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Melanoma: HELP
Articles by Richard G. Vile
Based on 48 articles published since 2008
(Why 48 articles?)
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Between 2008 and 2019, R. Vile wrote the following 48 articles about Melanoma.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Editorial What new immunotherapeutic techniques are currently being investigated for the treatment of melanoma? 2012

Donnelly, Oliver G / Melcher, Alan A / Vile, Richard G / Pulido, Jose. · ·Immunotherapy · Pubmed #22947000.

ABSTRACT: -- No abstract --

2 Review Metastatic malignant melanoma. 2009

Markovic, S N / Erickson, L A / Flotte, T J / Kottschade, L A / McWilliams, R R / Jakub, J W / Farley, D R / Tran, N V / Schild, S E / Olivier, K R / Vuk-Pavlovic, S / Sekulic, A / Weenig, R H / Pulido, J S / Quevedo, J F / Vile, R G / Wiseman, G A / Stoian, I / Pittelkow, M R / Anonymous330622. ·Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA. markovic.svetomir@mayo.edu ·G Ital Dermatol Venereol · Pubmed #19218908.

ABSTRACT: Metastatic malignant melanoma is an incurable malignancy with extremely poor prognosis. Patients bearing this diagnosis face a median survival time of approximately 9 months with a probability of surviving 5 years after initial presentation at less than 5%. This is contrasted by the curative nature of surgical resection of early melanoma detected in the skin. To date, no systemic therapy has consistently and predictably impacted the overall survival of patients with metastatic melanoma. However, in recent years, a resurgence of innovative diagnostic and therapeutic developments have broadened our understanding of the natural history of melanoma and identified rational therapeutic targets/strategies that seem poised to significantly change the clinical outcomes in these patients. Herein we review the state-of-the-art in metastatic melanoma diagnostics and therapeutics with particular emphasis on multi-disciplinary clinical management.

3 Review Malignant melanoma in the 21st century: the emerging molecular landscape. 2008

Sekulic, Aleksandar / Haluska, Paul / Miller, Arlo J / Genebriera De Lamo, Josep / Ejadi, Samuel / Pulido, Jose S / Salomao, Diva R / Thorland, Erik C / Vile, Richard G / Swanson, David L / Pockaj, Barbara A / Laman, Susan D / Pittelkow, Mark R / Markovic, Svetomir N / Anonymous3621216. ·Department of Dermatology, Mayo Clinic, Scottsdale, AZ 85259, USA. sekulic.aleksandar@mayo.edu ·Mayo Clin Proc · Pubmed #18613999.

ABSTRACT: Malignant melanoma presents a substantial clinical challenge. Current diagnostic methods are limited in their ability to diagnose early disease and accurately predict individual risk of disease progression and outcome. The lack of adequate approaches to properly define disease subgroups precludes rational treatment design and selection. Better tools are urgently needed to provide more accurate and personalized melanoma patient management. Recent progress in the understanding of the molecular aberrations that underlie melanoma oncogenesis will likely advance the diagnosis, prognosis, and treatment of melanoma. The emerging pattern of molecular complexity in melanoma tumors mirrors the clinical diversity of the disease and highlights the notion that melanoma, like other cancers, is not a single disease but a heterogeneous group of disorders that arise from complex molecular changes. Understanding of molecular aberrations involving important cellular processes, such as cellular signaling networks, cell cycle regulation, and cell death, will be essential for better diagnosis, accurate assessment of prognosis, and rational design of effective therapeutics. Defining an individual patient's unique tumor characteristics may lead to personalized prediction of outcomes and selection of therapy. We review the emerging molecular landscape of melanoma and its implications for better management of patients with melanoma.

4 Clinical Trial Phase II trial of intravenous administration of Reolysin(®) (Reovirus Serotype-3-dearing Strain) in patients with metastatic melanoma. 2012

Galanis, Evanthia / Markovic, Svetomir N / Suman, Vera J / Nuovo, Gerard J / Vile, Richard G / Kottke, Timothy J / Nevala, Wendy K / Thompson, Michael A / Lewis, Jean E / Rumilla, Kandelaria M / Roulstone, Victoria / Harrington, Kevin / Linette, Gerald P / Maples, William J / Coffey, Matt / Zwiebel, James / Kendra, Kari. ·Mayo Clinic, Rochester, Minnesota 55905, USA. galanis.evanthia@mayo.edu ·Mol Ther · Pubmed #22871663.

ABSTRACT: Reovirus, a replication competent RNA virus, has preclinical activity against melanoma lines and xenografts. We conducted a phase II trial of reovirus in metastatic melanoma patients. Patients received 3 × 10(10) TCID50 on days 1-5 of each 28 day cycle, administered intravenously. Twenty-one eligible patients were enrolled. Treatment was well tolerated without any dose reductions having to be implemented. Post-treatment biopsy samples were obtained in 15 patients, 13/15 contained adequate tumor for correlative analysis. In two patients, productive reoviral replication (viral antigen coexpression with tubulin) was demonstrated, despite increase in neutralizing antibody titers. There were no objective responses although 75-90% tumor necrosis, consistent with treatment effect, was observed in one patient who had metastatic lesions surgically removed. Median time to progression and survival were 45 days (range 13-96 days) and 165 days (range 15 days-15.8 months) respectively. In conclusion, reovirus treatment was well tolerated in metastatic melanoma patients; viral replication was demonstrated in biopsy samples. Based on preclinical data showing synergy with taxane and platinum compounds, a phase II combination trial in metastatic melanoma patients is ongoing.

5 Article Subversion of NK-cell and TNFα Immune Surveillance Drives Tumor Recurrence. 2017

Kottke, Tim / Evgin, Laura / Shim, Kevin G / Rommelfanger, Diana / Boisgerault, Nicolas / Zaidi, Shane / Diaz, Rosa Maria / Thompson, Jill / Ilett, Elizabeth / Coffey, Matt / Selby, Peter / Pandha, Hardev / Harrington, Kevin / Melcher, Alan / Vile, Richard. ·Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota. · Leeds Institute of Cancer and Pathology, St. James' University Hospital, Leeds, United Kingdom. · Oncolytics Biotech Incorporated, Calgary, Canada. · University of Surrey, Guildford, United Kingdom. · The Institute of Cancer Research, London, United Kingdom. · Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota. vile.richard@mayo.edu. · Department of Immunology, Mayo Clinic, Rochester, Minnesota. ·Cancer Immunol Res · Pubmed #29038298.

ABSTRACT: Understanding how incompletely cleared primary tumors transition from minimal residual disease (MRD) into treatment-resistant, immune-invisible recurrences has major clinical significance. We show here that this transition is mediated through the subversion of two key elements of innate immunosurveillance. In the first, the role of TNFα changes from an antitumor effector against primary tumors into a growth promoter for MRD. Second, whereas primary tumors induced a natural killer (NK)-mediated cytokine response characterized by low IL6 and elevated IFNγ, PD-L1

6 Article Inhibitory Receptors Induced by VSV Viroimmunotherapy Are Not Necessarily Targets for Improving Treatment Efficacy. 2017

Shim, Kevin G / Zaidi, Shane / Thompson, Jill / Kottke, Tim / Evgin, Laura / Rajani, Karishma R / Schuelke, Matthew / Driscoll, Christopher B / Huff, Amanda / Pulido, Jose S / Vile, Richard G. ·Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55905, USA; Medical Scientist Training Program, Mayo Clinic, Rochester, MN 55905, USA. · Targeted Therapy Laboratory, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JJ, UK. · Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55905, USA. · Department of Ophthalmology, Mayo Clinic, Rochester, MN 55905, USA. · Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55905, USA. Electronic address: vile.richard@mayo.edu. ·Mol Ther · Pubmed #28237836.

ABSTRACT: Systemic viroimmunotherapy activates endogenous innate and adaptive immune responses against both viral and tumor antigens. We have shown that therapy with vesicular stomatitis virus (VSV) engineered to express a tumor-associated antigen activates antigen-specific adoptively transferred T cells (adoptive cell therapy, ACT) in vivo to generate effective therapy. The overall goal of this study was to phenotypically characterize the immune response to VSV+ACT therapy and use the information gained to rationally improve combination therapy. We observed rapid expansion of blood CD8

7 Article Prime-boost using separate oncolytic viruses in combination with checkpoint blockade improves anti-tumour therapy. 2017

Ilett, E / Kottke, T / Thompson, J / Rajani, K / Zaidi, S / Evgin, L / Coffey, M / Ralph, C / Diaz, R / Pandha, H / Harrington, K / Selby, P / Bram, R / Melcher, A / Vile, R. ·Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA. · Leeds Institute of Cancer and Pathology, St James' University Hospital, Leeds, UK. · The Institute of Cancer Research, London, UK. · Oncolytics Biotech Incorporated, Calgary, Canada. · Vyriad, Rochester, MN. · University of Surrey, Guildford, UK. · Department of Immunology, Mayo Clinic, Rochester, MN, USA. ·Gene Ther · Pubmed #27779616.

ABSTRACT: The anti-tumour effects associated with oncolytic virus therapy are mediated significantly through immune-mediated mechanisms, which depend both on the type of virus and the route of delivery. Here, we show that intra-tumoral oncolysis by Reovirus induced the priming of a CD8+, Th1-type anti-tumour response. By contrast, systemically delivered Vesicular Stomatitis Virus expressing a cDNA library of melanoma antigens (VSV-ASMEL) promoted a potent anti-tumour CD4+ Th17 response. Therefore, we hypothesised that combining the Reovirus-induced CD8+ T cell response, with the VSV-ASMEL CD4+ Th17 helper response, would produce enhanced anti-tumour activity. Consistent with this, priming with intra-tumoral Reovirus, followed by an intra-venous VSV-ASMEL Th17 boost, significantly improved survival of mice bearing established subcutaneous B16 melanoma tumours. We also show that combination of either therapy alone with anti-PD-1 immune checkpoint blockade augmented both the Th1 response induced by systemically delivered Reovirus in combination with GM-CSF, and also the Th17 response induced by VSV-ASMEL. Significantly, anti-PD-1 also uncovered an anti-tumour Th1 response following VSV-ASMEL treatment that was not seen in the absence of checkpoint blockade. Finally, the combination of all three treatments (priming with systemically delivered Reovirus, followed by double boosting with systemic VSV-ASMEL and anti-PD-1) significantly enhanced survival, with long-term cures, compared to any individual, or double, combination therapies, associated with strong Th1 and Th17 responses to tumour antigens. Our data show that it is possible to generate fully systemic, highly effective anti-tumour immunovirotherapy by combining oncolytic viruses, along with immune checkpoint blockade, to induce complementary mechanisms of anti-tumour immune responses.

8 Article Combination viroimmunotherapy with checkpoint inhibition to treat glioma, based on location-specific tumor profiling. 2016

Cockle, Julia V / Rajani, Karishma / Zaidi, Shane / Kottke, Timothy / Thompson, Jill / Diaz, Rosa Maria / Shim, Kevin / Peterson, Tim / Parney, Ian F / Short, Susan / Selby, Peter / Ilett, Elizabeth / Melcher, Alan / Vile, Richard. ·Leeds Institute of Cancer Studies and Pathology, University of Leeds, Leeds, UK (J.V.C., S.S., P.S., E.I., A.M., R.V.) · Department of Immunology, Mayo Clinic, Rochester, Minnesota (K.R., S.Z., T.K., J.T., R.M.D., K.S., R.V.) · Division of Cancer Biology, The Institute of Cancer Research, Chester Beatty Laboratories, London, UK (S.Z., R.V.) · Department of Neurologic Surgery, Mayo Clinic, Rochester, Minnesota (T.P., I.F.P.). ·Neuro Oncol · Pubmed #26409567.

ABSTRACT: BACKGROUND: Systemic delivery of a complementary cDNA library expressed from the vesicular stomatitis virus (VSV) treats tumors by vaccinating against a wide range of tumor associated antigens (TAAs). For subcutaneous B16 melanomas, therapy was achieved using a specific combination of self-TAAs (neuroblastoma-Ras, cytochrome c, and tyrosinase-related protein 1) expressed from VSV. However, for intracranial B16 tumors, a different combination was therapeutic (consisting of VSV-expressed hypoxia-inducible factor [HIF]-2α, Sox-10, c-Myc, and tyrosinase-related protein 1). Therefore, we tested the hypothesis that tumors of different histological types growing in the brain share a common immunogenic signature which can be exploited for immunotherapy. METHODS: Syngeneic tumors, including GL261 gliomas, in the brains of immune competent mice were analyzed for their antigenic profiles or were treated with systemic viroimmunotherapy. RESULTS: Several different histological types of tumors growing intracranially, as well as freshly resected human brain tumor explants, expressed a HIF-2α(Hi) phenotype imposed by brain-derived CD11b+ cells. This location-specific antigen expression was exploited therapeutically against intracranial GL261 gliomas using systemically delivered VSV expressing HIF-2α, Sox-10, and c-Myc. Viroimmunotherapy was enhanced by immune checkpoint inhibitors, associated with the de-repression of antitumor T-helper cell type 1 (Th1) interferon-γ and Th17 T cell responses. CONCLUSIONS: Since different tumor types growing in the same location in the brain share a location-specific phenotype, we suggest that antigen-specific immunotherapies should be based upon expression of both histological type-specific tumor antigens and location-specific antigens. Our findings support clinical application of VSV-TAA therapy with checkpoint inhibition for aggressive brain tumors and highlight the importance of the intracranial microenvironment in sculpting a location-specific profile of tumor antigen expression.

9 Article Combination Therapy With Reovirus and Anti-PD-1 Blockade Controls Tumor Growth Through Innate and Adaptive Immune Responses. 2016

Rajani, Karishma / Parrish, Christopher / Kottke, Timothy / Thompson, Jill / Zaidi, Shane / Ilett, Liz / Shim, Kevin G / Diaz, Rosa-Maria / Pandha, Hardev / Harrington, Kevin / Coffey, Matt / Melcher, Alan / Vile, Richard. ·Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA. · Cancer Research UK Clinical Centre, St. James' University Hospital, Leeds, UK. · University of Surrey, Guildford, UK. · The Institute of Cancer Research, London, UK. · Oncolytics Biotech Incorporated, Calgary, Alberta, Canada. · Department of Immunology, Mayo Clinic, Rochester, Minnesota, USA. ·Mol Ther · Pubmed #26310630.

ABSTRACT: Oncolytic reovirus can be delivered both systemically and intratumorally, in both preclinical models and in early phase clinical trials. Reovirus has direct oncolytic activity against a variety of tumor types and antitumor activity is directly associated with immune activation by virus replication in tumors. Immune mechanisms of therapy include both innate immune activation against virally infected tumor cells, and the generation of adaptive antitumor immune responses as a result of in vivo priming against tumor-associated antigens. We tested the combination of local oncolytic reovirus therapy with systemic immune checkpoint inhibition. We show that treatment of subcutaneous B16 melanomas with a combination of intravenous (i.v.) anti-PD-1 antibody and intratumoral (i.t.) reovirus significantly enhanced survival of mice compared to i.t. reovirus (P < 0.01) or anti-PD-1 therapy alone. In vitro immune analysis demonstrated that checkpoint inhibition improved the ability of NK cells to kill reovirus-infected tumor cells, reduced T(reg) activity, and increased the adaptive CD8(+) T-cell-dependent antitumor T-cell response. PD-1 blockade also enhanced the antiviral immune response but through effector mechanisms which overlapped with but also differed from those affecting the antitumor response. Therefore, combination with checkpoint inhibition represents a readily translatable next step in the clinical development of reovirus viroimmunotherapy.

10 Article Definitive Management of Oligometastatic Melanoma in a Murine Model Using Combined Ablative Radiation Therapy and Viral Immunotherapy. 2015

Blanchard, Miran / Shim, Kevin G / Grams, Michael P / Rajani, Karishma / Diaz, Rosa M / Furutani, Keith M / Thompson, Jill / Olivier, Kenneth R / Park, Sean S / Markovic, Svetomir N / Pandha, Hardev / Melcher, Alan / Harrington, Kevin / Zaidi, Shane / Vile, Richard. ·Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota; Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota. · Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota; Department of Immunology, Mayo Clinic, Rochester, Minnesota. · Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota. · Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota. · Department of Immunology, Mayo Clinic, Rochester, Minnesota; Department of Medical Oncology, Mayo Clinic, Rochester, Minnesota. · The Postgraduate Medical School, University of Surrey, Guildford, United Kingdom. · Leeds Institute of Cancer Studies and Pathology, University of Leeds, Leeds, United Kingdom. · Targeted Therapy Laboratory, The Institute of Cancer Research, London, United Kingdom. · Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota; Targeted Therapy Laboratory, The Institute of Cancer Research, London, United Kingdom. · Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota; Department of Immunology, Mayo Clinic, Rochester, Minnesota; Leeds Institute of Cancer Studies and Pathology, University of Leeds, Leeds, United Kingdom. Electronic address: vile.richard@mayo.edu. ·Int J Radiat Oncol Biol Phys · Pubmed #26461000.

ABSTRACT: PURPOSE: The oligometastatic state is an intermediate state between a malignancy that can be completely eradicated with conventional modalities and one in which a palliative approach is undertaken. Clinically, high rates of local tumor control are possible with stereotactic ablative radiation therapy (SABR), using precisely targeted, high-dose, low-fraction radiation therapy. However, in oligometastatic melanoma, virtually all patients develop progression systemically at sites not initially treated with ablative radiation therapy that cannot be managed with conventional chemotherapy and immunotherapy. We have demonstrated in mice that intravenous administration of vesicular stomatitis virus (VSV) expressing defined tumor-associated antigens (TAAs) generates systemic immune responses capable of clearing established tumors. Therefore, in the present preclinical study, we tested whether the combination of systemic VSV-mediated antigen delivery and SABR would be effective against oligometastatic disease. METHODS AND MATERIALS: We generated a model of oligometastatic melanoma in C57BL/6 immunocompetent mice and then used a combination of SABR and systemically administered VSV-TAA viral immunotherapy to treat both local and systemic disease. RESULTS: Our data showed that SABR generates excellent control or cure of local, clinically detectable, and accessible tumor through direct cell ablation. Also, the immunotherapeutic activity of systemically administered VSV-TAA generated T-cell responses that cleared subclinical metastatic tumors. We also showed that SABR induced weak T-cell-mediated tumor responses, which, particularly if boosted by VSV-TAA, might contribute to control of local and systemic disease. In addition, VSV-TAA therapy alone had significant effects on control of both local and metastatic tumors. CONCLUSIONS: We have shown in the present preliminary murine study using a single tumor model that this approach represents an effective, complementary combination therapy model that addresses the need for both systemic and local control in oligometastatic melanoma.

11 Article BRAF- and MEK-Targeted Small Molecule Inhibitors Exert Enhanced Antimelanoma Effects in Combination With Oncolytic Reovirus Through ER Stress. 2015

Roulstone, Victoria / Pedersen, Malin / Kyula, Joan / Mansfield, David / Khan, Aadil A / McEntee, Grainne / Wilkinson, Michelle / Karapanagiotou, Eleni / Coffey, Matt / Marais, Richard / Jebar, Adel / Errington-Mais, Fiona / Melcher, Alan / Vile, Richard / Pandha, Hardev / McLaughlin, Martin / Harrington, Kevin J. ·Targeted Therapy Team, The Institute of Cancer Research, London, UK. · Oncolytics Biotech. Inc., Calgary, Alberta, Canada. · Cancer Research UK Manchester Institute, Manchester, UK. · Leeds Institute of Molecular Medicine, Leeds, UK. · Molecular Medicine Program, Mayo Clinic, Rochester, Minnesota, USA. · University of Surrey, Guildford, UK. · Targeted Therapy Team, The Institute of Cancer Research, London, UK. Electronic address: Kevin.Harrington@icr.ac.uk. ·Mol Ther · Pubmed #25619724.

ABSTRACT: Reovirus type 3 (Dearing) (RT3D) infection is selective for cells harboring a mutated/activated RAS pathway. Therefore, in a panel of melanoma cell lines (including RAS mutant, BRAF mutant and RAS/BRAF wild-type), we assessed therapeutic combinations that enhance/suppress ERK1/2 signaling through use of BRAF/MEK inhibitors. In RAS mutant cells, the combination of RT3D with the BRAF inhibitor PLX4720 (paradoxically increasing ERK1/2 signaling in this context) did not enhance reoviral cytotoxicity. Instead, and somewhat surprisingly, RT3D and BRAF inhibition led to enhanced cell kill in BRAF mutated cell lines. Likewise, ERK1/2 inhibition, using the MEK inhibitor PD184352, in combination with RT3D resulted in enhanced cell kill in the entire panel. Interestingly, TCID50 assays showed that BRAF and MEK inhibitors did not affect viral replication. Instead, enhanced efficacy was mediated through ER stress-induced apoptosis, induced by the combination of ERK1/2 inhibition and reovirus infection. In vivo, combined treatments of RT3D and PLX4720 showed significantly increased activity in BRAF mutant tumors in both immune-deficient and immune-competent models. These data provide a strong rationale for clinical translation of strategies in which RT3D is combined with BRAF inhibitors (in BRAF mutant melanoma) and/or MEK inhibitors (in BRAF and RAS mutant melanoma).

12 Article Mutated BRAF Emerges as a Major Effector of Recurrence in a Murine Melanoma Model After Treatment With Immunomodulatory Agents. 2015

Zaidi, Shane / Blanchard, Miran / Shim, Kevin / Ilett, Elizabeth / Rajani, Karishma / Parrish, Christopher / Boisgerault, Nicolas / Kottke, Tim / Thompson, Jill / Celis, Esteban / Pulido, Jose / Selby, Peter / Pandha, Hardev / Melcher, Alan / Harrington, Kevin / Vile, Richard. ·Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA; Targeted Therapy Team, Division of Cancer Biology, The Institute of Cancer Research, London, UK. · Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA. · Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA; Targeted and Biological Therapies Group, Leeds Institute of Cancer and Pathology, St. James' University Hospital, Leeds, UK. · Targeted and Biological Therapies Group, Leeds Institute of Cancer and Pathology, St. James' University Hospital, Leeds, UK. · Cancer Immunology, Inflammation and Tolerance Program, Georgia Regents University Cancer Center, Augusta, Georgia, USA. · Leggett Building, Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK. · Targeted Therapy Team, Division of Cancer Biology, The Institute of Cancer Research, London, UK. · Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA; Targeted and Biological Therapies Group, Leeds Institute of Cancer and Pathology, St. James' University Hospital, Leeds, UK; Department of Immunology, Mayo Clinic, Rochester, Minnesota, USA. Electronic address: vile.richard@mayo.edu. ·Mol Ther · Pubmed #25544599.

ABSTRACT: We used a VSV-cDNA library to treat recurrent melanoma, identifying immunogenic antigens, allowing us to target recurrences with immunotherapy or chemotherapy. Primary B16 melanoma tumors were induced to regress by frontline therapy. Mice with recurrent tumors were treated with VSV-cDNA immunotherapy. A Th17 recall response was used to screen the VSV-cDNA library for individual viruses encoding rejection antigens, subsequently targeted using immunotherapy or chemotherapy. Recurrent tumors were effectively treated with a VSV-cDNA library using cDNA from recurrent B16 tumors. Recurrence-associated rejection antigens identified included Topoisomerase-IIα, YB-1, cdc7 kinase, and BRAF. Fourteen out of 16 recurrent tumors carried BRAF mutations (595-605 region) following frontline therapy, even though the parental B16 tumors were BRAF wild type. The emergence of mutated BRAF-containing recurrences served as an excellent target for BRAF-specific immune-(VSV-BRAF), or chemo-(PLX-4720) therapies. Successful PLX-4720 therapy of recurrent tumors was associated with the development of a broad spectrum of T-cell responses. VSV-cDNA technology can be used to identify recurrence specific antigens. Emergence of mutated BRAF may be a major effector of melanoma recurrence which could serve as a target for chemo or immune therapy. This study suggests a rationale for offering patients with initially wild-type BRAF melanomas an additional biopsy to screen for mutant BRAF upon recurrence.

13 Article How to train your oncolytic virus: the immunological sequel. 2014

Vile, Richard G. ·1] Departments of Molecular Medicine and Immunology, Mayo Clinic, Rochester, Minnesota, USA [2] Cancer Research UK Clinical Centre, St. James' University Hospital, Leeds, UK. ·Mol Ther · Pubmed #25365984.

ABSTRACT: -- No abstract --

14 Article The profile of tumor antigens which can be targeted by immunotherapy depends upon the tumor's anatomical site. 2014

Alonso-Camino, Vanesa / Rajani, Karishma / Kottke, Timothy / Rommelfanger-Konkol, Diana / Zaidi, Shane / Thompson, Jill / Pulido, Jose / Ilett, Elizabeth / Donnelly, Oliver / Selby, Peter / Pandha, Hardev / Melcher, Alan / Harrington, Kevin / Diaz, Rosa Maria / Vile, Richard. ·Department of Molecular Medicine, The Institute of Cancer Research, London, UK. · 1] Department of Molecular Medicine, The Institute of Cancer Research, London, UK [2] The Institute of Cancer Research, Division of Cancer Biology, Chester Beatty Laboratories, London, UK. · 1] Department of Molecular Medicine, The Institute of Cancer Research, London, UK [2] Department of Ophthalmology and Ocular Oncology Mayo Clinic, Rochester, Minnesota, USA. · Faculty of Medicine and Health, Leeds Institute of Cancer and Pathology, Leeds, UK. · Leggett Building, Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK. · The Institute of Cancer Research, Division of Cancer Biology, Chester Beatty Laboratories, London, UK. · 1] Department of Molecular Medicine, The Institute of Cancer Research, London, UK [2] Faculty of Medicine and Health, Leeds Institute of Cancer and Pathology, Leeds, UK [3] Department of Immunology, Mayo Clinic, Rochester, Minnesota, USA. ·Mol Ther · Pubmed #25059678.

ABSTRACT: Previously, we showed that vesicular stomatitis virus (VSV) engineered to express a cDNA library from human melanoma cells (ASMEL, Altered Self Melanoma Epitope Library) was an effective systemic therapy to treat subcutaneous (s.c.) murine B16 melanomas. Here, we show that intravenous treatment with the same ASMEL VSV-cDNA library was an effective treatment for established intra-cranial (i.c.) melanoma brain tumors. The optimal combination of antigens identified from the ASMEL which treated s.c. B16 tumors (VSV-N-RAS+VSV-CYTC-C+VSV-TYRP-1) was ineffective against i.c. B16 brain tumors. In contrast, combination of VSV-expressed antigens-VSV-HIF-2α+VSV-SOX-10+VSV-C-MYC+VSV-TYRP1-from ASMEL which was highly effective against i.c. B16 brain tumors, had no efficacy against the same tumors growing subcutaneously. Correspondingly, i.c. B16 tumors expressed a HIF-2α(Hi), SOX-10(Hi), c-myc(Hi), TYRP1, N-RAS(lo)Cytc(lo) antigen profile, which differed significantly from the HIF-2α(lo), SOX-10(lo), c-myc(lo), TYRP1, N-RAS(Hi)Cytc(Hi) phenotype of s.c. B16 tumors, and was imposed upon the tumor cells by CD11b(+) cells within the local brain tumor microenvironment. Combining T-cell costimulation with systemic VSV-cDNA treatment, long-term cures of mice with established i.c. tumors were achieved in about 75% of mice. Our data show that the anatomical location of a tumor profoundly affects the profile of antigens that it expresses.

15 Article Cytokine conditioning enhances systemic delivery and therapy of an oncolytic virus. 2014

Ilett, Elizabeth / Kottke, Timothy / Donnelly, Oliver / Thompson, Jill / Willmon, Candice / Diaz, Rosa / Zaidi, Shane / Coffey, Matt / Selby, Peter / Harrington, Kevin / Pandha, Hardev / Melcher, Alan / Vile, Richard. ·1] Leeds Institute of Cancer and Pathology, St. James' University Hospital, Leeds, UK [2] Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA. · Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA. · Leeds Institute of Cancer and Pathology, St. James' University Hospital, Leeds, UK. · Oncolytics Biotech Incorporated, Calgary, Alberta, Canada. · The Institute of Cancer Research, London, UK. · Department of Microbial and Cellular Sciences, University of Surrey, Guildford, UK. · 1] Leeds Institute of Cancer and Pathology, St. James' University Hospital, Leeds, UK [2] Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA [3] Department of Immunology, Mayo Clinic, Rochester, Minnesota, USA. ·Mol Ther · Pubmed #24957982.

ABSTRACT: Optimum clinical protocols require systemic delivery of oncolytic viruses in the presence of an intact immune system. We show that preconditioning with immune modulators, or loading virus onto carrier cells ex vivo, enhances virus-mediated antitumor activity. Our early trials of systemic reovirus delivery showed that after infusion reovirus could be recovered from blood cells--but not from plasma--suggesting that rapid association with blood cells may protect virus from neutralizing antibody. We therefore postulated that stimulation of potential carrier cells directly in vivo before intravenous viral delivery would enhance delivery of cell-associated virus to tumor. We show that mobilization of the CD11b(+) cell compartment by granulocyte macrophage-colony stimulating factor immediately before intravenous reovirus, eliminated detectable tumor in mice with small B16 melanomas, and achieved highly significant therapy in mice bearing well-established tumors. Unexpectedly, cytokine conditioning therapy was most effective in the presence of preexisting neutralizing antibody. Consistent with this, reovirus bound by neutralizing antibody effectively accessed monocytes/macrophages and was handed off to tumor cells. Thus, preconditioning with cytokine stimulated recipient cells in vivo for enhanced viral delivery to tumors. Moreover, preexisting neutralizing antibody to an oncolytic virus may, therefore, even be exploited for systemic delivery to tumors in the clinic.

16 Article Synergistic cytotoxicity of radiation and oncolytic Lister strain vaccinia in (V600D/E)BRAF mutant melanoma depends on JNK and TNF-α signaling. 2014

Kyula, J N / Khan, A A / Mansfield, D / Karapanagiotou, E M / McLaughlin, M / Roulstone, V / Zaidi, S / Pencavel, T / Touchefeu, Y / Seth, R / Chen, N G / Yu, Y A / Zhang, Q / Melcher, A A / Vile, R G / Pandha, H S / Ajaz, M / Szalay, A A / Harrington, K J. ·Targeted Therapy Team, Divisions of Cancer Biology, The Institute of Cancer Research, London, UK. · Genelux Corp, San Diego Science Center, San Diego, CA, USA. · Leeds Institute of Molecular Medicine, Leeds, UK. · 1] Leeds Institute of Molecular Medicine, Leeds, UK [2] Molecular Medicine Program, Mayo Clinic, Rochester, MN, USA. · Postgraduate Medical School, The University of Surrey, Guildford, UK. ·Oncogene · Pubmed #23624923.

ABSTRACT: Melanoma is an aggressive skin cancer that carries an extremely poor prognosis when local invasion, nodal spread or systemic metastasis has occurred. Recent advances in melanoma biology have revealed that RAS-RAF-MEK-ERK signaling has a pivotal role in governing disease progression and treatment resistance. Proof-of-concept clinical studies have shown that direct BRAF inhibition yields impressive responses in advanced disease but these are short-lived as treatment resistance rapidly emerges. Therefore, there is a pressing need to develop new targeted strategies for BRAF mutant melanoma. As such, oncolytic viruses represent a promising cancer-specific approach with significant activity in melanoma. This study investigated interactions between genetically-modified vaccinia virus (GLV-1h68) and radiotherapy in melanoma cell lines with BRAF mutant, Ras mutant or wild-type genotype. Preclinical studies revealed that GLV-1h68 combined with radiotherapy significantly increased cytotoxicity and apoptosis relative to either single agent in (V600D)BRAF/(V600E)BRAF mutant melanoma in vitro and in vivo. The mechanism of enhanced cytotoxicity with GLV-1h68/radiation (RT) was independent of viral replication and due to attenuation of JNK, p38 and ERK MAPK phosphorylation specifically in BRAF mutant cells. Further studies showed that JNK pathway inhibition sensitized BRAF mutant cells to GLV-1h68-mediated cell death, mimicking the effect of RT. GLV-1h68 infection activated MAPK signaling in (V600D)BRAF/(V600E)BRAF mutant cell lines and this was associated with TNF-α secretion which, in turn, provided a prosurvival signal. Combination GLV-1h68/RT (or GLV-1h68/JNK inhibition) caused abrogation of TNF-α secretion. These data provide a strong rationale for combining GLV-1h68 with irradiation in (V600D/E)BRAF mutant tumors.

17 Article Detecting and targeting tumor relapse by its resistance to innate effectors at early recurrence. 2013

Kottke, Timothy / Boisgerault, Nicolas / Diaz, Rosa Maria / Donnelly, Oliver / Rommelfanger-Konkol, Diana / Pulido, Jose / Thompson, Jill / Mukhopadhyay, Debabrata / Kaspar, Roger / Coffey, Matt / Pandha, Hardev / Melcher, Alan / Harrington, Kevin / Selby, Peter / Vile, Richard. ·Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA. · Cancer Research UK Centre, St. James's University Hospital, Leeds, UK. · Department of Ophthalmology and Ocular Oncology, Mayo Clinic, Rochester, Minnesota, USA. · Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, USA. · TransDerm, Santa Cruz, California, USA. · Oncolytics Biotech, Calgary, Alberta, Canada. · Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK. · The Institute of Cancer Research, London, UK. · Department of Immunology, Mayo Clinic, Rochester, Minnesota, USA. ·Nat Med · Pubmed #24240185.

ABSTRACT: Tumor recurrence represents a major clinical challenge. Our data show that emergent recurrent tumors acquire a phenotype radically different from that of their originating primary tumors. This phenotype allows them to evade a host-derived innate immune response elicited by the progression from minimal residual disease (MRD) to actively growing recurrence. Screening for this innate response predicted accurately in which mice recurrence would occur. Premature induction of recurrence resensitized MRD to the primary therapy, suggesting a possible paradigm shift for clinical treatment of dormant disease in which the current expectant approach is replaced with active attempts to uncover MRD before evolution of the escape phenotype is complete. By combining screening with second-line treatments targeting innate insensitivity, up to 100% of mice that would have otherwise relapsed were cured. These data may open new avenues for early detection and appropriately timed, highly targeted treatment of tumor recurrence irrespective of tumor type or frontline treatment.

18 Article Functional cloning of recurrence-specific antigens identifies molecular targets to treat tumor relapse. 2013

Boisgerault, Nicolas / Kottke, Timothy / Pulido, Jose / Thompson, Jill / Diaz, Rosa Maria / Rommelfanger-Konkol, Diana / Embry, Addie / Saenz, Dyana / Poeschla, Eric / Pandha, Hardev / Harrington, Kevin / Melcher, Alan / Selby, Peter / Vile, Richard. ·Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA. ·Mol Ther · Pubmed #23752316.

ABSTRACT: Aggressive regrowth of recurrent tumors following treatment-induced dormancy represents a major clinical challenge for treatment of malignant disease. We reported previously that recurrent prostate tumors, which underwent complete macroscopic regression followed by aggressive regrowth, could be cured with a vesicular stomatitis virus (VSV)-expressed cDNA library derived from recurrent tumor cells. By screening the protective, recurrence-derived VSV-cDNA library, here we identify topoisomerase-IIα (TOPO-IIα) as a recurrence-specific tumor antigen against which tolerance can be broken. Tumor recurrences, in two different types of tumor (prostate and melanoma), which had evaded two different frontline treatments (immunotherapy or chemotherapy), significantly overexpressed TOPO-IIα compared with their primary tumor counterparts, which conferred a novel sensitivity to doxorubicin (DOX) chemotherapy upon the recurrent tumors. This was exploited in vivo using combination therapies to cure mice, which would otherwise have relapsed, after suboptimal primary therapy in both models. Our data show that recurrent tumors-across histologies and primary treatments-express distinct antigens compared with the primary tumor which can be identified using the VSV-cDNA library technology. These results suggest that it may be possible to design a few common second-line therapies against a variety of tumor recurrences, in some cases using agents with no obvious activity against the primary tumor.

19 Article Measles virus causes immunogenic cell death in human melanoma. 2013

Donnelly, O G / Errington-Mais, F / Steele, L / Hadac, E / Jennings, V / Scott, K / Peach, H / Phillips, R M / Bond, J / Pandha, H / Harrington, K / Vile, R / Russell, S / Selby, P / Melcher, A A. ·Leeds Institute for Molecular Medicine, University of Leeds, Leeds, UK. ·Gene Ther · Pubmed #22170342.

ABSTRACT: Oncolytic viruses (OV) are promising treatments for cancer, with several currently undergoing testing in randomised clinical trials. Measles virus (MV) has not yet been tested in models of human melanoma. This study demonstrates the efficacy of MV against human melanoma. It is increasingly recognised that an essential component of therapy with OV is the recruitment of host antitumour immune responses, both innate and adaptive. MV-mediated melanoma cell death is an inflammatory process, causing the release of inflammatory cytokines including type-1 interferons and the potent danger signal HMGB1. Here, using human in vitro models, we demonstrate that MV enhances innate antitumour activity, and that MV-mediated melanoma cell death is capable of stimulating a melanoma-specific adaptive immune response.

20 Article Systemic combination virotherapy for melanoma with tumor antigen-expressing vesicular stomatitis virus and adoptive T-cell transfer. 2012

Rommelfanger, Diana M / Wongthida, Phonphimon / Diaz, Rosa M / Kaluza, Karen M / Thompson, Jill M / Kottke, Timothy J / Vile, Richard G. ·Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA. ·Cancer Res · Pubmed #22836753.

ABSTRACT: Oncolytic virotherapy offers the potential to treat tumors both as a single agent and in combination with traditional modalities such as chemotherapy and radiotherapy. Here we describe an effective, fully systemic treatment regimen, which combines virotherapy, acting essentially as an adjuvant immunotherapy, with adoptive cell transfer (ACT). The combination of ACT with systemic administration of a vesicular stomatitis virus (VSV) engineered to express the endogenous melanocyte antigen glycoprotein 100 (gp100) resulted in regression of established melanomas and generation of antitumor immunity. Tumor response was associated with in vivo T-cell persistence and activation as well as treatment-related vitiligo. However, in a proportion of treated mice, initial tumor regressions were followed by recurrences. Therapy was further enhanced by targeting an additional tumor antigen with the VSV-antigen + ACT combination strategy, leading to sustained response in 100% of mice. Together, our findings suggest that systemic virotherapy combined with antigen-expressing VSV could be used to support and enhance clinical immunotherapy protocols with adoptive T-cell transfer, which are already used in the clinic.

21 Article A factor found in the IgG fraction of serum of patients with paraneoplastic bilateral diffuse uveal melanocytic proliferation causes proliferation of cultured human melanocytes. 2012

Miles, Sarah L / Niles, Richard M / Pittock, Sean / Vile, Richard / Davies, John / Winters, Jeffrey L / Abu-Yaghi, Nakhleh E / Grothey, Axel / Siddiqui, Mustaqeem / Kaur, Judith / Hartmann, Lynn / Kalli, Kimberly R / Pease, Larry / Kravitz, Daniel / Markovic, Svetomir / Pulido, Jose S. ·Department of Biochemistry and Microbiology, Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia, USA. ·Retina · Pubmed #22791177.

ABSTRACT: PURPOSE: To determine if there is a factor in the serum of patients with bilateral diffuse uveal melanocytic proliferation (BDUMP) that causes melanocytic proliferation. METHODS: Human melanocytes and melanoma cells were grown and exposed to serum or plasma of patients with BDUMP, other neoplastic conditions, or control media. Preliminary studies using serum were conducted in an unmasked fashion. In addition, IgG-depleted and IgG-enriched plasma was also tested in a similar fashion. Experiments using plasma were conducted triple masked. To show that the proliferation was melanocyte selective, human dermal fibroblasts, keratinocytes, and ovarian cancer cells were treated with plasma of the BDUMP cases or controls, and the effect of this exposure on their proliferation was quantified. RESULTS: At 72 hours, the serum of BDUMP patients caused statistically significant increased proliferation of normal human melanocytes. Further studies at 6 days demonstrated similar findings. In addition, melanocytes grown in BDUMP serum exhibited a disorganized morphology with foci of multilayered cells. Cultured melanoma cells also showed statistically significant increase in growth in serum from BDUMP patients compared with controls. Masked plasma studies further confirmed these findings and showed that the IgG fraction appeared to contain the melanocyte growth-stimulating factor. The human fibroblasts, keratinocytes, and ovarian cancer cells did not show an increase in growth with the BDUMP plasma treatment. CONCLUSION: Patients with BDUMP have a factor in the IgG fraction that selectively causes melanocyte proliferation. How it causes proliferation of human melanocytes and melanoma cells needs to be further elucidated.

22 Article Adoptive transfer of cytotoxic T lymphocytes targeting two different antigens limits antigen loss and tumor escape. 2012

Kaluza, Karen M / Kottke, Timothy / Diaz, Rosa Maria / Rommelfanger, Diana / Thompson, Jill / Vile, Richard. ·Department of Immunology, Mayo Clinic, Rochester, MN 55905, USA. ·Hum Gene Ther · Pubmed #22734672.

ABSTRACT: An antitumor T-cell response can lead to tumor control without clearing all tumor cells. As long as residual tumor cells remain, there is a constant risk of escape from that T-cell response. We previously showed that adoptive transfer of anti-ova OT-I T cells into B16ova-bearing mice led to tumor regression followed by escape of tumors that had lost the ova gene, rendering the OT-I T cells ineffective. In this study, we hypothesized that simultaneous transfer of cytotoxic T lymphocytes targeted against two independent antigens would reduce selection for single-antigen-loss cells, thereby limiting tumor escape. Using OT-I and Pmel T cells to treat B16ova tumors, we found that early cotransfer could prevent tumor emergence in most mice, whereas neither T-cell specificity alone was able to do so. When combined with total body irradiation for the treatment of larger 7-day tumors, cotransfer was also better at limiting tumor recurrence, and the tumors that did escape combination therapy continued to express both target antigens. As adoptively transferred T cells also persisted in vivo, even in mice with recurrent tumors, we hypothesized that restimulation of these antitumor T cells would prolong survival of mice with recurrent tumors. Consistent with this hypothesis, administration of a low-dose regimen of cyclophosphamide following tumor escape slowed tumor growth in mice that had previously received T-cell therapy, but not in control-treated mice, an effect that was associated with increased activation of T cells in vitro by low- but not high-dose cyclophosphamide.

23 Article Reovirus-associated reduction of microRNA-let-7d is related to the increased apoptotic death of cancer cells in clinical samples. 2012

Nuovo, Gerard J / Garofalo, Michela / Valeri, Nicola / Roulstone, Vicki / Volinia, Stefano / Cohn, David E / Phelps, Mitch / Harrington, Kevin J / Vile, Richard / Melcher, Alan / Galanis, Evanthia / Sehl, Sarah / Adair, Rob / Scott, Karen / Rose, Ailsa / Toogood, Giles / Coffey, Matthew C. ·The Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA. gnuovomd@pol.net ·Mod Pathol · Pubmed #22699519.

ABSTRACT: We analyzed the in situ molecular correlates of infection from cancer patients treated with reovirus. Melanoma, colorectal, and ovarian cancer samples from such patients showed variable infection of the cancer cells but not the intermingled benign cells. RT in situ PCR showed most cancer cells contained the viral genome with threefold less having productive viral infection as documented by either tubulin or reoviral protein co-expression. Productive infection in the cancer cells was strongly correlated with co-expression of p38 and caspase-3 as well as apoptosis-related death (P<0.001). The cancer cell apoptotic death was due to a marked viral-induced inhibition of microRNA-let-7d that, in turn, upregulated caspase-3 activity. In summary, reovirus shows a striking tropism to cancer cells in clinical samples. A rate-limiting factor of reovirus-induced cancer cell death is productive viral infection that operates via the marked reduction of microRNA-let-7d and concomitant elevated caspase-3 expression.

24 Article Using virally expressed melanoma cDNA libraries to identify tumor-associated antigens that cure melanoma. 2012

Pulido, Jose / Kottke, Timothy / Thompson, Jill / Galivo, Feorillo / Wongthida, Phonphimon / Diaz, Rosa Maria / Rommelfanger, Diana / Ilett, Elizabeth / Pease, Larry / Pandha, Hardev / Harrington, Kevin / Selby, Peter / Melcher, Alan / Vile, Richard. ·Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA. ·Nat Biotechnol · Pubmed #22426030.

ABSTRACT: Multiple intravenous injections of a cDNA library, derived from human melanoma cell lines and expressed using the highly immunogenic vector vesicular stomatitis virus (VSV), cured mice with established melanoma tumors. Successful tumor eradication was associated with the ability of mouse lymphoid cells to mount a tumor-specific CD4(+) interleukin (IL)-17 recall response in vitro. We used this characteristic IL-17 response to screen the VSV-cDNA library and identified three different VSV-cDNA virus clones that, when used in combination but not alone, achieved the same efficacy against tumors as the complete parental virus library. VSV-expressed cDNA libraries can therefore be used to identify tumor rejection antigens that can cooperate to induce anti-tumor responses. This technology should be applicable to antigen discovery for other cancers, as well as for other diseases in which immune reactivity against more than one target antigen contributes to disease pathology.

25 Article Histological findings of birdshot chorioretinopathy in an eye with ciliochoroidal melanoma. 2012

Pulido, J S / Canal, I / Salomão, D / Kravitz, D / Bradley, E / Vile, R. ·Department of Ophthalmology, Mayo Clinic, Rochester, MN 55902, USA. pulido.jose@mayo.edu ·Eye (Lond) · Pubmed #22402699.

ABSTRACT: PURPOSE: To describe the histological findings of birdshot chorioretinopathy. DESIGN/PARTICIPANT: This is a case study of a single patient who has both birdshot chorioretinopathy and ciliochoroidal melanoma. METHODS: A 55-year-old woman who was HLA-A29 positive and had birdshot chorioretinopathy had a large ciliochoroidal melanoma (T4b N0 M0) and underwent enucleation. OUTCOME MEASURES: Using histopathology, we hope to further define the pathological findings in an eye with both birdshot chorioretinopathy and coexistant ciliochoroidal melanomas. RESULTS: The eye showed a ciliochoroidal melanoma. In addition, elsewhere, there were multiple choroidal nodules of lymphocytes that showed the presence of CD3-positive cells, which also stained for CD4 or CD8. There were only a few CD20-positive B cells and rare CD68-positive histiocytes. No granulomas were present. DISCUSSION: To our knowledge, there are only two previous reports describing the histological findings in birdshot chorioretinopathy: one that was HLA-A29 negative showing choroidal granulomas and another that was HLA-A29 positive exhibiting histological findings similar to our case. Incidentally, the latter case had a history of cutaneous melanoma. CONCLUSION: Birdshot chorioretinopathy is a nongranulomatous nodular infiltration of the choroid.

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