Morbidity in immunosuppressed (SCID/NOD) mice treated with reovirus (Dearing 3) as an anti-cancer biotherapeutic

Loken, Steve D.; Norman, Kara L.; Hirasawa, Kensuke; Nodwell, Michael J.; Lester, Wanda M.; Demetrick, Douglas J.

doi:10.4161/cbt.3.8.963

Cited by 33 publications

(34 citation statements)

References 43 publications

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“…Conversely, immunosuppression had no effect on reovirus oncolysis of gliomas in a model in rats. 6 Reovirus therapy in immunocompromised SCID mice is associated with severe morbidity 10 but we have not observed this in the CyA-treated mice used in the present study. Apparently, CyA treatment sufficed to prevent Reovirus T3D clearance from the liver, without inducing a profound systemic infection and morbidity.…”

Section: Resultscontrasting

confidence: 44%

Immunosuppression promotes reovirus therapy of colorectal liver metastases

et al. 2006

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Mortality due to colorectal cancer (CRC) is high and is associated with the development of liver metastases. Approximately 40% of human CRCs harbor an activating mutation in the KRAS oncogene. Tumor cells with activated KRAS are particularly sensitive to Reovirus T3D, a non-pathogenic oncolytic virus. The efficacy of virus-based therapies may be positively or negatively modulated by the host immune system. This study was designed to assess the effect of immunosuppression on Reovirus T3D oncolysis of established colorectal micrometastases in the liver. Mouse C26 CRC cells harbor a mutant Kras gene and are susceptible to Krasdependent oncolysis by Reovirus T3D in vitro. Isolated C26 liver tumors were established in syngenic immunocompetent BALB/c mice by intrahepatic injection. Reovirus T3D therapy was given as a single intratumoral injection in control mice and in cyclosporin A-treated immunosuppressed mice. Tumor growth was analyzed over time by non-invasive bioluminescence imaging. The outgrowth of established CRC liver metastases in immunocompetent mice was efficiently but temporarily inhibited with a single injection of Reovirus T3D. Immunosuppression with cyclosporin A markedly increased and prolonged the therapeutic effect and allowed complete Reovirus T3D-induced tumor eradication in a subpopulation of the mice. We conclude that Reovirus T3D is an effective therapeutic agent against established C26 colorectal liver metastases and that immunosuppression enhances treatment efficacy.

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Section: Resultscontrasting

confidence: 44%

Immunosuppression promotes reovirus therapy of colorectal liver metastases

et al. 2006

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“…The tumorigenic effect is nullified by co-implantation with infected HTR1 cells, suggesting that residual virus can re-infect cured cells and prevent their growth. Consistent with this, both HTR1-implanted and HTR1/cured cell co-implanted SCID mice formed black tails 3-7 months after implantation (but no tumor formation) as a manifestation of reovirusmediated pathology in SCID mice (but not immunocompetent mice; Loken et al, 2004), suggesting viral persistence in the SCID mice.…”

Section: Htr1 Cells Showed Reduced Cellular Cathepsin B Activitysupporting

confidence: 57%

Acquired resistance to reoviral oncolysis in Ras-transformed fibrosarcoma cells

et al. 2007

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Reovirus shows considerable potential as an oncolytic agent for Ras-activated tumors and is currently in clinical trials. Here we ask whether such tumor cell lines can acquire resistance to reoviral oncolysis. We challenged human HT1080 fibrosarcoma cells that carry a Ras mutation by prolonged exposure to reovirus, thereby yielding highly virus-resistant HTR1 cells. These cells are persistently infected with reovirus, exhibit high Ras activity and retain the original Ras gene mutation, showing that resistance to reovirus can be displayed in cells with active Ras. The HTR1 cells also exhibit reduced cellular cathepsin B activity, which normally contributes to viral entry and activation. Persistently infected HTR1 cells were not tumorigenic in vivo, whereas immunologically cured virus-free HTR1 cells were highly tumorigenic. Thus, acquisition of resistance to reovirus may constrain therapeutic strategies. To determine whether reoviral resistance is associated with a general reduction in apoptotic potential, we challenged the HTR1 cells with apoptotic inducers and E1B-defective adenovirus, resulting in significant apoptosis and cell death following both approaches. Therefore, even if resistance to reoviral oncolysis should arise in tumor cells in vivo, other therapeutic strategies may nevertheless remain effective.

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“…We observed a variation of this syndrome in which tails of cyclophosphamide-treated mice became swollen, very sensitive, and, in a minority of cases, detached from the animal. This is the first time, to our knowledge, that black foot syndrome has been observed in wild-type mice; moreover, onset of both reovirus-induced myocarditis and black foot syndrome was more rapid under the influence of cyclophosphamide treatment than has been reported in SCID or SCID/ NOD mice (48,49), indicating that cyclophosphamide is having multiple effects in vivo, which can resemble the induction of a severely immunocompromised state.…”

Section: Discussionmentioning

confidence: 78%

“…Black foot syndrome was described as the discoloration and necrosis of feet, tails, distal legs, and ears in SCID/NOD mice several weeks after injection of reovirus intratumorally (48), again suggesting that virus replicating within the tumor serves as a source for systemic dissemination (49). The pathogenesis of black foot syndrome was characterized as due to venous vasculitis secondary to reovirus infection along with reovirus-induced myocarditis and heart failure (48,50) and typically, these symptoms developed weeks or months after the reovirus therapy into the tumor (48,49). We observed a variation of this syndrome in which tails of cyclophosphamide-treated mice became swollen, very sensitive, and, in a minority of cases, detached from the animal.…”

Section: Discussionmentioning

confidence: 99%

Cyclophosphamide Facilitates Antitumor Efficacy against Subcutaneous Tumors following Intravenous Delivery of Reovirus

Qiao¹,

Wang²,

Kottke³

et al. 2008

Clinical Cancer Research

158

155

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Purpose: The purpose of the present study was to investigate whether it is possible to achieve truly systemic delivery of oncolytic reovirus, in immunocompetent hosts, using cyclophosphamide to overcome some of the barriers to effective intratumoral delivery and replication of i.v. injected virus. Experimental Design: I.v. delivery of reovirus was combined with different regimens of i.p. administered cyclophosphamide in C57Bl/6 mice bearing established s.c. B16 tumors. Intratumoral viral replication, tumor size, and survival were measured along with levels of neutralizing antibody (NAb) in the blood. Finally, differential toxicities of the virus/cyclophosphamide regimens were monitored through viral replication in systemic organs, survival, and cardiac damage. Results: Repeated i.v. injection of reovirus was poorly effective at seeding intratumoral viral replication/oncolysis. However, by combining i.v. virus with cyclophosphamide, viral titers of between 107 and 108 plaque-forming units per milligram were recovered from regressing tumors. Doses of cyclophosphamide that ablated NAb were associated with severe toxicities, characterized by viral replication in systemic organs—toxicities that are mirrored by repeated reovirus injections into B-cell knockout mice. Next, we restructured the dosing of cyclophosphamide and i.v. virus such that a dose of 3 mg cyclophosphamide was administered 24 h before reovirus injection, and this schedule was repeated every 6 days. Using this protocol, high levels of intratumoral viral access and replication (∼107 plaque-forming units per milligram tumor) were maintained along with systemically protective levels of NAb and only very mild, non–life-threatening toxicity. Conclusion: NAb to oncolytic viruses play a dual role in the context of systemic viral delivery; on one hand, they hinder repeated administration of virus but on the other, they provide an important safety mechanism by which virus released from vigorous intratumoral replication is neutralized before it can disseminate and cause toxicity. These data support the use of cyclophosphamide to modulate, but not ablate, patient NAb, in development of carefully controlled clinical trials of the systemic administration of oncolytic viruses.

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Morbidity in immunosuppressed (SCID/NOD) mice treated with reovirus (Dearing 3) as an anti-cancer biotherapeutic

Cited by 33 publications

References 43 publications

Immunosuppression promotes reovirus therapy of colorectal liver metastases

Immunosuppression promotes reovirus therapy of colorectal liver metastases

Acquired resistance to reoviral oncolysis in Ras-transformed fibrosarcoma cells

Cyclophosphamide Facilitates Antitumor Efficacy against Subcutaneous Tumors following Intravenous Delivery of Reovirus

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