Journal Articles

Oncolytic viruses

Therapies based on tumor-targeting cytolytic viruses, including oncolytic viruses armed with immunomodulatory transgenes

Fusogenic Viruses in Oncolytic Immunotherapy

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Oncolytic viruses are under intense development and have earned their place among the novel class of cancer immunotherapeutics that are changing the face of cancer therapy. Their ability to specifically infect and efficiently kill tumor cells, while breaking immune tolerance and mediating immune responses directed against the tumor, make oncolytic viruses highly attractive candidates for immunotherapy. Increasing evidence indicates that a subclass of oncolytic viruses, which encodes for fusion proteins, could outperform non-fusogenic viruses, both in their direct oncolytic potential, as well as their immune-stimulatory properties. Tumor cell infection with these viruses leads to characteristic syncytia formation and cell death due to fusion, as infected cells become fused with neighboring cells, which promotes intratumoral spread of the infection and releases additional immunogenic signals. In this review, we discuss the potential of fusogenic oncolytic viruses as optimal candidates to enhance immunotherapy and initiate broad antitumor responses. We provide an overview of the cytopathic mechanism of syncytia formation through viral-mediated expression of fusion proteins, either endogenous or engineered, and their benefits for cancer therapy. Growing evidence indicates that fusogenicity could be an important feature to consider in the design of optimal oncolytic virus platforms for combinatorial oncolytic immunotherapy.

Author Info: (1) 2nd Department of Internal Medicine, Klinikum rechts der Isar, Technical University of Munich, 81675 Munchen, Germany. teresa.krabbe@tum.de. (2) 2nd Department of Internal Medicine, Klinikum

Author Info: (1) 2nd Department of Internal Medicine, Klinikum rechts der Isar, Technical University of Munich, 81675 Munchen, Germany. teresa.krabbe@tum.de. (2) 2nd Department of Internal Medicine, Klinikum rechts der Isar, Technical University of Munich, 81675 Munchen, Germany. jennifer.altomonte@tum.de.

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Recurrent Glioblastoma Treated with Recombinant Poliovirus

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Background The prognosis of patients with recurrent World Health Organization (WHO) grade IV malignant glioma is dismal, and there is currently no effective therapy. We conducted a dose-finding and toxicity study in this population of patients, evaluating convection-enhanced, intratumoral delivery of the recombinant nonpathogenic polio-rhinovirus chimera (PVSRIPO). PVSRIPO recognizes the poliovirus receptor CD155, which is widely expressed in neoplastic cells of solid tumors and in major components of the tumor microenvironment. Methods We enrolled consecutive adult patients who had recurrent supratentorial WHO grade IV malignant glioma, confirmed on histopathological testing, with measurable disease (contrast-enhancing tumor of >/=1 cm and

Author Info: (1) From the Departments of Neurosurgery (A.D., M.G., A.H.F., H.S.F., K.B.P., D.R., J.H.S., G.V., D.A., D.D.B.), Biostatistics (J.E.H., F.M.), Surgery (D.P.B., S.N.), and Pathology (W.T.H.

Author Info: (1) From the Departments of Neurosurgery (A.D., M.G., A.H.F., H.S.F., K.B.P., D.R., J.H.S., G.V., D.A., D.D.B.), Biostatistics (J.E.H., F.M.), Surgery (D.P.B., S.N.), and Pathology (W.T.H., R.E.M.) and the Preston Robert Tisch Brain Tumor Center (A.D., M.G., J.E.H., D.P.B., A.H.F., H.S.F., F.M., S.N., K.B.P., D.R., J.H.S., G.V., W.T.H., R.E.M., D.A., D.D.B.), Duke University Medical Center, and Istari Oncology (D.P.B.) - all in Durham, NC; Tempus Labs, Chicago (N.B.); and the School of Medicine, Deakin University, Geelong, VIC, Australia (A.M.M.). (2) From the Departments of Neurosurgery (A.D., M.G., A.H.F., H.S.F., K.B.P., D.R., J.H.S., G.V., D.A., D.D.B.), Biostatistics (J.E.H., F.M.), Surgery (D.P.B., S.N.), and Pathology (W.T.H., R.E.M.) and the Preston Robert Tisch Brain Tumor Center (A.D., M.G., J.E.H., D.P.B., A.H.F., H.S.F., F.M., S.N., K.B.P., D.R., J.H.S., G.V., W.T.H., R.E.M., D.A., D.D.B.), Duke University Medical Center, and Istari Oncology (D.P.B.) - all in Durham, NC; Tempus Labs, Chicago (N.B.); and the School of Medicine, Deakin University, Geelong, VIC, Australia (A.M.M.). (3) From the Departments of Neurosurgery (A.D., M.G., A.H.F., H.S.F., K.B.P., D.R., J.H.S., G.V., D.A., D.D.B.), Biostatistics (J.E.H., F.M.), Surgery (D.P.B., S.N.), and Pathology (W.T.H., R.E.M.) and the Preston Robert Tisch Brain Tumor Center (A.D., M.G., J.E.H., D.P.B., A.H.F., H.S.F., F.M., S.N., K.B.P., D.R., J.H.S., G.V., W.T.H., R.E.M., D.A., D.D.B.), Duke University Medical Center, and Istari Oncology (D.P.B.) - all in Durham, NC; Tempus Labs, Chicago (N.B.); and the School of Medicine, Deakin University, Geelong, VIC, Australia (A.M.M.). (4) From the Departments of Neurosurgery (A.D., M.G., A.H.F., H.S.F., K.B.P., D.R., J.H.S., G.V., D.A., D.D.B.), Biostatistics (J.E.H., F.M.), Surgery (D.P.B., S.N.), and Pathology (W.T.H., R.E.M.) and the Preston Robert Tisch Brain Tumor Center (A.D., M.G., J.E.H., D.P.B., A.H.F., H.S.F., F.M., S.N., K.B.P., D.R., J.H.S., G.V., W.T.H., R.E.M., D.A., D.D.B.), Duke University Medical Center, and Istari Oncology (D.P.B.) - all in Durham, NC; Tempus Labs, Chicago (N.B.); and the School of Medicine, Deakin University, Geelong, VIC, Australia (A.M.M.). (5) From the Departments of Neurosurgery (A.D., M.G., A.H.F., H.S.F., K.B.P., D.R., J.H.S., G.V., D.A., D.D.B.), Biostatistics (J.E.H., F.M.), Surgery (D.P.B., S.N.), and Pathology (W.T.H., R.E.M.) and the Preston Robert Tisch Brain Tumor Center (A.D., M.G., J.E.H., D.P.B., A.H.F., H.S.F., F.M., S.N., K.B.P., D.R., J.H.S., G.V., W.T.H., R.E.M., D.A., D.D.B.), Duke University Medical Center, and Istari Oncology (D.P.B.) - all in Durham, NC; Tempus Labs, Chicago (N.B.); and the School of Medicine, Deakin University, Geelong, VIC, Australia (A.M.M.). (6) From the Departments of Neurosurgery (A.D., M.G., A.H.F., H.S.F., K.B.P., D.R., J.H.S., G.V., D.A., D.D.B.), Biostatistics (J.E.H., F.M.), Surgery (D.P.B., S.N.), and Pathology (W.T.H., R.E.M.) and the Preston Robert Tisch Brain Tumor Center (A.D., M.G., J.E.H., D.P.B., A.H.F., H.S.F., F.M., S.N., K.B.P., D.R., J.H.S., G.V., W.T.H., R.E.M., D.A., D.D.B.), Duke University Medical Center, and Istari Oncology (D.P.B.) - all in Durham, NC; Tempus Labs, Chicago (N.B.); and the School of Medicine, Deakin University, Geelong, VIC, Australia (A.M.M.). (7) From the Departments of Neurosurgery (A.D., M.G., A.H.F., H.S.F., K.B.P., D.R., J.H.S., G.V., D.A., D.D.B.), Biostatistics (J.E.H., F.M.), Surgery (D.P.B., S.N.), and Pathology (W.T.H., R.E.M.) and the Preston Robert Tisch Brain Tumor Center (A.D., M.G., J.E.H., D.P.B., A.H.F., H.S.F., F.M., S.N., K.B.P., D.R., J.H.S., G.V., W.T.H., R.E.M., D.A., D.D.B.), Duke University Medical Center, and Istari Oncology (D.P.B.) - all in Durham, NC; Tempus Labs, Chicago (N.B.); and the School of Medicine, Deakin University, Geelong, VIC, Australia (A.M.M.). (8) From the Departments of Neurosurgery (A.D., M.G., A.H.F., H.S.F., K.B.P., D.R., J.H.S., G.V., D.A., D.D.B.), Biostatistics (J.E.H., F.M.), Surgery (D.P.B., S.N.), and Pathology (W.T.H., R.E.M.) and the Preston Robert Tisch Brain Tumor Center (A.D., M.G., J.E.H., D.P.B., A.H.F., H.S.F., F.M., S.N., K.B.P., D.R., J.H.S., G.V., W.T.H., R.E.M., D.A., D.D.B.), Duke University Medical Center, and Istari Oncology (D.P.B.) - all in Durham, NC; Tempus Labs, Chicago (N.B.); and the School of Medicine, Deakin University, Geelong, VIC, Australia (A.M.M.). (9) From the Departments of Neurosurgery (A.D., M.G., A.H.F., H.S.F., K.B.P., D.R., J.H.S., G.V., D.A., D.D.B.), Biostatistics (J.E.H., F.M.), Surgery (D.P.B., S.N.), and Pathology (W.T.H., R.E.M.) and the Preston Robert Tisch Brain Tumor Center (A.D., M.G., J.E.H., D.P.B., A.H.F., H.S.F., F.M., S.N., K.B.P., D.R., J.H.S., G.V., W.T.H., R.E.M., D.A., D.D.B.), Duke University Medical Center, and Istari Oncology (D.P.B.) - all in Durham, NC; Tempus Labs, Chicago (N.B.); and the School of Medicine, Deakin University, Geelong, VIC, Australia (A.M.M.). (10) From the Departments of Neurosurgery (A.D., M.G., A.H.F., H.S.F., K.B.P., D.R., J.H.S., G.V., D.A., D.D.B.), Biostatistics (J.E.H., F.M.), Surgery (D.P.B., S.N.), and Pathology (W.T.H., R.E.M.) and the Preston Robert Tisch Brain Tumor Center (A.D., M.G., J.E.H., D.P.B., A.H.F., H.S.F., F.M., S.N., K.B.P., D.R., J.H.S., G.V., W.T.H., R.E.M., D.A., D.D.B.), Duke University Medical Center, and Istari Oncology (D.P.B.) - all in Durham, NC; Tempus Labs, Chicago (N.B.); and the School of Medicine, Deakin University, Geelong, VIC, Australia (A.M.M.). (11) From the Departments of Neurosurgery (A.D., M.G., A.H.F., H.S.F., K.B.P., D.R., J.H.S., G.V., D.A., D.D.B.), Biostatistics (J.E.H., F.M.), Surgery (D.P.B., S.N.), and Pathology (W.T.H., R.E.M.) and the Preston Robert Tisch Brain Tumor Center (A.D., M.G., J.E.H., D.P.B., A.H.F., H.S.F., F.M., S.N., K.B.P., D.R., J.H.S., G.V., W.T.H., R.E.M., D.A., D.D.B.), Duke University Medical Center, and Istari Oncology (D.P.B.) - all in Durham, NC; Tempus Labs, Chicago (N.B.); and the School of Medicine, Deakin University, Geelong, VIC, Australia (A.M.M.). (12) From the Departments of Neurosurgery (A.D., M.G., A.H.F., H.S.F., K.B.P., D.R., J.H.S., G.V., D.A., D.D.B.), Biostatistics (J.E.H., F.M.), Surgery (D.P.B., S.N.), and Pathology (W.T.H., R.E.M.) and the Preston Robert Tisch Brain Tumor Center (A.D., M.G., J.E.H., D.P.B., A.H.F., H.S.F., F.M., S.N., K.B.P., D.R., J.H.S., G.V., W.T.H., R.E.M., D.A., D.D.B.), Duke University Medical Center, and Istari Oncology (D.P.B.) - all in Durham, NC; Tempus Labs, Chicago (N.B.); and the School of Medicine, Deakin University, Geelong, VIC, Australia (A.M.M.). (13) From the Departments of Neurosurgery (A.D., M.G., A.H.F., H.S.F., K.B.P., D.R., J.H.S., G.V., D.A., D.D.B.), Biostatistics (J.E.H., F.M.), Surgery (D.P.B., S.N.), and Pathology (W.T.H., R.E.M.) and the Preston Robert Tisch Brain Tumor Center (A.D., M.G., J.E.H., D.P.B., A.H.F., H.S.F., F.M., S.N., K.B.P., D.R., J.H.S., G.V., W.T.H., R.E.M., D.A., D.D.B.), Duke University Medical Center, and Istari Oncology (D.P.B.) - all in Durham, NC; Tempus Labs, Chicago (N.B.); and the School of Medicine, Deakin University, Geelong, VIC, Australia (A.M.M.). (14) From the Departments of Neurosurgery (A.D., M.G., A.H.F., H.S.F., K.B.P., D.R., J.H.S., G.V., D.A., D.D.B.), Biostatistics (J.E.H., F.M.), Surgery (D.P.B., S.N.), and Pathology (W.T.H., R.E.M.) and the Preston Robert Tisch Brain Tumor Center (A.D., M.G., J.E.H., D.P.B., A.H.F., H.S.F., F.M., S.N., K.B.P., D.R., J.H.S., G.V., W.T.H., R.E.M., D.A., D.D.B.), Duke University Medical Center, and Istari Oncology (D.P.B.) - all in Durham, NC; Tempus Labs, Chicago (N.B.); and the School of Medicine, Deakin University, Geelong, VIC, Australia (A.M.M.). (15) From the Departments of Neurosurgery (A.D., M.G., A.H.F., H.S.F., K.B.P., D.R., J.H.S., G.V., D.A., D.D.B.), Biostatistics (J.E.H., F.M.), Surgery (D.P.B., S.N.), and Pathology (W.T.H., R.E.M.) and the Preston Robert Tisch Brain Tumor Center (A.D., M.G., J.E.H., D.P.B., A.H.F., H.S.F., F.M., S.N., K.B.P., D.R., J.H.S., G.V., W.T.H., R.E.M., D.A., D.D.B.), Duke University Medical Center, and Istari Oncology (D.P.B.) - all in Durham, NC; Tempus Labs, Chicago (N.B.); and the School of Medicine, Deakin University, Geelong, VIC, Australia (A.M.M.). (16) From the Departments of Neurosurgery (A.D., M.G., A.H.F., H.S.F., K.B.P., D.R., J.H.S., G.V., D.A., D.D.B.), Biostatistics (J.E.H., F.M.), Surgery (D.P.B., S.N.), and Pathology (W.T.H., R.E.M.) and the Preston Robert Tisch Brain Tumor Center (A.D., M.G., J.E.H., D.P.B., A.H.F., H.S.F., F.M., S.N., K.B.P., D.R., J.H.S., G.V., W.T.H., R.E.M., D.A., D.D.B.), Duke University Medical Center, and Istari Oncology (D.P.B.) - all in Durham, NC; Tempus Labs, Chicago (N.B.); and the School of Medicine, Deakin University, Geelong, VIC, Australia (A.M.M.). (17) From the Departments of Neurosurgery (A.D., M.G., A.H.F., H.S.F., K.B.P., D.R., J.H.S., G.V., D.A., D.D.B.), Biostatistics (J.E.H., F.M.), Surgery (D.P.B., S.N.), and Pathology (W.T.H., R.E.M.) and the Preston Robert Tisch Brain Tumor Center (A.D., M.G., J.E.H., D.P.B., A.H.F., H.S.F., F.M., S.N., K.B.P., D.R., J.H.S., G.V., W.T.H., R.E.M., D.A., D.D.B.), Duke University Medical Center, and Istari Oncology (D.P.B.) - all in Durham, NC; Tempus Labs, Chicago (N.B.); and the School of Medicine, Deakin University, Geelong, VIC, Australia (A.M.M.). (18) From the Departments of Neurosurgery (A.D., M.G., A.H.F., H.S.F., K.B.P., D.R., J.H.S., G.V., D.A., D.D.B.), Biostatistics (J.E.H., F.M.), Surgery (D.P.B., S.N.), and Pathology (W.T.H., R.E.M.) and the Preston Robert Tisch Brain Tumor Center (A.D., M.G., J.E.H., D.P.B., A.H.F., H.S.F., F.M., S.N., K.B.P., D.R., J.H.S., G.V., W.T.H., R.E.M., D.A., D.D.B.), Duke University Medical Center, and Istari Oncology (D.P.B.) - all in Durham, NC; Tempus Labs, Chicago (N.B.); and the School of Medicine, Deakin University, Geelong, VIC, Australia (A.M.M.).

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Current understanding of reovirus oncolysis mechanisms

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Mammalian orthoreovirus (reovirus) is under development as a cancer virotherapy. Clinical trials demonstrate that reovirus-based therapies are safe and tolerated in patients with a wide variety of cancers. Although reovirus monotherapy has proven largely ineffective, reovirus sensitizes cancer cells to existing chemotherapeutic agents and radiation. Clinical trials are underway to test the efficacy of reovirus in combination with chemotherapeutic and radiation regimens and to evaluate the effectiveness of reovirus in conjunction with immunotherapies. Central to the use of reovirus to treat cancer is its capacity to directly kill cancer cells and alter the cellular environment to augment other therapies. Apoptotic cell death is a prominent mechanism of reovirus cancer cell killing. However, reoviruses can also kill cancer cells through nonapoptotic mechanisms. Here, we describe mechanisms of reovirus cancer cell killing, highlight how reovirus is used in combination with existing cancer treatments, and discuss what is known as to how reovirus modulates cancer immunotherapy.

Author Info: (1) Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Atlanta, GA, USA. (2) Department of Microbiology and Immunology, University of Arkansas for

Author Info: (1) Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Atlanta, GA, USA. (2) Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Atlanta, GA, USA. (3) Department of Pediatrics, Emory University, Atlanta, GA, USA. (4) Department of Pediatrics, Emory University, Atlanta, GA, USA. (5) Department of Pediatrics, Emory University, Atlanta, GA, USA. (6) Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Atlanta, GA, USA.

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Oncolytic Reovirus and Immune Checkpoint Inhibition as a Novel Immunotherapeutic Strategy for Breast Cancer

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As the current efficacy of oncolytic viruses (OVs) as monotherapy is limited, exploration of OVs as part of a broader immunotherapeutic treatment strategy for cancer is necessary. Here, we investigated the ability for immune checkpoint blockade to enhance the efficacy of oncolytic reovirus (RV) for the treatment of breast cancer (BrCa). In vitro, oncolysis and cytokine production were assessed in human and murine BrCa cell lines following RV exposure. Furthermore, RV-induced upregulation of tumor cell PD-L1 was evaluated. In vivo, the immunocompetent, syngeneic EMT6 murine model of BrCa was employed to determine therapeutic and tumor-specific immune responses following treatment with RV, anti-PD-1 antibodies or in combination. RV-mediated oncolysis and cytokine production were observed following BrCa cell infection and RV upregulated tumor cell expression of PD-L1. In vivo, RV monotherapy significantly reduced disease burden and enhanced survival in treated mice, and was further enhanced by PD-1 blockade. RV therapy increased the number of intratumoral regulatory T cells, which was reversed by the addition of PD-1 blockade. Finally, dual treatment led to the generation of a systemic adaptive anti-tumor immune response evidenced by an increase in tumor-specific IFN-γ producing CD8(+) T cells, and immunity from tumor re-challenge. The combination of PD-1 blockade and RV appears to be an efficacious immunotherapeutic strategy for the treatment of BrCa, and warrants further investigation in early-phase clinical trials.

Author Info: (1) Department of Pathology and Laboratory Medicine, University of Calgary, 2500 University Drive NW, Calgary, AB T2N 1N4, Canada. ahmed.mostafa@cls.ab.ca. Histocompatibility and Immunogenetics, Calgary Lab

Author Info: (1) Department of Pathology and Laboratory Medicine, University of Calgary, 2500 University Drive NW, Calgary, AB T2N 1N4, Canada. ahmed.mostafa@cls.ab.ca. Histocompatibility and Immunogenetics, Calgary Lab Services, 3535 Research Road NW, Calgary, AB T2L 2K8, Canada. ahmed.mostafa@cls.ab.ca. (2) Department of Oncology, University of Calgary, 1331 29 Street NW, Calgary, AB T2N 4N2, Canada. daniel.meyers@ucalgary.ca. Tom Baker Cancer Centre, 1331 29 Street NW, Calgary, AB T2N 4N2, Canada. daniel.meyers@ucalgary.ca. (3) Department of Oncology, University of Calgary, 1331 29 Street NW, Calgary, AB T2N 4N2, Canada. cmthiruk@ucalgary.ca. Tom Baker Cancer Centre, 1331 29 Street NW, Calgary, AB T2N 4N2, Canada. cmthiruk@ucalgary.ca. (4) Faculty of Medicine, University of Toronto, King's College Circle, Toronto, ON M5S 1A8, Canada. peterjr.liu@mail.utoronto.ca. (5) Department of Oncology, University of Calgary, 1331 29 Street NW, Calgary, AB T2N 4N2, Canada. kgratton@ucalgary.ca. (6) Department of Oncology, University of Calgary, 1331 29 Street NW, Calgary, AB T2N 4N2, Canada. scienceofkungfu@gmail.com. Tom Baker Cancer Centre, 1331 29 Street NW, Calgary, AB T2N 4N2, Canada. scienceofkungfu@gmail.com. (7) Tom Baker Cancer Centre, 1331 29 Street NW, Calgary, AB T2N 4N2, Canada. qiao.shi@albertahealthservices.ca. (8) Department of Oncology, University of Calgary, 1331 29 Street NW, Calgary, AB T2N 4N2, Canada. sthakur@ucalgary.ca. Tom Baker Cancer Centre, 1331 29 Street NW, Calgary, AB T2N 4N2, Canada. sthakur@ucalgary.ca. (9) Department of Oncology, University of Calgary, 1331 29 Street NW, Calgary, AB T2N 4N2, Canada. don.morris@albertahealthservices.ca. Tom Baker Cancer Centre, 1331 29 Street NW, Calgary, AB T2N 4N2, Canada. don.morris@albertahealthservices.ca.

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The oncolytic Adenovirus XVir-N-31 as a novel therapy in muscle-invasive bladder cancer

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Muscle-invasive bladder cancer represents approximately 25% of patients diagnosed with bladder cancer and carries a significant risk of death. Oncolytic viruses (OV) are novel antitumor agents with the ability to selectively replicate and lyse tumor cells while sparing healthy tissue. Thus, we explored the efficiency of the oncolytic, YB-1 selective adenovirus XVir-N-31 in vitro and in an orthotopic mouse model for bladder cancer by intramural injection under ultrasound guidance. We demonstrated that XVir-N-31 replicates in bladder cancer cells and induced a stronger immunogenic cell death than adenovirus wildtype by facilitating enhanced release of HMGB1 and exosomal Hsp70. The intratumoral delivery of XVir-N-31 by ultrasound guidance delayed tumor growth in an immunodeficient model, demonstrating the feasibility of this approach to deliver oncolytic viruses directly into the tumor.

Author Info: (1) Klinikum rechts der Isar der Technischen Universitat Munchen, 27190, Munich, Bayern, Germany ; eva.lichtenegger@tum.de. (2) Klinikum rechts der Isar der Technischen Universitat Munchen, 27190

Author Info: (1) Klinikum rechts der Isar der Technischen Universitat Munchen, 27190, Munich, Bayern, Germany ; eva.lichtenegger@tum.de. (2) Klinikum rechts der Isar der Technischen Universitat Munchen, 27190, Munich, Bayern, Germany ; florestan.koll@tum.de. (3) Klinikum rechts der Isar der Technischen Universitat Munchen, 27190, Munich, Bayern, Germany ; helena.haas@tum.de. (4) Klinikum rechts der Isar der Technischen Universitat Munchen, 27190, Department of Urology, Munich, Bayern, Germany ; klaus.mantwill@tum.de. (5) Klinikum rechts der Isar der Technischen Universitat Munchen, 27190, Munich, Bayern, Germany ; klaus-peter.janssen@tum.de. (6) Klinikum rechts der Isar der Technischen Universitat Munchen, 27190, Munich, Bayern, Germany ; melanie.laschinger@tum.de. (7) Klinikum rechts der Isar der Technischen Universitat Munchen, 27190, Munich, Bayern, Germany ; juergen.gschwend@tum.de. (8) Klinikum rechts der Isar der Technischen Universitat Munchen, 27190, Munich, Bayern, Germany ; katja.steiger@tum.de. (9) University of British Columbia , Department of Urologic Sciences, Vancouver, British Columbia, Canada ; pblack@mail.ubc.ca. (10) Munich, Germany. Vancouver, Canada. Vancouver Prostate Centre, 483154, Vancouver, British Columbia, Canada ; imoskalev@prostatecentre.com. (11) Klinikum rechts der Isar der Technischen Universitat Munchen, 27190, Munich, Bayern, Germany ; roman.nawroth@tum.de. (12) Klinikum rechts der Isar der Technischen Universitat Munchen, 27190, Munich, Bayern, Germany. XVir Therapeutics GmbH, Munich, Germany ; per.holm@tum.de.

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An oncolytic measles virus-sensitive Group 3 medulloblastoma model in immune-competent mice

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Background: Oncolytic measles virus (MV) is effective in xenograft models of many tumor types in immune-compromised mice. However, no murine cell line exists that is tumorigenic, grows in immune-competent mice, and is killed by MV. The lack of such a model prevents an examination of the effect of the immune system on MV oncotherapy. Methods: Cerebellar stem cells from human CD46-transgenic immunocompetent mice were transduced to express Sendai virus C-protein, murine C-Myc, and Gfi1b proteins. The resultant cells were injected into the brain of NSG mice, and a cell line, called CSCG, was prepared from the resulting tumor. Results: CSCG cells are highly proliferative, and express stem cell markers. These cells are permissive for replication of MV and are killed by the virus in a dose- and time-dependent manner. CSCG cells form aggressive tumors that morphologically resemble medulloblastoma when injected into the brains of immune-competent mice. On the molecular level, CSCG tumors overexpress natriuretic peptide receptor 3 and gamma-aminobutyric acid type A receptor alpha 5, markers of Group 3 medulloblastoma. A single intratumoral injection of MVgreen fluorescent protein resulted in complete tumor regression and prolonged survival of animals compared with treatments with phosphate buffered saline (P = 0.0018) or heat-inactivated MV (P = 0.0027). Conclusions: This immune-competent model provides the first platform to test therapeutic regimens of oncolytic MV for Group 3 medulloblastoma in the presence of anti-measles immunity. The strategy presented here can be used to make MV-sensitive murine models of any human tumor for which the driving mutations are known.

Author Info: (1) Department of Neurological Surgery, Brain Tumor Research Center, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco (UCSF), San Francisco, California. (2)

Author Info: (1) Department of Neurological Surgery, Brain Tumor Research Center, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco (UCSF), San Francisco, California. (2) Department of Neurological Surgery, Brain Tumor Research Center, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco (UCSF), San Francisco, California. (3) Department of Neurological Surgery, Brain Tumor Research Center, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco (UCSF), San Francisco, California. (4) Department of Neurology, Pediatrics, and Neurological Surgery and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California. (5) Department of Neurological Surgery, Brain Tumor Research Center, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco (UCSF), San Francisco, California.

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Designer Oncolytic Adenovirus: Coming of Age

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The licensing of talimogene laherparepvec (T-Vec) represented a landmark moment for oncolytic virotherapy, since it provided unequivocal evidence for the long-touted potential of genetically modified replicating viruses as anti-cancer agents. Whilst T-Vec is promising as a locally delivered virotherapy, especially in combination with immune-checkpoint inhibitors, the quest continues for a virus capable of specific tumour cell killing via systemic administration. One candidate is oncolytic adenovirus (Ad); it’s double stranded DNA genome is easily manipulated and a wide range of strategies and technologies have been employed to empower the vector with improved pharmacokinetics and tumour targeting ability. As well characterised clinical and experimental agents, we have detailed knowledge of adenoviruses’ mechanisms of pathogenicity, supported by detailed virological studies and in vivo interactions. In this review we highlight the strides made in the engineering of bespoke adenoviral vectors to specifically infect, replicate within, and destroy tumour cells. We discuss how mutations in genes regulating adenoviral replication after cell entry can be used to restrict replication to the tumour, and summarise how detailed knowledge of viral capsid interactions enable rational modification to eliminate native tropisms, and simultaneously promote active uptake by cancerous tissues. We argue that these designer-viruses, exploiting the viruses natural mechanisms and regulated at every level of replication, represent the ideal platforms for local overexpression of therapeutic transgenes such as immunomodulatory agents. Where T-Vec has paved the way, Ad-based vectors now follow. The era of designer oncolytic virotherapies looks decidedly as though it will soon become a reality.

Author Info: (1) Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff CF14 4XN, UK. BakerAT@Cardiff.ac.uk. (2) Centre for Molecular Oncology, Barts Cancer Institute, Queen

Author Info: (1) Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff CF14 4XN, UK. BakerAT@Cardiff.ac.uk. (2) Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK. etheluin@gmail.com. (3) Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK. g.hallden@qmul.ac.uk. (4) Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff CF14 4XN, UK. ParkerAL@cardiff.ac.uk.

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Oncolytic Viruses for Multiple Myeloma Therapy

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Although recent treatment advances have improved outcomes for patients with multiple myeloma (MM), the disease frequently becomes refractory to current therapies. MM thus remains incurable for most patients and new therapies are urgently needed. Oncolytic viruses are a promising new class of therapeutics that provide tumor-targeted therapy by specifically infecting and replicating within cancerous cells. Oncolytic therapy yields results from both direct killing of malignant cells and induction of an anti-tumor immune response. In this review, we will describe oncolytic viruses that are being tested for MM therapy with a focus on those agents that have advanced into clinical trials.

Author Info: (1) Division of Translational and Regenerative Medicine, Department of Medicine and The University of Arizona Cancer Center, Tucson, AZ 85724, USA. calton@email.arizona.edu. (2) Jane Anne

Author Info: (1) Division of Translational and Regenerative Medicine, Department of Medicine and The University of Arizona Cancer Center, Tucson, AZ 85724, USA. calton@email.arizona.edu. (2) Jane Anne Nohl Division of Hematology and Center for the Study of Blood Diseases, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA 90033, USA. kevin.kelly@med.usc.edu. (3) Division of Hematology and Oncology, University of Arizona Cancer Center, Tucson, AZ 85724, USA. anwerf@email.arizona.edu. (4) Division of Translational and Regenerative Medicine, Department of Medicine and The University of Arizona Cancer Center, Tucson, AZ 85724, USA. jcarew@email.arizona.edu. (5) Division of Translational and Regenerative Medicine, Department of Medicine and The University of Arizona Cancer Center, Tucson, AZ 85724, USA. snawrocki@email.arizona.edu.

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Transforming the prostatic tumor microenvironment with oncolytic virotherapy

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Prostate cancer (PCa) was estimated to have the second highest global incidence rate for male non-skin tumors and is the fifth most deadly in men thus mandating the need for novel treatment options. MG1-Maraba is a potent and versatile oncolytic virus capable of lethally infecting a variety of prostatic tumor cell lines alongside primary PCa biopsies and exerts direct oncolytic effects against large TRAMP-C2 tumors in vivo. An oncolytic immunotherapeutic strategy utilizing a priming vaccine and intravenously administered MG1-Maraba both expressing the human six-transmembrane antigen of the prostate (STEAP) protein generated specific CD8+ T-cell responses against multiple STEAP epitopes and resulted in functional breach of tolerance. Treatment of mice with bulky TRAMP-C2 tumors using oncolytic STEAP immunotherapy induced an overt delay in tumor progression, marked intratumoral lymphocytic infiltration with an active transcriptional profile and up-regulation of MHC class I. The preclinical data generated here offers clear rationale for clinically evaluating this approach for men with advanced PCa.

Author Info: (1) McMaster Immunology Research Centre, Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Canada. (2) Turnstone Biologics, Ottawa, Canada. (3) Centre for Cancer Therapeutics

Author Info: (1) McMaster Immunology Research Centre, Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Canada. (2) Turnstone Biologics, Ottawa, Canada. (3) Centre for Cancer Therapeutics, The Ottawa Hospital Research Institute, Ottawa, Canada. (4) McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Canada. Department of Biochemistry and Biomedical Sciences, Faculty of Health Sciences, McMaster University, Hamilton, Canada. (5) Turnstone Biologics, Ottawa, Canada. (6) Centre for Cancer Therapeutics, The Ottawa Hospital Research Institute, Ottawa, Canada. Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Canada. (7) Centre for Cancer Therapeutics, The Ottawa Hospital Research Institute, Ottawa, Canada. Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Canada. (8) Stojdl Lab, CHEO Research Institute, Children's Hospital of Eastern Ontario, Ottawa, Canada. (9) McMaster Immunology Research Centre, Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Canada. (10) McMaster Immunology Research Centre, Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Canada. (11) McMaster Immunology Research Centre, Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Canada. (12) Turnstone Biologics, Ottawa, Canada. Stojdl Lab, CHEO Research Institute, Children's Hospital of Eastern Ontario, Ottawa, Canada. (13) Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, Canada. (14) Department of Surgery, The Ottawa Hospital, Ottawa, Canada. (15) Turnstone Biologics, Ottawa, Canada. Centre for Cancer Therapeutics, The Ottawa Hospital Research Institute, Ottawa, Canada. (16) Department of Surgery, Centre Hospitalier de l'Universite de Montreal (CHUM), Montreal, Canada. (17) McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Canada. Department of Biochemistry and Biomedical Sciences, Faculty of Health Sciences, McMaster University, Hamilton, Canada. Department of Surgery, Faculty of Health Sciences, McMaster University, Hamilton, Canada. Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Canada. (18) Centre for Cancer Therapeutics, The Ottawa Hospital Research Institute, Ottawa, Canada. Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Canada. (19) McMaster Immunology Research Centre, Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Canada. Turnstone Biologics, Ottawa, Canada.

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Oncolytic Virotherapy by HSV

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Oncolytic virotherapy is a kind of antitumor therapy using viruses with natural or engineered tumor-selective replication to intentionally infect and kill tumor cells. An early clinical trial has been performed in the 1950s using wild-type and non-engineered in vitro-passaged virus strains and vaccine strains (first generation oncolytic viruses). Because of the advances in biotechnology and virology, the field of virotherapy has rapidly evolved over the past two decades and innovative recombinant selectivity-enhanced viruses (second generation oncolytic viruses). Nowadays, therapeutic transgene-delivering "armed" oncolytic viruses (third generation oncolytic viruses) have been engineered using many kinds of viruses. In this chapter, the history, mechanisms, rationality, and advantages of oncolytic virotherapy by herpes simplex virus (HSV) are mentioned. Past and ongoing clinical trials by oncolytic HSVs (G207, HSV1716, NV1020, HF10, Talimogene laherparepvec (T-VEC, OncoVEX(GM-CSF))) are also summarized. Finally, the way of enhancement of oncolytic virotherapy by gene modification or combination therapy with radiation, chemotherapy, or immune checkpoint inhibitors are discussed.

Author Info: (1) Department of Dermatology, Aichi Medical University School of Medicine, Nagakute, Japan. dwatanab@aichi-med-u.ac.jp. (2) Department of Virology, Graduate School of Medicine, Nagoya University, Nagoya, Japan

Author Info: (1) Department of Dermatology, Aichi Medical University School of Medicine, Nagakute, Japan. dwatanab@aichi-med-u.ac.jp. (2) Department of Virology, Graduate School of Medicine, Nagoya University, Nagoya, Japan.

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