immune compromised mice implanted with human colon, ovarian, breast, lymphoma, brain and spinal cancer derived cells. 12,[15][16][17]58 Subsequently, reovirus, especially when combined with immune suppression drugs, was successful in significantly reducing metastatic and/or distal tumors in immunocompetent mice. 14 Phase II clinical studies testing the applicability of reovirus oncolysis as a cancer therapy are underway.…”

Section: Reovirus As a Cancer Therapymentioning

confidence: 99%

“…[6][7][8][9][10] Unlike other oncloytic viruses, reovirus is being assessed as a cancer therapeutic in its naturally isolated state. [11][12][13][14][15][16][17] A benign virus often found in human gastrointestinal and respiratory tracts, reovirus was historically studied has a prototypic model of double stranded RNA viruses. 18 Most humans have been infected by reovirus, usually unnoticeable.…”

Section: Introductionmentioning

confidence: 99%

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Connecting Reovirus Oncolysis and Ras Signaling

Marcato

Shmulevitz²,

Lee³

2005

Cell Cycle

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Reovirus is a benign virus with innate oncolytic activity and is a potential novel therapeutic for a number of cancers. Reovirus can replicate in, and induce death of cancerous cells having an activated Ras pathway. Ras activation leads to the inactivation of cellular antiviral mechanisms, specifically removing the translation block on reovirus transcripts. This review outlines recent progress towards elucidating the molecular connection between the Ras-signaling pathway and reovirus replication.

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“…Reoviruses preferentially replicate in cells with an activated Ras pathway [41][42][43], a feature of many human cancers. Reovirus infection results in oncolysis of numerous human cancer cells in vitro [44][45][46][47][48], including ovarian cancer cells [44] and in the significant regression of a variety of tumors established in mice from human cancer cells [43][44][45][46][47][48]. In mouse models both intratumoral and intravenous inoculation of reovirus induce the significant regression of ovarian tumors implanted in the hind flank [44].…”

Section: Introductionmentioning

confidence: 99%

Down-regulation of cFLIP following reovirus infection sensitizes human ovarian cancer cells to TRAIL-induced apoptosis

Clarke

Tyler

2006

Apoptosis

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Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) shows promise as a chemotherapeutic agent. However, many human cancer cells are resistant to killing by TRAIL. We have previously demonstrated that reovirus infection increases the susceptibility of human lung (H157) and breast (ZR75-1) cancer cell lines to TRAIL-induced apoptosis. We now show that reovirus also increases the susceptibility of human ovarian cancer cell lines (OVCAR3, PA-1 and SKOV-3) to TRAIL-induced apoptosis. Reovirus-induced increases in susceptibility of OVCAR3 cells to TRAIL require virus uncoating and involve increased activation of caspases 3 and 8. Reovirus infection results in the down-regulation of cFLIP (cellular FLICE inhibitory protein) in OVCAR3 cells. Down-regulation of cFLIP following treatment of OVCAR3 cells with antisense cFLIP oligonucleotides or PI3 kinase inhibition also increases the susceptibility of OVCAR3 cells to TRAIL-induced apoptosis. Finally, over-expression of cFLIP blocks reovirus-induced sensitization of OVCAR3 cells to TRAIL-induced apoptosis. The combination of reovirus and TRAIL thus represents a promising new therapeutic approach for the treatment of ovarian cancer.

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Reovirus therapy of lymphoid malignancies

Abstract: Reoviruses infect cells that manifest an

Cited by 106 publications

References 40 publications

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

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

Connecting Reovirus Oncolysis and Ras Signaling

Down-regulation of cFLIP following reovirus infection sensitizes human ovarian cancer cells to TRAIL-induced apoptosis

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