PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-25 (54)
 

Clipboard (0)
None

Select a Filter Below

Year of Publication
more »
1.  Phase I/II Trial of Carboplatin and Paclitaxel Chemotherapy in Combination with Intravenous Oncolytic Reovirus in Patients with Advanced Malignancies 
Purpose
Reovirus type 3 Dearing (RT3D) replicates preferentially in Ras-activated cancers. RT3D shows synergistic in vitro cytotoxicity in combination with platins and taxanes. The purpose of this phase I/II study was to assess RT3D combined with carboplatin/paclitaxel in patients with advanced cancers.
Experimental Design
Patients were initially treated in a dose-escalating, phase I trial with intravenous RT3D days 1 to 5, carboplatin [area under curve (AUC) 5, day 1] and paclitaxel (175 mg/m2, day 1) 3-weekly. RT3D was escalated through three dose levels: 3 × 109, 1 × 1010, and 3 × 1010 TCID50 in cohorts of three. Primary endpoints were to define the maximum tolerated dose and dose-limiting toxicity and to recommend a dose for phase II studies. Secondary endpoints included pharmacokinetics, immune response, and antitumor activity. A subsequent phase II study using the 3 × 1010 TCID50 dose characterized the response rate in patients with head and neck cancer.
Results
Thirty-one heavily pretreated patients received study therapy. There were no dose-limiting toxicities during dose-escalation and most toxicities were grade I/II. Overall effectiveness rates were as follows: one patient had a complete response (3.8%), six patients (23.1%) had partial response, two patients (7.6%) had major clinical responses clinically evaluated in radiation pretreated lesions which are not evaluable by Response Evaluation Criteria in Solid Tumors (RECIST), nine patients (34.6%) had stable disease, and eight patients (30.8%) had disease progression. Viral shedding was minimal and antiviral immune responses were attenuated compared with previous single-agent data for RT3D.
Conclusions
The combination of RT3D plus carboplatin/paclitaxel is well tolerated with evidence of activity in cancer of the head and neck. A randomized phase III study is currently open for recruitment.
doi:10.1158/1078-0432.CCR-11-2181
PMCID: PMC5553618  PMID: 22316603
3.  Oncolytic Herpes Simplex Virus Inhibits Pediatric Brain Tumor Migration and Invasion 
Pediatric high-grade glioma (pHGG) and diffuse intrinsic pontine glioma (DIPG) are invasive tumors with poor survival. Oncolytic virotherapy, initially devised as a direct cytotoxic treatment, is now also known to act via immune-mediated mechanisms. Here we investigate a previously unreported mechanism of action: the inhibition of migration and invasion in pediatric brain tumors. We evaluated the effect of oncolytic herpes simplex virus 1716 (HSV1716) on the migration and invasion of pHGG and DIPG both in vitro using 2D (scratch assay, live cell imaging) and 3D (spheroid invasion in collagen) assays and in vivo using an orthotopic xenograft model of DIPG invasion. HSV1716 inhibited migration and invasion in pHGG and DIPG cell lines. pHGG cells demonstrated reduced velocity and changed morphology in the presence of virus. HSV1716 altered pHGG cytoskeletal dynamics by stabilizing microtubules, inhibiting glycogen synthase kinase-3, and preventing localized clustering of adenomatous polyposis coli (APC) to the leading edge of cells. HSV1716 treatment also reduced tumor infiltration in a mouse orthotopic xenograft DIPG model. Our results demonstrate that HSV1716 targets the migration and invasion of pHGG and DIPG and indicates the potential of an oncolytic virus (OV) to be used as a novel anti-invasive treatment strategy for pediatric brain tumors.
doi:10.1016/j.omto.2017.04.002
PMCID: PMC5435599
oncolytic virus paediatric brain tumor invasion migration
4.  Prime-boost using Separate Oncolytic Viruses in Combination with Checkpoint Blockade Improves Anti-tumor Therapy 
Gene therapy  2016;24(1):21-30.
The anti-tumor effects associated with oncolytic virus therapy are mediated significantly through immune-mediated mechanisms which depends both on the type of virus and the route of delivery. Here, we show that intra-tumoral (i.t.) oncolysis by Reovirus induced the priming of a CD8+, Th1-type anti-tumor response. In contrast, systemically delivered VSV expressing a cDNA library of melanoma antigens (VSV-ASMEL) promoted a potent anti-tumor 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-tumor activity. Consistent with this, priming with i.t. Reovirus, followed by an intra-venous VSV-ASMEL Th17 boost, significantly improved survival of mice bearing established subcutaneous (s.c.) B16 melanoma tumors. 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-tumor 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 tumor antigens. Our data show that it is possible to generate fully systemic, highly effective anti-tumor immunovirotherapy by combining oncolytic viruses, along with immune checkpoint blockade, to induce complimentary mechanisms of anti-tumor immune responses.
doi:10.1038/gt.2016.70
PMCID: PMC5387692  PMID: 27779616
5.  Combination viroimmunotherapy with checkpoint inhibition to treat glioma, based on location-specific tumor profiling 
Neuro-Oncology  2015;18(4):518-527.
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-2αHi 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.
doi:10.1093/neuonc/nov173
PMCID: PMC4799678  PMID: 26409567
cancer immunotherapy; checkpoint inhibitor; glioma; oncolytic virus; vesicular stomatitis virus
6.  Immunogenicity of self tumor associated proteins is enhanced through protein truncation 
We showed previously that therapy with Vesicular Stomatitis Virus (VSV) expressing tumor-associated proteins eradicates established tumors. We show here that when cellular cDNA were cloned into VSV which retained their own poly-A signal, viral species emerged in culture which had deleted the cellular poly-A signal and also contained a truncated form of the protein coding sequence. Typically, the truncation occurred such that a Tyrosine-encoding codon was converted into a STOP codon. We believe that the truncation of tumor-associated proteins expressed from VSV in this way occurred to preserve the ability of the virus to replicate efficiently. Truncated cDNA expressed from VSV were significantly more effective than full length cDNA in treating established tumors. Moreover, tumor therapy with truncated cDNA was completely abolished by depletion of CD4+ T cells, whereas therapy with full length cDNA was CD8+ T cell dependent. These data show that the type/potency of antitumor immune responses against self-tumor-associated proteins can be manipulated in vivo through the nature of the self protein (full length or truncated). Therefore, in addition to generation of neoantigens through sequence mutation, immunological tolerance against self-tumor-associated proteins can be broken through manipulation of protein integrity, allowing for rational design of better self-immunogens for cancer immunotherapy.
doi:10.1038/mto.2016.30
PMCID: PMC5142466  PMID: 27933315
7.  31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016): part two 
Ager, Casey | Reilley, Matthew | Nicholas, Courtney | Bartkowiak, Todd | Jaiswal, Ashvin | Curran, Michael | Albershardt, Tina C. | Bajaj, Anshika | Archer, Jacob F. | Reeves, Rebecca S. | Ngo, Lisa Y. | Berglund, Peter | ter Meulen, Jan | Denis, Caroline | Ghadially, Hormas | Arnoux, Thomas | Chanuc, Fabien | Fuseri, Nicolas | Wilkinson, Robert W. | Wagtmann, Nicolai | Morel, Yannis | Andre, Pascale | Atkins, Michael B. | Carlino, Matteo S. | Ribas, Antoni | Thompson, John A. | Choueiri, Toni K. | Hodi, F. Stephen | Hwu, Wen-Jen | McDermott, David F. | Atkinson, Victoria | Cebon, Jonathan S. | Fitzharris, Bernie | Jameson, Michael B. | McNeil, Catriona | Hill, Andrew G. | Mangin, Eric | Ahamadi, Malidi | van Vugt, Marianne | van Zutphen, Mariëlle | Ibrahim, Nageatte | Long, Georgina V. | Gartrell, Robyn | Blake, Zoe | Simoes, Ines | Fu, Yichun | Saito, Takuro | Qian, Yingzhi | Lu, Yan | Saenger, Yvonne M. | Budhu, Sadna | De Henau, Olivier | Zappasodi, Roberta | Schlunegger, Kyle | Freimark, Bruce | Hutchins, Jeff | Barker, Christopher A. | Wolchok, Jedd D. | Merghoub, Taha | Burova, Elena | Allbritton, Omaira | Hong, Peter | Dai, Jie | Pei, Jerry | Liu, Matt | Kantrowitz, Joel | Lai, Venus | Poueymirou, William | MacDonald, Douglas | Ioffe, Ella | Mohrs, Markus | Olson, William | Thurston, Gavin | Capasso, Cristian | Frascaro, Federica | Carpi, Sara | Tähtinen, Siri | Feola, Sara | Fusciello, Manlio | Peltonen, Karita | Martins, Beatriz | Sjöberg, Madeleine | Pesonen, Sari | Ranki, Tuuli | Kyruk, Lukasz | Ylösmäki, Erkko | Cerullo, Vincenzo | Cerignoli, Fabio | Xi, Biao | Guenther, Garret | Yu, Naichen | Muir, Lincoln | Zhao, Leyna | Abassi, Yama | Cervera-Carrascón, Víctor | Siurala, Mikko | Santos, João | Havunen, Riikka | Parviainen, Suvi | Hemminki, Akseli | Dalgleish, Angus | Mudan, Satvinder | DeBenedette, Mark | Plachco, Ana | Gamble, Alicia | Grogan, Elizabeth W. | Krisko, John | Tcherepanova, Irina | Nicolette, Charles | Dhupkar, Pooja | Yu, Ling | Kleinerman, Eugenie S. | Gordon, Nancy | Grenga, Italia | Lepone, Lauren | Gameiro, Sofia | Knudson, Karin M. | Fantini, Massimo | Tsang, Kwong | Hodge, James | Donahue, Renee | Schlom, Jeffrey | Evans, Elizabeth | Bussler, Holm | Mallow, Crystal | Reilly, Christine | Torno, Sebold | Scrivens, Maria | Foster, Cathie | Howell, Alan | Balch, Leslie | Knapp, Alyssa | Leonard, John E. | Paris, Mark | Fisher, Terry | Hu-Lieskovan, Siwen | Ribas, Antoni | Smith, Ernest | Zauderer, Maurice | Fogler, William | Franklin, Marilyn | Thayer, Matt | Saims, Dan | Magnani, John L. | Gong, Jian | Gray, Michael | Hutchins, Jeff | Freimark, Bruce | Fromm, George | de Silva, Suresh | Giffin, Louise | Xu, Xin | Rose, Jason | Schreiber, Taylor H. | Fantini, Massimo | Gameiro, Sofia R. | Knudson, Karin M. | Clavijo, Paul E. | Allen, Clint T. | Donahue, Renee | Lepone, Lauren | Grenga, Italia | Hodge, James W. | Tsang, Kwong Y. | Schlom, Jeffrey | Gray, Michael | Gong, Jian | Hutchins, Jeff | Freimark, Bruce | Grogan, Jane | Manieri, Nicholas | Chiang, Eugene | Caplazi, Patrick | Yadav, Mahesh | Hagner, Patrick | Chiu, Hsiling | Waldman, Michelle | Klippel, Anke | Thakurta, Anjan | Pourdehnad, Michael | Gandhi, Anita | Henrich, Ian | Quick, Laura | Young, Rob | Chou, Margaret | Hotson, Andrew | Willingham, Stephen | Ho, Po | Choy, Carmen | Laport, Ginna | McCaffery, Ian | Miller, Richard | Tipton, Kimberly A. | Wong, Kenneth R. | Singson, Victoria | Wong, Chihunt | Chan, Chanty | Huang, Yuanhiu | Liu, Shouchun | Richardson, Jennifer H. | Kavanaugh, W. Michael | West, James | Irving, Bryan A. | Tipton, Kimberly A. | Wong, Kenneth R. | Singson, Victoria | Wong, Chihunt | Chan, Chanty | Huang, Yuanhiu | Liu, Shouchun | Richardson, Jennifer H. | Kavanaugh, W. Michael | West, James | Irving, Bryan A. | Jaini, Ritika | Loya, Matthew | Eng, Charis | Johnson, Melissa L. | Adjei, Alex A. | Opyrchal, Mateusz | Ramalingam, Suresh | Janne, Pasi A. | Dominguez, George | Gabrilovich, Dmitry | de Leon, Laura | Hasapidis, Jeannette | Diede, Scott J. | Ordentlich, Peter | Cruickshank, Scott | Meyers, Michael L. | Hellmann, Matthew D. | Kalinski, Pawel | Zureikat, Amer | Edwards, Robert | Muthuswamy, Ravi | Obermajer, Nataša | Urban, Julie | Butterfield, Lisa H. | Gooding, William | Zeh, Herbert | Bartlett, David | Zubkova, Olga | Agapova, Larissa | Kapralova, Marina | Krasovskaia, Liudmila | Ovsepyan, Armen | Lykov, Maxim | Eremeev, Artem | Bokovanov, Vladimir | Grigoryeva, Olga | Karpov, Andrey | Ruchko, Sergey | Nicolette, Charles | Shuster, Alexandr | Khalil, Danny N. | Campesato, Luis Felipe | Li, Yanyun | Merghoub, Taha | Wolchok, Jedd D. | Lazorchak, Adam S. | Patterson, Troy D. | Ding, Yueyun | Sasikumar, Pottayil | Sudarshan, Naremaddepalli | Gowda, Nagaraj | Ramachandra, Raghuveer | Samiulla, Dodheri | Giri, Sanjeev | Eswarappa, Rajesh | Ramachandra, Murali | Tuck, David | Wyant, Timothy | Leshem, Jasmin | Liu, Xiu-fen | Bera, Tapan | Terabe, Masaki | Bossenmaier, Birgit | Niederfellner, Gerhard | Reiter, Yoram | Pastan, Ira | Xia, Leiming | Xia, Yang | Hu, Yangyang | Wang, Yi | Bao, Yangyi | Dai, Fu | Huang, Shiang | Hurt, Elaine | Hollingsworth, Robert E. | Lum, Lawrence G. | Chang, Alfred E. | Wicha, Max S. | Li, Qiao | Mace, Thomas | Makhijani, Neil | Talbert, Erin | Young, Gregory | Guttridge, Denis | Conwell, Darwin | Lesinski, Gregory B. | Gonzales, Rodney JM Macedo | Huffman, Austin P. | Wang, Ximi K. | Reshef, Ran | MacKinnon, Andy | Chen, Jason | Gross, Matt | Marguier, Gisele | Shwonek, Peter | Sotirovska, Natalija | Steggerda, Susanne | Parlati, Francesco | Makkouk, Amani | Bennett, Mark K. | Chen, Jason | Emberley, Ethan | Gross, Matt | Huang, Tony | Li, Weiqun | MacKinnon, Andy | Marguier, Gisele | Neou, Silinda | Pan, Alison | Zhang, Jing | Zhang, Winter | Parlati, Francesco | Marshall, Netonia | Marron, Thomas U. | Agudo, Judith | Brown, Brian | Brody, Joshua | McQuinn, Christopher | Mace, Thomas | Farren, Matthew | Komar, Hannah | Shakya, Reena | Young, Gregory | Ludwug, Thomas | Lesinski, Gregory B. | Morillon, Y. Maurice | Hammond, Scott A. | Schlom, Jeffrey | Greiner, John W. | Nath, Pulak R. | Schwartz, Anthony L. | Maric, Dragan | Roberts, David D. | Obermajer, Nataša | Bartlett, David | Kalinski, Pawel | Naing, Aung | Papadopoulos, Kyriakos P. | Autio, Karen A. | Wong, Deborah J. | Patel, Manish | Falchook, Gerald | Pant, Shubham | Ott, Patrick A. | Whiteside, Melinda | Patnaik, Amita | Mumm, John | Janku, Filip | Chan, Ivan | Bauer, Todd | Colen, Rivka | VanVlasselaer, Peter | Brown, Gail L. | Tannir, Nizar M. | Oft, Martin | Infante, Jeffrey | Lipson, Evan | Gopal, Ajay | Neelapu, Sattva S. | Armand, Philippe | Spurgeon, Stephen | Leonard, John P. | Hodi, F. Stephen | Sanborn, Rachel E. | Melero, Ignacio | Gajewski, Thomas F. | Maurer, Matthew | Perna, Serena | Gutierrez, Andres A. | Clynes, Raphael | Mitra, Priyam | Suryawanshi, Satyendra | Gladstone, Douglas | Callahan, Margaret K. | Crooks, James | Brown, Sheila | Gauthier, Audrey | de Boisferon, Marc Hillairet | MacDonald, Andrew | Brunet, Laura Rosa | Rothwell, William T. | Bell, Peter | Wilson, James M. | Sato-Kaneko, Fumi | Yao, Shiyin | Zhang, Shannon S. | Carson, Dennis A. | Guiducci, Cristina | Coffman, Robert L. | Kitaura, Kazutaka | Matsutani, Takaji | Suzuki, Ryuji | Hayashi, Tomoko | Cohen, Ezra E. W. | Schaer, David | Li, Yanxia | Dobkin, Julie | Amatulli, Michael | Hall, Gerald | Doman, Thompson | Manro, Jason | Dorsey, Frank Charles | Sams, Lillian | Holmgaard, Rikke | Persaud, Krishnadatt | Ludwig, Dale | Surguladze, David | Kauh, John S. | Novosiadly, Ruslan | Kalos, Michael | Driscoll, Kyla | Pandha, Hardev | Ralph, Christy | Harrington, Kevin | Curti, Brendan | Sanborn, Rachel E. | Akerley, Wallace | Gupta, Sumati | Melcher, Alan | Mansfield, David | Kaufman, David R. | Schmidt, Emmett | Grose, Mark | Davies, Bronwyn | Karpathy, Roberta | Shafren, Darren | Shamalov, Katerina | Cohen, Cyrille | Sharma, Naveen | Allison, James | Shekarian, Tala | Valsesia-Wittmann, Sandrine | Caux, Christophe | Marabelle, Aurelien | Slomovitz, Brian M. | Moore, Kathleen M. | Youssoufian, Hagop | Posner, Marshall | Tewary, Poonam | Brooks, Alan D. | Xu, Ya-Ming | Wijeratne, Kithsiri | Gunatilaka, Leslie A. A. | Sayers, Thomas J. | Vasilakos, John P. | Alston, Tesha | Dovedi, Simon | Elvecrog, James | Grigsby, Iwen | Herbst, Ronald | Johnson, Karen | Moeckly, Craig | Mullins, Stefanie | Siebenaler, Kristen | SternJohn, Julius | Tilahun, Ashenafi | Tomai, Mark A. | Vogel, Katharina | Wilkinson, Robert W. | Vietsch, Eveline E. | Wellstein, Anton | Wythes, Martin | Crosignani, Stefano | Tumang, Joseph | Alekar, Shilpa | Bingham, Patrick | Cauwenberghs, Sandra | Chaplin, Jenny | Dalvie, Deepak | Denies, Sofie | De Maeseneire, Coraline | Feng, JunLi | Frederix, Kim | Greasley, Samantha | Guo, Jie | Hardwick, James | Kaiser, Stephen | Jessen, Katti | Kindt, Erick | Letellier, Marie-Claire | Li, Wenlin | Maegley, Karen | Marillier, Reece | Miller, Nichol | Murray, Brion | Pirson, Romain | Preillon, Julie | Rabolli, Virginie | Ray, Chad | Ryan, Kevin | Scales, Stephanie | Srirangam, Jay | Solowiej, Jim | Stewart, Al | Streiner, Nicole | Torti, Vince | Tsaparikos, Konstantinos | Zheng, Xianxian | Driessens, Gregory | Gomes, Bruno | Kraus, Manfred | Xu, Chunxiao | Zhang, Yanping | Kradjian, Giorgio | Qin, Guozhong | Qi, Jin | Xu, Xiaomei | Marelli, Bo | Yu, Huakui | Guzman, Wilson | Tighe, Rober | Salazar, Rachel | Lo, Kin-Ming | English, Jessie | Radvanyi, Laszlo | Lan, Yan | Zappasodi, Roberta | Budhu, Sadna | Hellmann, Matthew D. | Postow, Michael | Senbabaoglu, Yasin | Gasmi, Billel | Zhong, Hong | Li, Yanyun | Liu, Cailian | Hirschhorhn-Cymerman, Daniel | Wolchok, Jedd D. | Merghoub, Taha | Zha, Yuanyuan | Malnassy, Gregory | Fulton, Noreen | Park, Jae-Hyun | Stock, Wendy | Nakamura, Yusuke | Gajewski, Thomas F. | Liu, Hongtao | Ju, Xiaoming | Kosoff, Rachelle | Ramos, Kimberly | Coder, Brandon | Petit, Robert | Princiotta, Michael | Perry, Kyle | Zou, Jun | Arina, Ainhoa | Fernandez, Christian | Zheng, Wenxin | Beckett, Michael A. | Mauceri, Helena J. | Fu, Yang-Xin | Weichselbaum, Ralph R. | DeBenedette, Mark | Lewis, Whitney | Gamble, Alicia | Nicolette, Charles | Han, Yanyan | Wu, Yeting | Yang, Chou | Huang, Jing | Wu, Dongyun | Li, Jin | Liang, Xiaoling | Zhou, Xiangjun | Hou, Jinlin | Hassan, Raffit | Jahan, Thierry | Antonia, Scott J. | Kindler, Hedy L. | Alley, Evan W. | Honarmand, Somayeh | Liu, Weiqun | Leong, Meredith L. | Whiting, Chan C. | Nair, Nitya | Enstrom, Amanda | Lemmens, Edward E. | Tsujikawa, Takahiro | Kumar, Sushil | Coussens, Lisa M. | Murphy, Aimee L. | Brockstedt, Dirk G. | Koch, Sven D. | Sebastian, Martin | Weiss, Christian | Früh, Martin | Pless, Miklos | Cathomas, Richard | Hilbe, Wolfgang | Pall, Georg | Wehler, Thomas | Alt, Jürgen | Bischoff, Helge | Geissler, Michael | Griesinger, Frank | Kollmeier, Jens | Papachristofilou, Alexandros | Doener, Fatma | Fotin-Mleczek, Mariola | Hipp, Madeleine | Hong, Henoch S. | Kallen, Karl-Josef | Klinkhardt, Ute | Stosnach, Claudia | Scheel, Birgit | Schroeder, Andreas | Seibel, Tobias | Gnad-Vogt, Ulrike | Zippelius, Alfred | Park, Ha-Ram | Ahn, Yong-Oon | Kim, Tae Min | Kim, Soyeon | Kim, Seulki | Lee, Yu Soo | Keam, Bhumsuk | Kim, Dong-Wan | Heo, Dae Seog | Pilon-Thomas, Shari | Weber, Amy | Morse, Jennifer | Kodumudi, Krithika | Liu, Hao | Mullinax, John | Sarnaik, Amod A. | Pike, Luke | Bang, Andrew | Ott, Patrick A. | Balboni, Tracy | Taylor, Allison | Spektor, Alexander | Wilhite, Tyler | Krishnan, Monica | Cagney, Daniel | Alexander, Brian | Aizer, Ayal | Buchbinder, Elizabeth | Awad, Mark | Ghandi, Leena | Hodi, F. Stephen | Schoenfeld, Jonathan | Schwartz, Anthony L. | Nath, Pulak R. | Lessey-Morillon, Elizabeth | Ridnour, Lisa | Roberts, David D. | Segal, Neil H. | Sharma, Manish | Le, Dung T. | Ott, Patrick A. | Ferris, Robert L. | Zelenetz, Andrew D. | Neelapu, Sattva S. | Levy, Ronald | Lossos, Izidore S. | Jacobson, Caron | Ramchandren, Radhakrishnan | Godwin, John | Colevas, A. Dimitrios | Meier, Roland | Krishnan, Suba | Gu, Xuemin | Neely, Jaclyn | Suryawanshi, Satyendra | Timmerman, John | Vanpouille-Box, Claire I. | Formenti, Silvia C. | Demaria, Sandra | Wennerberg, Erik | Mediero, Aranzazu | Cronstein, Bruce N. | Formenti, Silvia C. | Demaria, Sandra | Gustafson, Michael P. | DiCostanzo, AriCeli | Wheatley, Courtney | Kim, Chul-Ho | Bornschlegl, Svetlana | Gastineau, Dennis A. | Johnson, Bruce D. | Dietz, Allan B. | MacDonald, Cameron | Bucsek, Mark | Qiao, Guanxi | Hylander, Bonnie | Repasky, Elizabeth | Turbitt, William J. | Xu, Yitong | Mastro, Andrea | Rogers, Connie J. | Withers, Sita | Wang, Ziming | Khuat, Lam T. | Dunai, Cordelia | Blazar, Bruce R. | Longo, Dan | Rebhun, Robert | Grossenbacher, Steven K. | Monjazeb, Arta | Murphy, William J. | Rowlinson, Scott | Agnello, Giulia | Alters, Susan | Lowe, David | Scharping, Nicole | Menk, Ashley V. | Whetstone, Ryan | Zeng, Xue | Delgoffe, Greg M. | Santos, Patricia M. | Menk, Ashley V. | Shi, Jian | Delgoffe, Greg M. | Butterfield, Lisa H. | Whetstone, Ryan | Menk, Ashley V. | Scharping, Nicole | Delgoffe, Greg | Nagasaka, Misako | Sukari, Ammar | Byrne-Steele, Miranda | Pan, Wenjing | Hou, Xiaohong | Brown, Brittany | Eisenhower, Mary | Han, Jian | Collins, Natalie | Manguso, Robert | Pope, Hans | Shrestha, Yashaswi | Boehm, Jesse | Haining, W. Nicholas | Cron, Kyle R. | Sivan, Ayelet | Aquino-Michaels, Keston | Gajewski, Thomas F. | Orecchioni, Marco | Bedognetti, Davide | Hendrickx, Wouter | Fuoco, Claudia | Spada, Filomena | Sgarrella, Francesco | Cesareni, Gianni | Marincola, Francesco | Kostarelos, Kostas | Bianco, Alberto | Delogu, Lucia | Hendrickx, Wouter | Roelands, Jessica | Boughorbel, Sabri | Decock, Julie | Presnell, Scott | Wang, Ena | Marincola, Franco M. | Kuppen, Peter | Ceccarelli, Michele | Rinchai, Darawan | Chaussabel, Damien | Miller, Lance | Bedognetti, Davide | Nguyen, Andrew | Sanborn, J. Zachary | Vaske, Charles | Rabizadeh, Shahrooz | Niazi, Kayvan | Benz, Steven | Patel, Shashank | Restifo, Nicholas | White, James | Angiuoli, Sam | Sausen, Mark | Jones, Sian | Sevdali, Maria | Simmons, John | Velculescu, Victor | Diaz, Luis | Zhang, Theresa | Sims, Jennifer S. | Barton, Sunjay M. | Gartrell, Robyn | Kadenhe-Chiweshe, Angela | Dela Cruz, Filemon | Turk, Andrew T. | Lu, Yan | Mazzeo, Christopher F. | Kung, Andrew L. | Bruce, Jeffrey N. | Saenger, Yvonne M. | Yamashiro, Darrell J. | Connolly, Eileen P. | Baird, Jason | Crittenden, Marka | Friedman, David | Xiao, Hong | Leidner, Rom | Bell, Bryan | Young, Kristina | Gough, Michael | Bian, Zhen | Kidder, Koby | Liu, Yuan | Curran, Emily | Chen, Xiufen | Corrales, Leticia P. | Kline, Justin | Dunai, Cordelia | Aguilar, Ethan G. | Khuat, Lam T. | Murphy, William J. | Guerriero, Jennifer | Sotayo, Alaba | Ponichtera, Holly | Pourzia, Alexandra | Schad, Sara | Carrasco, Ruben | Lazo, Suzan | Bronson, Roderick | Letai, Anthony | Kornbluth, Richard S. | Gupta, Sachin | Termini, James | Guirado, Elizabeth | Stone, Geoffrey W. | Meyer, Christina | Helming, Laura | Tumang, Joseph | Wilson, Nicholas | Hofmeister, Robert | Radvanyi, Laszlo | Neubert, Natalie J. | Tillé, Laure | Barras, David | Soneson, Charlotte | Baumgaertner, Petra | Rimoldi, Donata | Gfeller, David | Delorenzi, Mauro | Fuertes Marraco, Silvia A. | Speiser, Daniel E. | Abraham, Tara S. | Xiang, Bo | Magee, Michael S. | Waldman, Scott A. | Snook, Adam E. | Blogowski, Wojciech | Zuba-Surma, Ewa | Budkowska, Marta | Salata, Daria | Dolegowska, Barbara | Starzynska, Teresa | Chan, Leo | Somanchi, Srinivas | McCulley, Kelsey | Lee, Dean | Buettner, Nico | Shi, Feng | Myers, Paisley T. | Curbishley, Stuart | Penny, Sarah A. | Steadman, Lora | Millar, David | Speers, Ellen | Ruth, Nicola | Wong, Gabriel | Thimme, Robert | Adams, David | Cobbold, Mark | Thomas, Remy | Hendrickx, Wouter | Al-Muftah, Mariam | Decock, Julie | Wong, Michael KK | Morse, Michael | McDermott, David F. | Clark, Joseph I. | Kaufman, Howard L. | Daniels, Gregory A. | Hua, Hong | Rao, Tharak | Dutcher, Janice P. | Kang, Kai | Saunthararajah, Yogen | Velcheti, Vamsidhar | Kumar, Vikas | Anwar, Firoz | Verma, Amita | Chheda, Zinal | Kohanbash, Gary | Sidney, John | Okada, Kaori | Shrivastav, Shruti | Carrera, Diego A. | Liu, Shuming | Jahan, Naznin | Mueller, Sabine | Pollack, Ian F. | Carcaboso, Angel M. | Sette, Alessandro | Hou, Yafei | Okada, Hideho | Field, Jessica J. | Zeng, Weiping | Shih, Vincent FS | Law, Che-Leung | Senter, Peter D. | Gardai, Shyra J. | Okeley, Nicole M. | Penny, Sarah A. | Abelin, Jennifer G. | Saeed, Abu Z. | Malaker, Stacy A. | Myers, Paisley T. | Shabanowitz, Jeffrey | Ward, Stephen T. | Hunt, Donald F. | Cobbold, Mark | Profusek, Pam | Wood, Laura | Shepard, Dale | Grivas, Petros | Kapp, Kerstin | Volz, Barbara | Oswald, Detlef | Wittig, Burghardt | Schmidt, Manuel | Sefrin, Julian P. | Hillringhaus, Lars | Lifke, Valeria | Lifke, Alexander | Skaletskaya, Anna | Ponte, Jose | Chittenden, Thomas | Setiady, Yulius | Valsesia-Wittmann, Sandrine | Sivado, Eva | Thomas, Vincent | El Alaoui, Meddy | Papot, Sébastien | Dumontet, Charles | Dyson, Mike | McCafferty, John | El Alaoui, Said | Verma, Amita | Kumar, Vikas | Bommareddy, Praveen K. | Kaufman, Howard L. | Zloza, Andrew | Kohlhapp, Frederick | Silk, Ann W. | Jhawar, Sachin | Paneque, Tomas | Bommareddy, Praveen K. | Kohlhapp, Frederick | Newman, Jenna | Beltran, Pedro | Zloza, Andrew | Kaufman, Howard L. | Cao, Felicia | Hong, Bang-Xing | Rodriguez-Cruz, Tania | Song, Xiao-Tong | Gottschalk, Stephen | Calderon, Hugo | Illingworth, Sam | Brown, Alice | Fisher, Kerry | Seymour, Len | Champion, Brian | Eriksson, Emma | Wenthe, Jessica | Hellström, Ann-Charlotte | Paul-Wetterberg, Gabriella | Loskog, Angelica | Eriksson, Emma | Milenova, Ioanna | Wenthe, Jessica | Ståhle, Magnus | Jarblad-Leja, Justyna | Ullenhag, Gustav | Dimberg, Anna | Moreno, Rafael | Alemany, Ramon | Loskog, Angelica | Eriksson, Emma | Milenova, Ioanna | Moreno, Rafael | Alemany, Ramon
Journal for Immunotherapy of Cancer  2016;4(Suppl 1):107-221.
doi:10.1186/s40425-016-0173-6
PMCID: PMC5123381
8.  31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016): part one 
Lundqvist, Andreas | van Hoef, Vincent | Zhang, Xiaonan | Wennerberg, Erik | Lorent, Julie | Witt, Kristina | Sanz, Laia Masvidal | Liang, Shuo | Murray, Shannon | Larsson, Ola | Kiessling, Rolf | Mao, Yumeng | Sidhom, John-William | Bessell, Catherine A. | Havel, Jonathan | Schneck, Jonathan | Chan, Timothy A. | Sachsenmeier, Eliot | Woods, David | Berglund, Anders | Ramakrishnan, Rupal | Sodre, Andressa | Weber, Jeffrey | Zappasodi, Roberta | Li, Yanyun | Qi, Jingjing | Wong, Philip | Sirard, Cynthia | Postow, Michael | Newman, Walter | Koon, Henry | Velcheti, Vamsidhar | Callahan, Margaret K. | Wolchok, Jedd D. | Merghoub, Taha | Lum, Lawrence G. | Choi, Minsig | Thakur, Archana | Deol, Abhinav | Dyson, Gregory | Shields, Anthony | Haymaker, Cara | Uemura, Marc | Murthy, Ravi | James, Marihella | Wang, Daqing | Brevard, Julie | Monaghan, Catherine | Swann, Suzanne | Geib, James | Cornfeld, Mark | Chunduru, Srinivas | Agrawal, Sudhir | Yee, Cassian | Wargo, Jennifer | Patel, Sapna P. | Amaria, Rodabe | Tawbi, Hussein | Glitza, Isabella | Woodman, Scott | Hwu, Wen-Jen | Davies, Michael A. | Hwu, Patrick | Overwijk, Willem W. | Bernatchez, Chantale | Diab, Adi | Massarelli, Erminia | Segal, Neil H. | Ribrag, Vincent | Melero, Ignacio | Gangadhar, Tara C. | Urba, Walter | Schadendorf, Dirk | Ferris, Robert L. | Houot, Roch | Morschhauser, Franck | Logan, Theodore | Luke, Jason J. | Sharfman, William | Barlesi, Fabrice | Ott, Patrick A. | Mansi, Laura | Kummar, Shivaani | Salles, Gilles | Carpio, Cecilia | Meier, Roland | Krishnan, Suba | McDonald, Dan | Maurer, Matthew | Gu, Xuemin | Neely, Jaclyn | Suryawanshi, Satyendra | Levy, Ronald | Khushalani, Nikhil | Wu, Jennifer | Zhang, Jinyu | Basher, Fahmin | Rubinstein, Mark | Bucsek, Mark | Qiao, Guanxi | MacDonald, Cameron | Hylander, Bonnie | Repasky, Elizabeth | Chatterjee, Shilpak | Daenthanasanmak, Anusara | Chakraborty, Paramita | Toth, Kyle | Meek, Megan | Garrett-Mayer, Elizabeth | Nishimura, Michael | Paulos, Chrystal | Beeson, Craig | Yu, Xuezhong | Mehrotra, Shikhar | Zhao, Fei | Evans, Kathy | Xiao, Christine | Holtzhausen, Alisha | Hanks, Brent A. | Scharping, Nicole | Menk, Ashley V. | Moreci, Rebecca | Whetstone, Ryan | Dadey, Rebekah | Watkins, Simon | Ferris, Robert | Delgoffe, Greg M. | Peled, Jonathan | Devlin, Sean | Staffas, Anna | Lumish, Melissa | Rodriguez, Kori Porosnicu | Ahr, Katya | Perales, Miguel | Giralt, Sergio | Taur, Ying | Pamer, Eric | van den Brink, Marcel R. M. | Jenq, Robert | Annels, Nicola | Pandha, Hardev | Simpson, Guy | Mostafid, Hugh | Harrington, Kevin | Melcher, Alan | Grose, Mark | Davies, Bronwyn | Au, Gough | Karpathy, Roberta | Shafren, Darren | Ricca, Jacob | Merghoub, Taha | Wolchok, Jedd D. | Zamarin, Dmitriy | Batista, Luciana | Marliot, Florence | Vasaturo, Angela | Carpentier, Sabrina | Poggionovo, Cécile | Frayssinet, Véronique | Fieschi, Jacques | Van den Eynde, Marc | Pagès, Franck | Galon, Jérôme | Hermitte, Fabienne | Smith, Sean G. | Nguyen, Khue | Ravindranathan, Sruthi | Koppolu, Bhanu | Zaharoff, David | Schvartsman, Gustavo | Bassett, Roland | McQuade, Jennifer L. | Haydu, Lauren E. | Davies, Michael A. | Tawbi, Hussein | Glitza, Isabella | Kline, Douglas | Chen, Xiufen | Fosco, Dominick | Kline, Justin | Overacre, Abigail | Chikina, Maria | Brunazzi, Erin | Shayan, Gulidanna | Horne, William | Kolls, Jay | Ferris, Robert L. | Delgoffe, Greg M. | Bruno, Tullia C. | Workman, Creg | Vignali, Dario | Adusumilli, Prasad S. | Ansa-Addo, Ephraim A | Li, Zihai | Gerry, Andrew | Sanderson, Joseph P. | Howe, Karen | Docta, Roslin | Gao, Qian | Bagg, Eleanor A. L. | Tribble, Nicholas | Maroto, Miguel | Betts, Gareth | Bath, Natalie | Melchiori, Luca | Lowther, Daniel E. | Ramachandran, Indu | Kari, Gabor | Basu, Samik | Binder-Scholl, Gwendolyn | Chagin, Karen | Pandite, Lini | Holdich, Tom | Amado, Rafael | Zhang, Hua | Glod, John | Bernstein, Donna | Jakobsen, Bent | Mackall, Crystal | Wong, Ryan | Silk, Jonathan D. | Adams, Katherine | Hamilton, Garth | Bennett, Alan D. | Brett, Sara | Jing, Junping | Quattrini, Adriano | Saini, Manoj | Wiedermann, Guy | Gerry, Andrew | Jakobsen, Bent | Binder-Scholl, Gwendolyn | Brewer, Joanna | Duong, MyLinh | Lu, An | Chang, Peter | Mahendravada, Aruna | Shinners, Nicholas | Slawin, Kevin | Spencer, David M. | Foster, Aaron E. | Bayle, J. Henri | Bergamaschi, Cristina | Ng, Sinnie Sin Man | Nagy, Bethany | Jensen, Shawn | Hu, Xintao | Alicea, Candido | Fox, Bernard | Felber, Barbara | Pavlakis, George | Chacon, Jessica | Yamamoto, Tori | Garrabrant, Thomas | Cortina, Luis | Powell, Daniel J. | Donia, Marco | Kjeldsen, Julie Westerlin | Andersen, Rikke | Westergaard, Marie Christine Wulff | Bianchi, Valentina | Legut, Mateusz | Attaf, Meriem | Dolton, Garry | Szomolay, Barbara | Ott, Sascha | Lyngaa, Rikke | Hadrup, Sine Reker | Sewell, Andrew Kelvin | Svane, Inge Marie | Fan, Aaron | Kumai, Takumi | Celis, Esteban | Frank, Ian | Stramer, Amanda | Blaskovich, Michelle A. | Wardell, Seth | Fardis, Maria | Bender, James | Lotze, Michael T. | Goff, Stephanie L. | Zacharakis, Nikolaos | Assadipour, Yasmine | Prickett, Todd D. | Gartner, Jared J. | Somerville, Robert | Black, Mary | Xu, Hui | Chinnasamy, Harshini | Kriley, Isaac | Lu, Lily | Wunderlich, John | Robbins, Paul F. | Rosenberg, Steven | Feldman, Steven A. | Trebska-McGowan, Kasia | Kriley, Isaac | Malekzadeh, Parisa | Payabyab, Eden | Sherry, Richard | Rosenberg, Steven | Goff, Stephanie L. | Gokuldass, Aishwarya | Blaskovich, Michelle A. | Kopits, Charlene | Rabinovich, Brian | Lotze, Michael T. | Green, Daniel S. | Kamenyeva, Olena | Zoon, Kathryn C. | Annunziata, Christina M. | Hammill, Joanne | Helsen, Christopher | Aarts, Craig | Bramson, Jonathan | Harada, Yui | Yonemitsu, Yoshikazu | Helsen, Christopher | Hammill, Joanne | Mwawasi, Kenneth | Denisova, Galina | Bramson, Jonathan | Giri, Rajanish | Jin, Benjamin | Campbell, Tracy | Draper, Lindsey M. | Stevanovic, Sanja | Yu, Zhiya | Weissbrich, Bianca | Restifo, Nicholas P. | Trimble, Cornelia L. | Rosenberg, Steven | Hinrichs, Christian S. | Tsang, Kwong | Fantini, Massimo | Hodge, James W. | Fujii, Rika | Fernando, Ingrid | Jochems, Caroline | Heery, Christopher | Gulley, James | Soon-Shiong, Patrick | Schlom, Jeffrey | Jing, Weiqing | Gershan, Jill | Blitzer, Grace | Weber, James | McOlash, Laura | Johnson, Bryon D. | Kiany, Simin | Gangxiong, Huang | Kleinerman, Eugenie S. | Klichinsky, Michael | Ruella, Marco | Shestova, Olga | Kenderian, Saad | Kim, Miriam | Scholler, John | June, Carl H. | Gill, Saar | Moogk, Duane | Zhong, Shi | Yu, Zhiya | Liadi, Ivan | Rittase, William | Fang, Victoria | Dougherty, Janna | Perez-Garcia, Arianne | Osman, Iman | Zhu, Cheng | Varadarajan, Navin | Restifo, Nicholas P. | Frey, Alan | Krogsgaard, Michelle | Landi, Daniel | Fousek, Kristen | Mukherjee, Malini | Shree, Ankita | Joseph, Sujith | Bielamowicz, Kevin | Byrd, Tiara | Ahmed, Nabil | Hegde, Meenakshi | Lee, Sylvia | Byrd, David | Thompson, John | Bhatia, Shailender | Tykodi, Scott | Delismon, Judy | Chu, Liz | Abdul-Alim, Siddiq | Ohanian, Arpy | DeVito, Anna Marie | Riddell, Stanley | Margolin, Kim | Magalhaes, Isabelle | Mattsson, Jonas | Uhlin, Michael | Nemoto, Satoshi | Villarroel, Patricio Pérez | Nakagawa, Ryosuke | Mule, James J. | Mailloux, Adam W. | Mata, Melinda | Nguyen, Phuong | Gerken, Claudia | DeRenzo, Christopher | Spencer, David M. | Gottschalk, Stephen | Mathieu, Mélissa | Pelletier, Sandy | Stagg, John | Turcotte, Simon | Minutolo, Nicholas | Sharma, Prannda | Tsourkas, Andrew | Powell, Daniel J. | Mockel-Tenbrinck, Nadine | Mauer, Daniela | Drechsel, Katharina | Barth, Carola | Freese, Katharina | Kolrep, Ulrike | Schult, Silke | Assenmacher, Mario | Kaiser, Andrew | Mullinax, John | Hall, MacLean | Le, Julie | Kodumudi, Krithika | Royster, Erica | Richards, Allison | Gonzalez, Ricardo | Sarnaik, Amod | Pilon-Thomas, Shari | Nielsen, Morten | Krarup-Hansen, Anders | Hovgaard, Dorrit | Petersen, Michael Mørk | Loya, Anand Chainsukh | Junker, Niels | Svane, Inge Marie | Rivas, Charlotte | Parihar, Robin | Gottschalk, Stephen | Rooney, Cliona M. | Qin, Haiying | Nguyen, Sang | Su, Paul | Burk, Chad | Duncan, Brynn | Kim, Bong-Hyun | Kohler, M. Eric | Fry, Terry | Rao, Arjun A. | Teyssier, Noam | Pfeil, Jacob | Sgourakis, Nikolaos | Salama, Sofie | Haussler, David | Richman, Sarah A. | Nunez-Cruz, Selene | Gershenson, Zack | Mourelatos, Zissimos | Barrett, David | Grupp, Stephan | Milone, Michael | Rodriguez-Garcia, Alba | Robinson, Matthew K. | Adams, Gregory P. | Powell, Daniel J. | Santos, João | Havunen, Riikka | Siurala, Mikko | Cervera-Carrascón, Víctor | Parviainen, Suvi | Antilla, Marjukka | Hemminki, Akseli | Sethuraman, Jyothi | Santiago, Laurelis | Chen, Jie Qing | Dai, Zhimin | Wardell, Seth | Bender, James | Lotze, Michael T. | Sha, Huizi | Su, Shu | Ding, Naiqing | Liu, Baorui | Stevanovic, Sanja | Pasetto, Anna | Helman, Sarah R. | Gartner, Jared J. | Prickett, Todd D. | Robbins, Paul F. | Rosenberg, Steven A. | Hinrichs, Christian S. | Bhatia, Shailender | Burgess, Melissa | Zhang, Hui | Lee, Tien | Klingemann, Hans | Soon-Shiong, Patrick | Nghiem, Paul | Kirkwood, John M. | Rossi, John M. | Sherman, Marika | Xue, Allen | Shen, Yueh-wei | Navale, Lynn | Rosenberg, Steven A. | Kochenderfer, James N. | Bot, Adrian | Veerapathran, Anandaraman | Gokuldass, Aishwarya | Stramer, Amanda | Sethuraman, Jyothi | Blaskovich, Michelle A. | Wiener, Doris | Frank, Ian | Santiago, Laurelis | Rabinovich, Brian | Fardis, Maria | Bender, James | Lotze, Michael T. | Waller, Edmund K. | Li, Jian-Ming | Petersen, Christopher | Blazar, Bruce R. | Li, Jingxia | Giver, Cynthia R. | Wang, Ziming | Grossenbacher, Steven K. | Sturgill, Ian | Canter, Robert J. | Murphy, William J. | Zhang, Congcong | Burger, Michael C. | Jennewein, Lukas | Waldmann, Anja | Mittelbronn, Michel | Tonn, Torsten | Steinbach, Joachim P. | Wels, Winfried S. | Williams, Jason B. | Zha, Yuanyuan | Gajewski, Thomas F. | Williams, LaTerrica C. | Krenciute, Giedre | Kalra, Mamta | Louis, Chrystal | Gottschalk, Stephen | Xin, Gang | Schauder, David | Jiang, Aimin | Joshi, Nikhil | Cui, Weiguo | Zeng, Xue | Menk, Ashley V. | Scharping, Nicole | Delgoffe, Greg M. | Zhao, Zeguo | Hamieh, Mohamad | Eyquem, Justin | Gunset, Gertrude | Bander, Neil | Sadelain, Michel | Askmyr, David | Abolhalaj, Milad | Lundberg, Kristina | Greiff, Lennart | Lindstedt, Malin | Angell, Helen K. | Kim, Kyoung-Mee | Kim, Seung-Tae | Kim, Sung | Sharpe, Alan D. | Ogden, Julia | Davenport, Anna | Hodgson, Darren R. | Barrett, Carl | Lee, Jeeyun | Kilgour, Elaine | Hanson, Jodi | Caspell, Richard | Karulin, Alexey | Lehmann, Paul | Ansari, Tameem | Schiller, Annemarie | Sundararaman, Srividya | Lehmann, Paul | Hanson, Jodi | Roen, Diana | Karulin, Alexey | Lehmann, Paul | Ayers, Mark | Levitan, Diane | Arreaza, Gladys | Liu, Fang | Mogg, Robin | Bang, Yung-Jue | O’Neil, Bert | Cristescu, Razvan | Friedlander, Philip | Wassman, Karl | Kyi, Chrisann | Oh, William | Bhardwaj, Nina | Bornschlegl, Svetlana | Gustafson, Michael P. | Gastineau, Dennis A. | Parney, Ian F. | Dietz, Allan B. | Carvajal-Hausdorf, Daniel | Mani, Nikita | Velcheti, Vamsidhar | Schalper, Kurt | Rimm, David | Chang, Serena | Levy, Ronald | Kurland, John | Krishnan, Suba | Ahlers, Christoph Matthias | Jure-Kunkel, Maria | Cohen, Lewis | Maecker, Holden | Kohrt, Holbrook | Chen, Shuming | Crabill, George | Pritchard, Theresa | McMiller, Tracee | Pardoll, Drew | Pan, Fan | Topalian, Suzanne | Danaher, Patrick | Warren, Sarah | Dennis, Lucas | White, Andrew M. | D’Amico, Leonard | Geller, Melissa | Disis, Mary L. | Beechem, Joseph | Odunsi, Kunle | Fling, Steven | Derakhshandeh, Roshanak | Webb, Tonya J. | Dubois, Sigrid | Conlon, Kevin | Bryant, Bonita | Hsu, Jennifer | Beltran, Nancy | Müller, Jürgen | Waldmann, Thomas | Duhen, Rebekka | Duhen, Thomas | Thompson, Lucas | Montler, Ryan | Weinberg, Andrew | Kates, Max | Early, Brandon | Yusko, Erik | Schreiber, Taylor H. | Bivalacqua, Trinity J. | Ayers, Mark | Lunceford, Jared | Nebozhyn, Michael | Murphy, Erin | Loboda, Andrey | Kaufman, David R. | Albright, Andrew | Cheng, Jonathan | Kang, S. Peter | Shankaran, Veena | Piha-Paul, Sarina A. | Yearley, Jennifer | Seiwert, Tanguy | Ribas, Antoni | McClanahan, Terrill K. | Cristescu, Razvan | Mogg, Robin | Ayers, Mark | Albright, Andrew | Murphy, Erin | Yearley, Jennifer | Sher, Xinwei | Liu, Xiao Qiao | Nebozhyn, Michael | Lunceford, Jared | Joe, Andrew | Cheng, Jonathan | Plimack, Elizabeth | Ott, Patrick A. | McClanahan, Terrill K. | Loboda, Andrey | Kaufman, David R. | Forrest-Hay, Alex | Guyre, Cheryl A. | Narumiya, Kohei | Delcommenne, Marc | Hirsch, Heather A. | Deshpande, Amit | Reeves, Jason | Shu, Jenny | Zi, Tong | Michaelson, Jennifer | Law, Debbie | Trehu, Elizabeth | Sathyanaryanan, Sriram | Hodkinson, Brendan P. | Hutnick, Natalie A. | Schaffer, Michael E. | Gormley, Michael | Hulett, Tyler | Jensen, Shawn | Ballesteros-Merino, Carmen | Dubay, Christopher | Afentoulis, Michael | Reddy, Ashok | David, Larry | Fox, Bernard | Jayant, Kumar | Agrawal, Swati | Agrawal, Rajendra | Jeyakumar, Ghayathri | Kim, Seongho | Kim, Heejin | Silski, Cynthia | Suisham, Stacey | Heath, Elisabeth | Vaishampayan, Ulka | Vandeven, Natalie | Viller, Natasja Nielsen | O’Connor, Alison | Chen, Hui | Bossen, Bolette | Sievers, Eric | Uger, Robert | Nghiem, Paul | Johnson, Lisa | Kao, Hsiang-Fong | Hsiao, Chin-Fu | Lai, Shu-Chuan | Wang, Chun-Wei | Ko, Jenq-Yuh | Lou, Pei-Jen | Lee, Tsai-Jan | Liu, Tsang-Wu | Hong, Ruey-Long | Kearney, Staci J. | Black, Joshua C. | Landis, Benjamin J. | Koegler, Sally | Hirsch, Brooke | Gianani, Roberto | Kim, Jeffrey | He, Ming-Xiao | Zhang, Bingqing | Su, Nan | Luo, Yuling | Ma, Xiao-Jun | Park, Emily | Kim, Dae Won | Copploa, Domenico | Kothari, Nishi | doo Chang, Young | Kim, Richard | Kim, Namyong | Lye, Melvin | Wan, Ee | Kim, Namyong | Lye, Melvin | Wan, Ee | Kim, Namyong | Lye, Melvin | Wan, Ee | Knaus, Hanna A. | Berglund, Sofia | Hackl, Hubert | Karp, Judith E. | Gojo, Ivana | Luznik, Leo | Hong, Henoch S. | Koch, Sven D. | Scheel, Birgit | Gnad-Vogt, Ulrike | Kallen, Karl-Josef | Wiegand, Volker | Backert, Linus | Kohlbacher, Oliver | Hoerr, Ingmar | Fotin-Mleczek, Mariola | Billingsley, James M. | Koguchi, Yoshinobu | Conrad, Valerie | Miller, William | Gonzalez, Iliana | Poplonski, Tomasz | Meeuwsen, Tanisha | Howells-Ferreira, Ana | Rattray, Rogan | Campbell, Mary | Bifulco, Carlo | Dubay, Christopher | Bahjat, Keith | Curti, Brendan | Urba, Walter | Vetsika, E-K | Kallergi, G. | Aggouraki, Despoina | Lyristi, Z. | Katsarlinos, P. | Koinis, Filippos | Georgoulias, V. | Kotsakis, Athanasios | Martin, Nathan T. | Aeffner, Famke | Kearney, Staci J. | Black, Joshua C. | Cerkovnik, Logan | Pratte, Luke | Kim, Rebecca | Hirsch, Brooke | Krueger, Joseph | Gianani, Roberto | Martínez-Usatorre, Amaia | Jandus, Camilla | Donda, Alena | Carretero-Iglesia, Laura | Speiser, Daniel E. | Zehn, Dietmar | Rufer, Nathalie | Romero, Pedro | Panda, Anshuman | Mehnert, Janice | Hirshfield, Kim M. | Riedlinger, Greg | Damare, Sherri | Saunders, Tracie | Sokol, Levi | Stein, Mark | Poplin, Elizabeth | Rodriguez-Rodriguez, Lorna | Silk, Ann | Chan, Nancy | Frankel, Melissa | Kane, Michael | Malhotra, Jyoti | Aisner, Joseph | Kaufman, Howard L. | Ali, Siraj | Ross, Jeffrey | White, Eileen | Bhanot, Gyan | Ganesan, Shridar | Monette, Anne | Bergeron, Derek | Amor, Amira Ben | Meunier, Liliane | Caron, Christine | Morou, Antigoni | Kaufmann, Daniel | Liberman, Moishe | Jurisica, Igor | Mes-Masson, Anne-Marie | Hamzaoui, Kamel | Lapointe, Rejean | Mongan, Ann | Ku, Yuan-Chieh | Tom, Warren | Sun, Yongming | Pankov, Alex | Looney, Tim | Au-Young, Janice | Hyland, Fiona | Conroy, Jeff | Morrison, Carl | Glenn, Sean | Burgher, Blake | Ji, He | Gardner, Mark | Mongan, Ann | Omilian, Angela R. | Conroy, Jeff | Bshara, Wiam | Angela, Omilian | Burgher, Blake | Ji, He | Glenn, Sean | Morrison, Carl | Mongan, Ann | Obeid, Joseph M. | Erdag, Gulsun | Smolkin, Mark E. | Deacon, Donna H. | Patterson, James W. | Chen, Lieping | Bullock, Timothy N. | Slingluff, Craig L. | Obeid, Joseph M. | Erdag, Gulsun | Deacon, Donna H. | Slingluff, Craig L. | Bullock, Timothy N. | Loffredo, John T. | Vuyyuru, Raja | Beyer, Sophie | Spires, Vanessa M. | Fox, Maxine | Ehrmann, Jon M. | Taylor, Katrina A. | Korman, Alan J. | Graziano, Robert F. | Page, David | Sanchez, Katherine | Ballesteros-Merino, Carmen | Martel, Maritza | Bifulco, Carlo | Urba, Walter | Fox, Bernard | Patel, Sapna P. | De Macedo, Mariana Petaccia | Qin, Yong | Reuben, Alex | Spencer, Christine | Guindani, Michele | Bassett, Roland | Wargo, Jennifer | Racolta, Adriana | Kelly, Brian | Jones, Tobin | Polaske, Nathan | Theiss, Noah | Robida, Mark | Meridew, Jeffrey | Habensus, Iva | Zhang, Liping | Pestic-Dragovich, Lidija | Tang, Lei | Sullivan, Ryan J. | Logan, Theodore | Khushalani, Nikhil | Margolin, Kim | Koon, Henry | Olencki, Thomas | Hutson, Thomas | Curti, Brendan | Roder, Joanna | Blackmon, Shauna | Roder, Heinrich | Stewart, John | Amin, Asim | Ernstoff, Marc S. | Clark, Joseph I. | Atkins, Michael B. | Kaufman, Howard L. | Sosman, Jeffrey | Weber, Jeffrey | McDermott, David F. | Weber, Jeffrey | Kluger, Harriet | Halaban, Ruth | Snzol, Mario | Roder, Heinrich | Roder, Joanna | Asmellash, Senait | Steingrimsson, Arni | Blackmon, Shauna | Sullivan, Ryan J. | Wang, Chichung | Roman, Kristin | Clement, Amanda | Downing, Sean | Hoyt, Clifford | Harder, Nathalie | Schmidt, Guenter | Schoenmeyer, Ralf | Brieu, Nicolas | Yigitsoy, Mehmet | Madonna, Gabriele | Botti, Gerardo | Grimaldi, Antonio | Ascierto, Paolo A. | Huss, Ralf | Athelogou, Maria | Hessel, Harald | Harder, Nathalie | Buchner, Alexander | Schmidt, Guenter | Stief, Christian | Huss, Ralf | Binnig, Gerd | Kirchner, Thomas | Sellappan, Shankar | Thyparambil, Sheeno | Schwartz, Sarit | Cecchi, Fabiola | Nguyen, Andrew | Vaske, Charles | Hembrough, Todd
Journal for Immunotherapy of Cancer  2016;4(Suppl 1):1-106.
doi:10.1186/s40425-016-0172-7
PMCID: PMC5123387
11.  A phase-I trial of pre‐operative, margin intensive, stereotactic body radiation therapy for pancreatic cancer: the ‘SPARC’ trial protocol 
BMC Cancer  2016;16(1):728.
Background
Standard therapy for borderline-resectable pancreatic cancer in the UK is surgery with adjuvant chemotherapy, but rates of resection with clear margins are unsatisfactory and overall survival remains poor. Meta-analysis of single-arm studies shows the potential of neo-adjuvant chemo-radiotherapy but the relative radio-resistance of pancreatic cancer means the efficacy of conventional dose schedules is limited. Stereotactic radiotherapy achieves sufficient accuracy and precision to enable pre-operative margin-intensive dose escalation with the goal of increasing rates of clear resection margins and local disease control.
Methods/Design
SPARC is a “rolling-six” design single-arm study to establish the maximum tolerated dose for margin-intensive stereotactic radiotherapy before resection of pancreatic cancer at high risk of positive resection margins. Eligible patients will have histologically or cytologically proven pancreatic cancer defined as borderline-resectable per National Comprehensive Cancer Network criteria or operable tumour in contact with vessels increasing the risk of positive margin. Up to 24 patients will be recruited from up to 5 treating centres and a ‘rolling-six’ design is utilised to minimise delays and facilitate ongoing recruitment during dose-escalation. Radiotherapy will be delivered in 5 daily fractions and surgery, if appropriate, will take place 5–6 weeks after radiotherapy. The margin-intense radiotherapy concept includes a systematic method to define the target volume for a simultaneous integrated boost in the region of tumour-vessel infiltration, and up to 4 radiotherapy dose levels will be investigated. Maximum tolerated dose is defined as the highest dose at which no more than 1 of 6 patients or 0 of 3 patients experience a dose limiting toxicity. Secondary endpoints include resection rate, resection margin status, response rate, overall survival and progression free survival at 12 and 24 months. Translational work will involve exploratory analyses of the cytological and humoral immunological responses to stereotactic radiotherapy in pancreatic cancer. Radiotherapy quality assurance of target definition and radiotherapy planning is enforced with pre-trial test cases and on-trial review. Recruitment began in April 2015.
Discussion
This prospective multi-centre study aims to establish the maximum tolerated dose of pre-operative margin-intensified stereotactic radiotherapy in pancreatic cancer at high risk of positive resection margins with a view to subsequent definitive comparison with other neoadjuvant treatment options.
Trial registration
ISRCTN14138956. Funded by CRUK
doi:10.1186/s12885-016-2765-4
PMCID: PMC5020462  PMID: 27619800
Pancreatic cancer; Borderline-resectable; Stereotactic body radiation therapy (SBRT)
12.  Live viruses to treat cancer 
Viruses that selectively replicate in cancer cells, leading to the death of the cell, are being studied for their potential as cancer therapies. Some of these viruses are naturally occurring but cause little if any illness in humans; others have been engineered to make them specifically able to kill cancer cells while sparing normal cells. These oncolytic viruses may be selective for cancer cells because viral receptors are over-expressed on the surface of cancer cells or because antiviral pathways are distorted in cancer cells. Additionally, when oncolytic viruses kill cancer cells, it can stimulate an antitumour immune response from the host that can enhance efficacy. Numerous early phase trials of at least six oncolytic viruses have been reported with no evidence of concerning toxicity either as single agents or in combination with chemotherapies and radiotherapy. Three oncolytic viruses have reached randomized testing in cancer patients; reolysin in head and neck cancer and JX594 in hepatocellular cancers, while results from the first-phase III trial of T-vec in metastatic melanoma are expected shortly.
doi:10.1177/0141076813494196
PMCID: PMC3725859  PMID: 23824333
oncolytic virotherapy; immunotherapy; delivery; cancer
13.  Definitive Management of Oligometastatic Melanoma in a Murine Model Using Combined Ablative Radiation Therapy and Viral Immunotherapy 
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.
doi:10.1016/j.ijrobp.2015.07.2274
PMCID: PMC4877702  PMID: 26461000
14.  Phase I Trial of Cyclophosphamide as an Immune Modulator for Optimizing Oncolytic Reovirus Delivery to Solid Tumors 
Purpose
Reovirus is a wild-type oncolytic virus that is ubiquitous in the environment; most patients are therefore preimmune. Therapeutic administration leads to an increase in neutralizing antireovirus antibody (NARA) titer. We hypothesized that if NARA limited reovirus antitumor activity, the effect might be attenuated by coadministration of cyclophosphamide.
Experimental design
In a phase I study, patients with advanced cancer received cyclophosphamide 3 days before intravenous reovirus serotype 3 Dearing (RT3D). The primary objective was to reduce the resulting rise in NARA titer. Cyclophosphamide dose was escalated from 25–1,000 mg/m2 through nine cohorts; we aimed to define a well-tolerated immunomodulatory dose.
Results
The combination was well tolerated in 36 patients, with grade 3/4 toxicities only seen at or above the maximum tolerated dose of cyclophosphamide, which was 800 mg/m2 combined with reovirus. Immunosuppressive effect, defined as maintaining NARA titer rise below a predefined threshold, was observed in only one patient. Furthermore, despite expected myelosuppression seen at higher cyclophosphamide doses, no changes in T-cell subsets, including Tregs, occurred with dose escalation. Viable virus was detected in association with peripheral blood mononuclear cells (PBMC) from 14% of patients 10 days after the last RT3D injection, despite high plasma NARA titer, demonstrating a potential mechanism for prolonged evasion of neutralization by reovirus.
Conclusions
Coadministration of cyclophosphamide with reovirus is safe, but does not attenuate host antiviral responses. Alternative immunomodulation approaches should be explored, but association with PBMCs may allow reovirus to persist and evade even high levels of neutralizing antibodies.
doi:10.1158/1078-0432.CCR-14-1770
PMCID: PMC4821068  PMID: 25424857
15.  Immune-Mediated Antitumor Activity of Reovirus Is Required for Therapy and Is Independent of Direct Viral Oncolysis and Replication 
Purpose
Reovirus is a naturally occurring oncolytic virus in clinical trials. Although tumor infection by reovirus can generate adaptive antitumor immunity, its therapeutic importance versus direct viral oncolysis is undefined. This study addresses the requirement for viral oncolysis and replication, and the relative importance of antitumor immunity and direct oncolysis in therapy.
Experimental Design
Nonantigen specific T cells loaded with reovirus were delivered i.v. to C57BL/6 and severe combined immunodeficient mice bearing lymph node and splenic metastases from the murine melanoma, B16ova, with assessment of viral replication, metastatic clearance by tumor colony outgrowth, and immune priming. Human cytotoxic lymphocyte priming assays were done with dendritic cells loaded with Mel888 cells before the addition of reovirus.
Results
B16ova was resistant to direct oncolysis in vitro, and failed to support reovirus replication in vitro or in vivo. Nevertheless, reovirus purged lymph node and splenic metastases in C57BL/6 mice and generated antitumor immunity. In contrast, reovirus failed to reduce tumor burden in severe combined immunodeficient mice bearing either B16ova or reovirus-sensitive B16tk metastases. In the human system, reovirus acted solely as an adjuvant when added to dendritic cells already loaded with Mel888, supporting priming of specific antitumor cytotoxic lymphocyte, in the absence of significant direct tumor oncolysis; UV-treated nonreplicating reovirus was similarly immunogenic.
Conclusion
The immune response is critical in mediating the efficacy of reovirus, and does not depend upon direct viral oncolysis or replication. The findings are of direct relevance to fulfilling the potential of this novel anticancer agent.
doi:10.1158/1078-0432.CCR-09-0334
PMCID: PMC4821072  PMID: 19509134
16.  Oncolytic reovirus enhances Rituximab-Mediated Antibody-Dependent Cellular Cytotoxicity against Chronic Lymphocytic Leukaemia 
Leukemia  2015;29(9):1799-1810.
The naturally occurring oncolytic virus (OV), reovirus, replicates in cancer cells causing direct cytotoxicity, and can activate innate and adaptive immune responses to facilitate tumour clearance. Reovirus is safe, well-tolerated and currently in clinical testing for the treatment of multiple myeloma, in combination with dexamethasone/carfilzomib. Activation of natural killer (NK) cells has been observed after systemic delivery of reovirus to cancer patients; however the ability of OV to potentiate NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC) is unexplored. This study elucidates the potential of oncolytic reovirus for the treatment of chronic lymphocytic leukaemia (CLL), both as a direct cytotoxic agent, and as an immune modulator. We demonstrate that reovirus: (i) is directly cytotoxic against CLL, which requires replication-competent virus; (ii) phenotypically and functionally activates patient NK cells via a monocyte-derived interferon alpha (IFNα)-dependent mechanism; and (iii) enhances ADCC-mediated killing of CLL in combination with anti-CD20 antibodies. Our data provide strong pre-clinical evidence to support the use of reovirus in combination with anti-CD20 immunotherapy for the treatment of CLL.
doi:10.1038/leu.2015.88
PMCID: PMC4490165  PMID: 25814029
17.  Cancer immunotherapy via combining oncolytic virotherapy with chemotherapy: recent advances 
Oncolytic Virotherapy  2016;5:1-13.
Oncolytic viruses are multifunctional anticancer agents with huge clinical potential, and have recently passed the randomized Phase III clinical trial hurdle. Both wild-type and engineered viruses have been selected for targeting of specific cancers, to elicit cytotoxicity, and also to generate antitumor immunity. Single-agent oncolytic virotherapy treatments have resulted in modest effects in the clinic. There is increasing interest in their combination with cytotoxic agents, radiotherapy and immune-checkpoint inhibitors. Similarly to oncolytic viruses, the benefits of chemotherapeutic agents may be that they induce systemic antitumor immunity through the induction of immunogenic cell death of cancer cells. Combining these two treatment modalities has to date resulted in significant potential in vitro and in vivo synergies through various mechanisms without any apparent additional toxicities. Chemotherapy has been and will continue to be integral to the management of advanced cancers. This review therefore focuses on the potential for a number of common cytotoxic agents to be combined with clinically relevant oncolytic viruses. In many cases, this combined approach has already advanced to the clinical trial arena.
doi:10.2147/OV.S66083
PMCID: PMC4996257  PMID: 27579292
oncolytic virotherapy; chemotherapy; immunogenic cell death
18.  Evidence for Oncolytic Virotherapy: Where Have We Got to and Where Are We Going? 
Viruses  2015;7(12):6291-6312.
The last few years have seen an increased interest in immunotherapy in the treatment of malignant disease. In particular, there has been significant enthusiasm for oncolytic virotherapy, with a large amount of pre-clinical data showing promise in animal models in a wide range of tumour types. How do we move forward into the clinical setting and translate something which has such potential into meaningful clinical outcomes? Here, we review how the field of oncolytic virotherapy has developed thus far and what the future may hold.
doi:10.3390/v7122938
PMCID: PMC4690862  PMID: 26633468
oncolytic virus; immunotherapy; reovirus; vaccinia; HSV; clinical trials
21.  Reovirus-associated reduction of microRNA-let-7d is related to the increased apoptotic death of cancer cells in clinical samples 
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.
doi:10.1038/modpathol.2012.95
PMCID: PMC4275064  PMID: 22699519
apoptosis; caspase-3; microRNA-let-7d; PKR; Ras; reovirus
22.  Detecting and targeting tumor relapse by its resistance to innate effectors at early recurrence 
Nature medicine  2013;19(12):1625-1631.
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.
doi:10.1038/nm.3397
PMCID: PMC3891504  PMID: 24240185
23.  Applications of coxsackievirus A21 in oncology 
Oncolytic Virotherapy  2014;3:47-55.
The clinical management of cancer continues to be dominated by macroscopic surgical resection, radiotherapy, and cytotoxic drugs. The major challenge facing oncology is to achieve more selective, less toxic and effective methods of targeting disseminated tumors, a challenge oncolytic virotherapy may be well-placed to meet. Characterization of coxsackievirus A21 (CVA21) receptor-based mechanism of virus internalization and lysis in the last decade has suggested promise for CVA21 as a virotherapy against malignancies which overexpress those receptors. Preclinical studies have demonstrated proof of principle, and with the results of early clinical trials awaited, CVA21 may be one of the few viruses to demonstrate benefit for patients. This review outlines the potential of CVA21 as an oncolytic agent, describing the therapeutic development of CVA21 in preclinical studies and early stage clinical trials. Preclinical evidence supports the potential use of CVA21 across a range of malignancies. Malignant melanoma is the most intensively studied cancer, and may represent a “test case” for future development of the virus. Although there are theoretical barriers to the clinical utility of oncolytic viruses like CVA21, whether these will block the efficacy of the virus in clinical practice remains to be established, and is a question which can only be answered by appropriate trials. As these data become available, the rapid journey of CVA21 from animal studies to clinical trials may offer a model for the translation of other oncolytic virotherapies from laboratory to clinic.
doi:10.2147/OV.S56322
PMCID: PMC4918364  PMID: 27512662
coxsackievirus A21; CVA21; cavatak; oncolytic virotherapy
24.  REO-10: A Phase I Study of Intravenous Reovirus and Docetaxel in Patients with Advanced Cancer 
Purpose
REOLYSIN (Oncolytics Biotech) consists of a wild-type oncolytic reovirus, which has selective cytotoxicity for tumor cells while sparing normal cells. In a phase I study as a single agent, repeated infusions of reovirus were safe with evidence of antitumor activity. Preclinical studies indicate potential for synergy between reovirus and chemotherapeutic agents. A multicenter, phase I dose escalation study was designed to assess the safety of combining reovirus with docetaxel chemotherapy in patients with advanced cancer.
Experimental Design
Patients received 75 mg/m2 docetaxel (day 1) and escalating doses of reovirus up to 3 × 1010 TCID50 (days 1-5) every 3 weeks.
Results
Twenty-five patients were enrolled, and 24 patients were exposed to treatment, with 23 completing at least one cycle and 16 suitable for response assessment. Dose-limiting toxicity of grade 4 neutropenia was seen in one patient, but the maximum tolerated dose was not reached. Antitumor activity was seen with one complete response and three partial responses. A disease control rate (combined complete response, partial response, and stable disease) of 88% was observed. Immunohistochemical analysis of reovirus protein expression was observed in posttreatment tumor biopsies from three patients.
Conclusion
The combination of reovirus and docetaxel is safe, with evidence of objective disease response, and warrants further evaluation in a phase II study at a recommended schedule of docetaxel (75 mg/m2, three times weekly) and reovirus (3 × 1010 TCID50, days 1-5, every 3 weeks).
doi:10.1158/1078-0432.CCR-10-1233
PMCID: PMC3934355  PMID: 20926400
25.  Single-Cycle Viral Gene Expression, Rather Than Progressive Replication and Oncolysis, Is Required for VSV Therapy of B16 Melanoma 
Gene therapy  2009;17(2):158-170.
A fully intact immune system would be expected to hinder the efficacy of oncolytic virotherapy by inhibiting viral replication. Simultaneously, however, it may also enhance antitumor therapy through initiation of pro-inflammatory, antiviral cytokine responses at the tumor site. The aim of the current study was to investigate the role of a fully intact immune system upon the antitumor efficacy of an oncolytic virus. In this respect, injection of oncolytic Vesicular Stomatitis Virus (VSV) into subcutaneous B16ova melanomas in C57Bl/6 mice leads to tumor regression, but it is not associated with viral replicative burst in the tumor. In contrast, intratumoral delivery of VSV induces an acute proinflammatory reaction, which quickly resolves concomitantly with virus clearance. Consistent with the hypothesis that therapy may not be dependent upon the ability of VSV to undergo progressive rounds of replication, a single-cycle VSV is equally effective as a fully replication-competent VSV, whereas, inactivated viruses do not generate therapy. Even though therapy is dependent upon host CD8+ and NK cells, these effects are not associated with IFN-γ-dependent responses against either the virus or tumor. There is, however, a strong correlation between viral gene expression, induction of proinflammatory reaction in the tumor and in vivo therapy. Overall, our results suggest that acute innate antiviral immune response, which rapidly clears VSV from B16ova tumors, is associated with the therapy observed in this model. Therefore, the antiviral immune response to an oncolytic virus mediates an intricate balance between safety, restriction of oncolysis and, potentially, significant immune-mediated antitumor therapy.
doi:10.1038/gt.2009.161
PMCID: PMC3934361  PMID: 20016540
Oncolytic viruses; Experimental Melanoma; Interferon Type I; Gene Therapy; Virus Replication; Rhabdovirus

Results 1-25 (54)