Journal Articles

Oncolytic viruses

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

TNFa and IL-2 armed adenoviruses enable complete responses by anti-PD-1 checkpoint blockade

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Releasing the patient's immune system against their own malignancy by the use of checkpoint inhibitors is delivering promising results. However, only a subset of patients currently benefit from them. One major limitation of these therapies relates to the inability of T cells to detect or penetrate into the tumor resulting in unresponsiveness to checkpoint inhibition. Virotherapy is an attractive tool for enabling checkpoint inhibitors as viruses are naturally recognized by innate defense elements which draws the attention of the immune system. Besides their intrinsic immune stimulating properties, the adenoviruses used here are armed to express tumor necrosis factor alpha (TNFa) and interleukin-2 (IL-2). These cytokines result in immunological danger signaling and multiple appealing T-cell effects, including trafficking, activation and propagation. When these viruses were injected into B16.OVA melanoma tumors in animals concomitantly receiving programmed cell-death protein 1 (PD-1) blocking antibodies both tumor growth control (p < 0.0001) and overall survival (p < 0.01) were improved. In this set-up, the addition of adoptive cell therapy with OT-I lymphocytes did not increase efficacy further. When virus injections were initiated before antibody treatment in a prime-boost approach, 100% of tumors regressed completely and all mice survived. Viral expression of IL2 and TNFa altered the cytokine balance in the tumor microenvironment towards Th1 and increased the intratumoral proportion of CD8+ and conventional CD4+ T cells. These preclinical studies provide the rationale and schedule for a clinical trial where oncolytic adenovirus coding for TNFa and IL-2 (TILT-123) is used in melanoma patients receiving an anti-PD-1 antibody.

Author Info: (1) TILT Biotherapeutics Ltd, Helsinki, Uusima, Finland. Department of Oncology, Cancer Gene Therapy Group, Faculty of Medicine, University of Helsinki, Helsinki, Uusima, Finland. (2) TILT

Author Info: (1) TILT Biotherapeutics Ltd, Helsinki, Uusima, Finland. Department of Oncology, Cancer Gene Therapy Group, Faculty of Medicine, University of Helsinki, Helsinki, Uusima, Finland. (2) TILT Biotherapeutics Ltd, Helsinki, Uusima, Finland. Department of Oncology, Cancer Gene Therapy Group, Faculty of Medicine, University of Helsinki, Helsinki, Uusima, Finland. (3) TILT Biotherapeutics Ltd, Helsinki, Uusima, Finland. Department of Oncology, Cancer Gene Therapy Group, Faculty of Medicine, University of Helsinki, Helsinki, Uusima, Finland. (4) TILT Biotherapeutics Ltd, Helsinki, Uusima, Finland. Department of Oncology, Cancer Gene Therapy Group, Faculty of Medicine, University of Helsinki, Helsinki, Uusima, Finland. (5) Department of Oncology, Cancer Gene Therapy Group, Faculty of Medicine, University of Helsinki, Helsinki, Uusima, Finland. (6) Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Uusima, Finland. (7) TILT Biotherapeutics Ltd, Helsinki, Uusima, Finland. Department of Oncology, Cancer Gene Therapy Group, Faculty of Medicine, University of Helsinki, Helsinki, Uusima, Finland. (8) Department of Oncology, Cancer Gene Therapy Group, Faculty of Medicine, University of Helsinki, Helsinki, Uusima, Finland. Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki, Uusima, Finland. (9) TILT Biotherapeutics Ltd, Helsinki, Uusima, Finland. Department of Oncology, Cancer Gene Therapy Group, Faculty of Medicine, University of Helsinki, Helsinki, Uusima, Finland. Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Uusima, Finland.

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Oncolytic influenza virus infection restores immunocompetence of lung tumor-associated alveolar macrophages

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Non-small-cell lung cancer (NSCLC) is the most frequent type of lung cancer and demonstrates high resistance to radiation and chemotherapy. These tumors evade immune system detection by promoting an immunosuppressive tumor microenvironment. Genetic analysis has revealed oncogenic activation of the Ras/Raf/MEK/ERK signaling pathway to be a hallmark of NSCLCs, which promotes influenza A virus (IAV) infection and replication in these cells. Thus, we aimed to unravel the oncolytic properties of IAV infection against NSCLCs in an immunocompetent model in vivo. Using Raf-BxB transgenic mice that spontaneously develop NSCLCs, we demonstrated that infection with low-pathogenic IAV leads to rapid and efficient oncolysis, eliminating 70% of the initial tumor mass. Interestingly, IAV infection of Raf-BxB mice caused a functional reversion of immunosuppressed tumor-associated lung macrophages into a M1-like pro-inflammatory active phenotype that additionally supported virus-induced oncolysis of cancer cells. Altogether, our data demonstrate for the first time in an immunocompetent in vivo model that oncolytic IAV infection is capable of restoring and redirecting immune cell functions within the tumor microenvironment of NSCLCs.

Author Info: (1) Institute of Virology (IMV), Westfaelische-Wilhelms University, Muenster, Germany. Cluster of Excellence "Cells in Motion", University of Muenster, Muenster, Germany. (2) Institute of Virology (IMV)

Author Info: (1) Institute of Virology (IMV), Westfaelische-Wilhelms University, Muenster, Germany. Cluster of Excellence "Cells in Motion", University of Muenster, Muenster, Germany. (2) Institute of Virology (IMV), Westfaelische-Wilhelms University, Muenster, Germany. Rentschler Biotechnologie GmbH, Laupheim, Germany. (3) Institute of Immunology, Westfaelische-Wilhelms University, Muenster, Germany. (4) Department of Pediatric, Rheumatology and Immunology, University Children s Hospital Muenster, Muenster, Germany. (5) Institute of Immunology, Westfaelische-Wilhelms University, Muenster, Germany. Cluster of Excellence "Cells in Motion", University of Muenster, Muenster, Germany. (6) Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada. (7) Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany. (8) Institute of Virology (IMV), Westfaelische-Wilhelms University, Muenster, Germany. Cluster of Excellence "Cells in Motion", University of Muenster, Muenster, Germany. (9) Institute of Virology (IMV), Westfaelische-Wilhelms University, Muenster, Germany. Cluster of Excellence "Cells in Motion", University of Muenster, Muenster, Germany.

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Combination of interferon-expressing oncolytic adenovirus with chemotherapy and radiation is highly synergistic in hamster model of pancreatic cancer

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Recent clinical trials utilizing Interferon-alpha (IFN) in combination with chemoradiation have demonstrated significant improvements in the survival of patients with pancreatic cancer. However, efficacy was limited by the systemic toxicity of IFN and low intratumoral levels of the cytokine. We sought to address these drawbacks by using an Oncolytic Adenovirus expressing IFN (OAd-hamIFN) in combination with chemotherapy and/or radiation in regimens mimicking the IFN-based therapies used in clinical trials. IFN expressed from OAd-hamIFN potentiated the cytotoxicity of radiation and chemotherapy (5-FU, Gemcitabine, and Cisplatin), and enhanced pancreatic cancer cell death in both in vitro and in vivo experimental settings. Notably, synergism was demonstrated in therapeutic groups that combined the interferon-expressing oncolytic virus with chemotherapy and radiation. In an in vivo immunocompetent hamster model, treatment regimens combining oncolytic virus therapy with 5-FU and radiation demonstrated significant tumor growth inhibition and enhanced survival. This is the first study to report synergism between an IFN-expressing oncolytic adenovirus and chemoradiation-based therapies. When combined with an IFN-expressing OAd, there is a significant enhancement of radiation and especially chemoradiation, which may broaden the application of this new therapeutic approach to the pancreatic cancer patients who cannot tolerate existing chemotherapy regimens.

Author Info: (1) Department of Surgery, University of Minnesota, Minneapolis, MN 55455, USA. (2) Department of Surgery, University of Minnesota, Minneapolis, MN 55455, USA. (3) Department of

Author Info: (1) Department of Surgery, University of Minnesota, Minneapolis, MN 55455, USA. (2) Department of Surgery, University of Minnesota, Minneapolis, MN 55455, USA. (3) Department of Surgery, University of Minnesota, Minneapolis, MN 55455, USA. (4) Biostatistics Core, Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA. (5) Department of Surgery, University of Minnesota, Minneapolis, MN 55455, USA. Institute of Molecular Virology, University of Minnesota, Minneapolis, MN 55455, USA. Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA. (6) Department of Surgery, University of Minnesota, Minneapolis, MN 55455, USA. Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.

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Zika virus selectively kills aggressive human embryonal CNS tumor cells in vitro and in vivo

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Zika virus (ZIKV) is largely known for causing brain abnormalities due to its ability to infect neural progenitor stem cells (NPC) during early development. Here we show that ZIKV is also capable of infecting and destroying stem-like cancer cells from aggressive human embryonal tumors of the central nervous system (CNS). When evaluating the oncolytic properties of Brazilian Zika virus strain (ZIKVBR) against human breast, prostate, colorectal, and embryonal CNS tumor cell lines, we verified a selective infection of CNS tumor cells followed by massive tumor cell death. ZIKVBR was more efficient in destroying embryonal CNS tumorspheres than normal stem cell neurospheres. A single intracerebroventricular injection of ZIKVBR in BALB/c nude mice bearing orthotopic human embryonal CNS tumor xenografts resulted in a significantly longer survival, decreased tumor burden, fewer metastasis, and complete remission in some animals. Tumor cells closely resembling neural stem cells at the molecular level with activated Wnt signaling were more susceptible to the oncolytic effects of ZIKVBR. Furthermore, modulation of Wnt signaling pathway significantly affected ZIKVBR-induced tumor cell death and viral shedding. Altogether, these preclinical findings indicate that ZIKVBR could be an efficient agent to treat aggressive forms of embryonal CNS tumors and provide mechanistic insights regarding its oncolytic effects.

Author Info: (1) Genetics and Evolutionary Biology, University of Sao Paulo. (2) Genetics and Evolutionary Biology, University of Sao Paulo. (3) Genetics and Evolutionary Biology, University of

Author Info: (1) Genetics and Evolutionary Biology, University of Sao Paulo. (2) Genetics and Evolutionary Biology, University of Sao Paulo. (3) Genetics and Evolutionary Biology, University of Sao Paulo. (4) Brazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials. (5) Butantan Institute. (6) Genetics and Evolutionary Biology, University of Sao Paulo. (7) Genetics and Evolutionary Biology, University of Sao Paulo. (8) Viral Immunology, Instituto Butantan. (9) Genetics and Evolutionary Biology, University of Sao Paulo. (10) Genetics and Evolutionary Biology, University of Sao Paulo. (11) Butanatn Institute. (12) Butantan Institute. (13) Viral Immunology, Butantan Institute. (14) Dept.Gen.e Biol.Evolutiva, University of Sao Paulo. (15) Genetics and Evolutionary Biology, University of Sao Paulo keith.okamoto@usp.br.

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Novel oncolytic chimeric orthopoxvirus causes regression of pancreatic cancer xenografts and exhibits abscopal effect at a single low dose

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BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) has been increasing by 0.5% per year in the United States. PDAC portends a dismal prognosis and novel therapies are needed. This study describes the generation and characterization of a novel oncolytic chimeric orthopoxvirus for the treatment of pancreatic cancer. METHODS: After chimerization and high-throughput screening, CF33 was chosen from 100 new chimeric orthopoxvirus isolates for its ability to kill pancreatic cancer cells. In vitro cytotoxicity was assayed in six pancreatic cancer cell lines. In vivo efficacy and toxicity were evaluated in PANC-1 and MIA PaCa-2 xenograft models. RESULTS: CF33 caused rapid killing of six pancreatic cancer cells lines in vitro, releasing damage-associated molecular patterns, and regression of PANC-1 injected and non-injected distant xenografts in vivo after a single low intratumoral dose of 10(3) plaque-forming units. Using luciferase imaging, CF33 was noted to preferentially replicate in tumors which corresponds to the low viral titers found in solid organs. CONCLUSION: The low dose of CF33 required to treat pancreatic cancer in this preclinical study may ease the manufacturing and dosing challenges currently facing oncolytic viral therapy.

Author Info: (1) Department of Surgery, Division of Surgical Oncology, City of Hope National Medical Center, 1500 Duarte Rd., Duarte, CA, 91010, USA. (2) Department of Surgery

Author Info: (1) Department of Surgery, Division of Surgical Oncology, City of Hope National Medical Center, 1500 Duarte Rd., Duarte, CA, 91010, USA. (2) Department of Surgery, Division of Surgical Oncology, City of Hope National Medical Center, 1500 Duarte Rd., Duarte, CA, 91010, USA. (3) Department of Surgery, Division of Surgical Oncology, City of Hope National Medical Center, 1500 Duarte Rd., Duarte, CA, 91010, USA. (4) Department of Surgery, Division of Surgical Oncology, City of Hope National Medical Center, 1500 Duarte Rd., Duarte, CA, 91010, USA. (5) Department of Surgery, Division of Surgical Oncology, City of Hope National Medical Center, 1500 Duarte Rd., Duarte, CA, 91010, USA. (6) Department of Surgery, Division of Surgical Oncology, City of Hope National Medical Center, 1500 Duarte Rd., Duarte, CA, 91010, USA. (7) Department of Surgery, Division of Surgical Oncology, City of Hope National Medical Center, 1500 Duarte Rd., Duarte, CA, 91010, USA. (8) Department of Surgery, Division of Surgical Oncology, City of Hope National Medical Center, 1500 Duarte Rd., Duarte, CA, 91010, USA. (9) Department of Surgery, Division of Surgical Oncology, City of Hope National Medical Center, 1500 Duarte Rd., Duarte, CA, 91010, USA. Center for Gene Therapy, Department of Hematologic and Hematopoietic Cell Transplantation, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, 91010, USA. (10) Department of Surgery, Division of Surgical Oncology, City of Hope National Medical Center, 1500 Duarte Rd., Duarte, CA, 91010, USA. nchen@coh.org. Center for Gene Therapy, Department of Hematologic and Hematopoietic Cell Transplantation, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, 91010, USA. nchen@coh.org. Gene Editing and Viral Vector Core, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, 91010, USA. nchen@coh.org.

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Oncolytic activity of the rhabdovirus VSV-GP against prostate cancer

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Oncolytic viruses, including the oncolytic rhabdovirus VSV-GP tested here, selectively infect and kill cancer cells and are a promising new therapeutic modality. Our aim was to study the efficacy of VSV-GP, a vesicular stomatitis virus carrying the glycoprotein of lymphocytic choriomeningitis virus, against prostate cancer, for which current treatment options still fail to cure metastatic disease. VSV-GP was found to infect 6 of 7 prostate cancer cell lines with great efficacy. However, susceptibility was reduced in one cell line with low virus receptor expression and in 3 cell lines after interferon alpha treatment. Four cell lines had developed resistance to interferon type I at different levels of the interferon signaling pathway, resulting in a deficient antiviral response. In prostate cancer mouse models, long-term remission was achieved upon intratumoral and, remarkably, also upon intravenous treatment of subcutaneous tumors and bone metastases. These promising efficacy data demonstrate that treatment of prostate cancer with VSV-GP is feasible and safe in pre-clinical models and encourage further preclinical and clinical development of VSV-GP for systemic treatment of metastatic prostate cancer. This article is protected by copyright. All rights reserved.

Author Info: (1) Division of Virology, Medical University of Innsbruck, Innsbruck, Austria. Christian Doppler Laboratory for Viral Immunotherapy of Cancer, Medical University of Innsbruck, Innsbruck, Austria. (2)

Author Info: (1) Division of Virology, Medical University of Innsbruck, Innsbruck, Austria. Christian Doppler Laboratory for Viral Immunotherapy of Cancer, Medical University of Innsbruck, Innsbruck, Austria. (2) Division of Experimental Urology, Medical University of Innsbruck, Austria. (3) Division of Virology, Medical University of Innsbruck, Innsbruck, Austria. ViraTherapeutics GmbH, Innsbruck, Austria. (4) Department of Urology, Leiden University Medical Centre, Leiden, The Netherlands. (5) Division of Experimental Urology, Medical University of Innsbruck, Austria. (6) ViraTherapeutics GmbH, Innsbruck, Austria. (7) Division of Virology, Medical University of Innsbruck, Innsbruck, Austria. Christian Doppler Laboratory for Viral Immunotherapy of Cancer, Medical University of Innsbruck, Innsbruck, Austria. (8) Division of Virology, Medical University of Innsbruck, Innsbruck, Austria. (9) Division of Experimental Urology, Medical University of Innsbruck, Austria. (10) Division of Virology, Medical University of Innsbruck, Innsbruck, Austria.

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Zika Virus has Oncolytic Activity Against Glioblastoma Stem Cells

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Brief Report

Author Info: (1) Department of Neurosurgery University of Wisconsin Madison, Wisconsin. (2) Department of Neurosurgery University of Wisconsin Madison, Wisconsin. (3) Department of Neurosurgery University of Wisconsin Madison, Wisconsin.

Author Info: (1) Department of Neurosurgery University of Wisconsin Madison, Wisconsin. (2) Department of Neurosurgery University of Wisconsin Madison, Wisconsin. (3) Department of Neurosurgery University of Wisconsin Madison, Wisconsin.

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A Novel Oncolytic Herpes Capable of Cell-Specific Transcriptional Targeting of CD133+/- Cancer Cells Induces Significant Tumor Regression

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The topic of cancer stem cells is of significant importance due to its implications in our understanding of the tumor biology, as well as the development of novel cancer therapeutics. However, the question of whether targeting cancer stem cells can hamper the growth of tumors remains mainly unanswered due to the lack of specific agents for this purpose. In order to address this issue, we have developed the first mutated version of herpes simplex virus-1 (HSV-1) that is transcriptionally targeted against CD133+ cells. CD133 has been portrayed as one of the most important markers in cancer stem cells involved in the biology of a number of human cancers, including liver, brain, colon, skin, and pancreas. The virus developed in this work, Signal-Smart 2 (SS2), showed specificity against CD133+ cells in three different models (hepatocellular carcinoma, colorectal cancer, and melanoma) resulting in a loss of viability and invasiveness of cancer cells. Additionally, the virus showed robust inhibitory activity against in vivo tumor growth in both preventive and therapeutic mouse models as well as orthotopic model highly relevant to potential clinical application of this virus. Therefore, we conclude that targeting CD133+ cancer stem cells has the potential to be pursued as a novel strategy against cancer. This article is protected by copyright. All rights reserved.

Author Info: (1) The University of Kansas Medical School, Molecular Medicine Laboratory, Kansas City, Kansas, USA. (2) The University of Kansas Medical School, Molecular Medicine Laboratory, Kansas

Author Info: (1) The University of Kansas Medical School, Molecular Medicine Laboratory, Kansas City, Kansas, USA. (2) The University of Kansas Medical School, Molecular Medicine Laboratory, Kansas City, Kansas, USA. (3) Midwest Biomedical Research Foundation, Kansas City Veterans Affairs Medical Center, Kansas City, MO, USA. (4) The University of Kansas Medical School, Molecular Medicine Laboratory, Kansas City, Kansas, USA. (5) The University of Kansas Medical School, Molecular Medicine Laboratory, Kansas City, Kansas, USA. (6) The University of Kansas Medical School, Molecular Medicine Laboratory, Kansas City, Kansas, USA. (7) The University of Kansas Medical School, Molecular Medicine Laboratory, Kansas City, Kansas, USA. (8) The University of Kansas Medical School, Molecular Medicine Laboratory, Kansas City, Kansas, USA. (9) The University of Kansas Medical School, Molecular Medicine Laboratory, Kansas City, Kansas, USA. (10) The University of Kansas Medical School, Molecular Medicine Laboratory, Kansas City, Kansas, USA. (11) The University of Kansas Medical School, Molecular Medicine Laboratory, Kansas City, Kansas, USA. (12) The University of Kansas Medical School, Molecular Medicine Laboratory, Kansas City, Kansas, USA. (13) Midwest Biomedical Research Foundation, Kansas City Veterans Affairs Medical Center, Kansas City, MO, USA. Saint Luke's Cancer Institute-Saint Luke's Marion Bloch Neuroscience Institute, Kansas City, MO, USA.

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Newcastle disease virus strain AF2240 as an oncolytic virus: a review

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The discovery of tumour selective virus-mediated apoptosis marked the birth of an alternative cancer treatment in the form of oncolytic viruses. Even though, its oncolytic efficiency was demonstrated more than 50 years ago, safety concerns which resulted from mild to lethal side effects hampered the progress of oncolytic virus research. Since the classical oncolytic virus studies rely heavily on its natural oncolytic ability, virus manipulation was limited, thereby, restricted efforts to improve its safety. In order to circumvent such restriction, experiments involving non-human viruses such as the avian Newcastle disease virus (NDV) was conducted using cultured cells, animal models and human subjects. The corresponding reports on its significant tumour cytotoxicity along with impressive safety profile initiated immense research interest in the field of oncolytic NDV. The varying degree of oncolytic efficiency and virulency among NDV strains encouraged researchers from all around the world to experiment with their respective local NDV isolates in order to develop an oncolytic virus with desirable characteristics. Such desirable features include high tumour-killing ability, selectivity and low systemic cytotoxicity. The Malaysian field outbreak isolate, NDV strain AF2240, also currently, receives significant research attention. Apart from its high cytotoxicity against tumour cells, this strain was also provided fundamental insight into NDV-mediated apoptosis mechanism which involves Bax protein recruitment as well as death receptor engagement. Studies on its ability to selectively induce apoptosis in tumour cells also resulted in a proposed p38 MAPK/NF-kappaB/IkappaBalpha pathway. The immunogenicity of AF2240 was also investigated through PBMC stimulation and macrophage infection. In addition, the enhanced oncolytic ability of this strain under hypoxic condition signifies its dynamic tumour tropism. This review is aimed to introduce and discuss the aforementioned details of the oncolytic AF2240 strain along with its current challenges which outlines the future research direction of this virus.

Author Info: (1) Department of Microbiology, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, 43400, UPM, Serdang, Selangor D.E., Malaysia; Malaysian Genome Institute, Jalan Bangi, 4300

Author Info: (1) Department of Microbiology, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, 43400, UPM, Serdang, Selangor D.E., Malaysia; Malaysian Genome Institute, Jalan Bangi, 43000 Kajang, Selangor D.E., Malaysia. (2) Department of Biomedical Sciences, Faculty of Medicine & Health Sciences, University of Nottingham Malaysia Campus, Jalan Broga, 43500 Semenyih, Selangor D.E., Malaysia. (3) Department of Microbiology, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, 43400, UPM, Serdang, Selangor D.E., Malaysia; Malaysian Genome Institute, Jalan Bangi, 43000 Kajang, Selangor D.E., Malaysia; Institute of Bioscience, Universiti Putra Malaysia, 43400, UPM, Serdang, Selangor D.E., Malaysia. (4) Department of Microbiology, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, 43400, UPM, Serdang, Selangor D.E., Malaysia; Malaysian Genome Institute, Jalan Bangi, 43000 Kajang, Selangor D.E., Malaysia; Institute of Bioscience, Universiti Putra Malaysia, 43400, UPM, Serdang, Selangor D.E., Malaysia. Electronic address: suetlin@upm.edu.my.

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Complete intracranial response to talimogene laherparepvec (T-Vec), pembrolizumab and whole brain radiotherapy in a patient with melanoma brain metastases refractory to dual checkpoint-inhibition

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BACKGROUND: Immunotherapy, in particular checkpoint blockade, has changed the clinical landscape of metastatic melanoma. Nonetheless, the majority of patients will either be primary refractory or progress over follow up. Management of patients progressing on first-line immunotherapy remains challenging. Expanded treatment options with combination immunotherapy has demonstrated efficacy in patients previously unresponsive to single agent or alternative combination therapy. CASE PRESENTATION: We describe the case of a patient with diffusely metastatic melanoma, including brain metastases, who, despite being treated with stereotactic radiosurgery and dual CTLA-4/PD-1 blockade (ipilimumab/nivolumab), developed systemic disease progression and innumerable brain metastases. This patient achieved a complete CNS response and partial systemic response with standard whole brain radiation therapy (WBRT) combined with Talimogene laherparepvec (T-Vec) and pembrolizumab. CONCLUSION: Patients who do not respond to one immunotherapy combination may respond during treatment with an alternate combination, even in the presence of multiple brain metastases. Biomarkers are needed to assist clinicians in evidence based clinical decision making after progression on first line immunotherapy to determine whether response can be achieved with second line immunotherapy.

Author Info: (1) Columbia University Medical Center, Hematology/Oncology, 650 West 168th Street, New York, NY, 10032, USA. (2) NewYork-Prebsyterian/Columbia, Hematology/Oncology, 177 Fort Washington Avenue, New York, NY

Author Info: (1) Columbia University Medical Center, Hematology/Oncology, 650 West 168th Street, New York, NY, 10032, USA. (2) NewYork-Prebsyterian/Columbia, Hematology/Oncology, 177 Fort Washington Avenue, New York, NY, 10032, USA. (3) Columbia University Medical Center, Hematology/Oncology, 650 West 168th Street, New York, NY, 10032, USA. (4) Columbia University Medical Center, Hematology/Oncology, 650 West 168th Street, New York, NY, 10032, USA. (5) NewYork-Prebsyterian/Columbia, Hematology/Oncology, 161 Fort Washington Ave, New York, NY, 10032, USA. (6) NewYork-Prebsyterian/Columbia, Radiation Oncology, 161 Fort Washington Ave, New York, NY, 10032, USA. (7) NewYork-Prebsyterian/Columbia, Surgery, 161 Fort Washington Ave, New York, NY, 10032, USA. (8) NewYork-Prebsyterian/Columbia, Dermatopathology, 630 W 168th Street, New York, NY, 10032, USA. (9) NewYork-Prebsyterian/Columbia, Hematology/Oncology, 161 Fort Washington Ave, New York, NY, 10032, USA. yms4@cumc.columbia.edu.

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