Multifaceted Therapeutic Targeting of Ovarian Peritoneal Carcinomatosis Through Virus-induced Immunomodulation

Gujar, Shashi; Dielschneider, Rebecca; Clements, Derek R.; Helson, Erin; Shmulevitz, Maya; Marcato, Paola; Pan, Da; Pan, Lu-Zhe; Ahn, Dong‐Gyu; Alawadhi, Abdulaziz; Lee, Patrick W.K.

doi:10.1038/mt.2012.228

Cited by 64 publications

(75 citation statements)

References 34 publications

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“…These reovirus-induced antitumor immunotherapeutic activities target existing cancer cells and can protect the host against subsequent tumor relapse even after discontinuation of the therapy (15). Following its therapeutic administration, reovirus invokes a sequence of immunological events that ultimately overturns numerous tumor-associated immune evasion mechanisms and facilitates the development of antitumor innate and adaptive immune responses (15)(16)(17)(18)(19)(20)(21). Thus, comprehensive characterization and subsequent therapeutic management of the virus-induced immunological events are absolutely necessary to harness the beneficial effects of reovirus-driven anticancer therapy.…”

mentioning

confidence: 99%

“…therapeutic injections of reovirus drive the accumulation of CD11b + , Gr-1 + myeloid cells in the tumor microenvironment of hosts with peritoneal carcinomatosis (PC) (17,18). However, the detailed characteristics, the pathophysiological significance of such virus-driven MDSCs, and the possible subpopulations in the context of tumor microenvironment are at present unknown.…”

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confidence: 99%

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Newly Recruited CD11b+, GR-1+, Ly6Chigh Myeloid Cells Augment Tumor-Associated Immunosuppression Immediately following the Therapeutic Administration of Oncolytic Reovirus

Clements

Sterea

Kim

et al. 2015

The Journal of Immunology

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Tumor-associated immunosuppression aids cancer cells to escape immune-mediated attack and subsequent elimination. Recently, however, many oncolytic viruses, including reovirus, have been reported to overturn such immunosuppression and promote the development of a clinically desired antitumor immunity, which is known to promote favorable patient outcomes. Contrary to this existing paradigm, in this article we demonstrate that reovirus augments tumor-associated immunosuppression immediately following its therapeutic administration. Our data show that reovirus induces preferential differentiation of highly suppressive CD11b+, Gr-1+, Ly6Chigh myeloid cells from bone marrow hematopoietic progenitor cells. Furthermore, reovirus administration in tumor-bearing hosts drives time-dependent recruitment of CD11b+, Gr-1+, Ly6Chigh myeloid cells in the tumor milieu, which is further supported by virus-induced increased expression of numerous immune factors involved in myeloid-derived suppressor cell survival and trafficking. Most importantly, CD11b+, Gr-1+, Ly6Chigh myeloid cells specifically potentiate the suppression of T cell proliferation and are associated with the absence of IFN-γ response in the tumor microenvironment early during oncotherapy. Considering that the qualitative traits of a specific antitumor immunity are largely dictated by the immunological events that precede its development, our findings are of critical importance and must be considered while devising complementary interventions aimed at promoting the optimum efficacy of oncolytic virus–based anticancer immunotherapies.

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confidence: 99%

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confidence: 99%

Newly Recruited CD11b+, GR-1+, Ly6Chigh Myeloid Cells Augment Tumor-Associated Immunosuppression Immediately following the Therapeutic Administration of Oncolytic Reovirus

Clements

Sterea

Kim

et al. 2015

The Journal of Immunology

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“…However, reovirus infection can also localize suppressive populations. Infection with reovirus initially increases the frequency of MDSCs and Tregs in the spleen and ascites of OC murine models (58). This spike in the numbers of suppressive cell populations may provide a mechanism for minimizing the "collateral damage" incurred during an antiviral immune response.…”

Section: Combination Immunotherapymentioning

confidence: 99%

Strategic Combinations: The Future of Oncolytic Virotherapy with Reovirus

Zhao

Chester

Rajasekaran

et al. 2016

Molecular Cancer Therapeutics

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The dominant cancer treatment modalities such as chemotherapy, radiotherapy, and even targeted kinase inhibitors and mAbs are limited by low efficacy, toxicity, and treatmentresistant tumor subclones. Oncolytic viral therapy offers a novel therapeutic strategy that has the potential to dramatically improve clinical outcomes. Reovirus, a double-stranded benign human RNA virus, is a leading candidate for therapeutic development and currently in phase III trials. Reovirus selectively targets transformed cells with activated Ras signaling pathways; Ras genes are some of the most frequently mutated oncogenes in human cancer and it is estimated that at least 30% of all human tumors exhibit aberrant Ras signaling. By targeting Rasactivated cells, reovirus can directly lyse cancer cells, disrupt tumor immunosuppressive mechanisms, reestablish multicellular immune surveillance, and generate robust antitumor responses. Reovirus therapy is currently being tested in combination with radiotherapy, chemotherapy, immunotherapy, and surgery. In this review, we discuss the current successes of these combinatorial therapeutic strategies and emphasize the importance of prioritizing combination oncolytic viral therapy as reovirus-based treatments progress in clinical development.

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“…[14 Although the use of reovirus in cancer therapy stems from the oncolytic capabilities of the virus, recent studies have illustrated that reovirus additionally invokes a sequence of immunological events that ultimately overturn various tumor-induced immunosuppressive mechanisms and promotes the development of an antitumor immune response. [34][35][36][37][38][39] Studies have shown that reovirus treatment promotes the secretion of a range of proinflammatory cytokines and chemokines following administration. [34,38,40] Additionally, upon exposure to reovirus, dendritic cells (DCs) produce various proinflammatory cytokines, undergo maturation, and migrate into the tumor microenvironment along with CD8 + T cells.…”

Section: Introductionmentioning

confidence: 99%

“…[34][35][36][37][38][39] Studies have shown that reovirus treatment promotes the secretion of a range of proinflammatory cytokines and chemokines following administration. [34,38,40] Additionally, upon exposure to reovirus, dendritic cells (DCs) produce various proinflammatory cytokines, undergo maturation, and migrate into the tumor microenvironment along with CD8 + T cells. [34,39] These reovirus-activated DCs possess the ability to prime tumor antigen-specific T cells (both in vitro and in vivo) [34] and increase the cytolytic activity of innate immune cells (natural killer [NK] cells).…”

Section: Introductionmentioning

confidence: 99%