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PubMed Central Canada to be taken offline in February 2018

On February 23, 2018, PubMed Central Canada (PMC Canada) will be taken offline permanently. No author manuscripts will be deleted, and the approximately 2,900 manuscripts authored by Canadian Institutes of Health Research (CIHR)-funded researchers currently in the archive will be copied to the National Research Council’s (NRC) Digital Repository over the coming months. These manuscripts along with all other content will also remain publicly searchable on PubMed Central (US) and Europe PubMed Central, meaning such manuscripts will continue to be compliant with the Tri-Agency Open Access Policy on Publications.

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1.  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
2.  A phase I study of recombinant (r) Vaccinia-CEA(6D)-TRICOM and rFowlpox-CEA(6D)-TRICOM vaccines with GM-CSF and IFN-α-2b in patients with CEA expressing carcinomas 
Cancer immunology, immunotherapy : CII  2016;65(11):1353-1364.
Prime-boost vaccination with recombinant (r) Vaccinia(V)-CEA(6D)-TRICOM (triad of co-stimulatory molecules B7.1, ICAM-1 and LFA-3) and rFowlpox(F)-CEA(6D)-TRICOM, infect antigen presenting cells and direct expression of co-stimulatory molecules. We hypothesized that co-administration of vaccine with GM-CSF and interferon-alpha (IFN-α) would have efficacy in CEA-expressing cancers. Patients with CEA-expressing cancers received the rV-CEA(6D)-TRICOM vaccine subcutaneously (s.c.) on day 1 followed by GM-CSF s.c. to the injection site on days 1–4. In Cycle 1, patients received thrice weekly s.c. injections of IFN-α-2b the week after rV-CEA(6D)-TRICOM. In Cycles 2–4, patients received thrice weekly s.c. injections of IFN-α-2b the same week that rF-CEA(6D)-TRICOM was given. The first cohort received no IFN followed by dose escalation of IFN-α in subsequent cohorts. Thirty-three patients were accrued (mean 59.8 years). Grade ≥3 toxicities included fatigue and hyperglycemia. Grade 4–5 adverse events (unrelated to treatment) were confusion (1), elevated aspartate transaminase (AST)/alanine transaminase (ALT) (1), and sudden death (1). No patients had a partial response, and eight patients exhibited stable disease of >3 months. Median progression-free survival and overall survival (OS) were 1.8 and 6.3 months, respectively. Significantly higher serum CD27 levels were observed after vaccine therapy (p=0.006 post 1–2 cycles, p=0.003 post 3 cycles, p=0.03 post 4–7 cycles) and 42% of patients assayed developed CEA-specific T-cell responses. Pre-treatment levels of myeloid derived suppressor cells correlated with overall survival (p=0.04). Administration of IFN-α led to significantly increased OS (p=0.02) compared to vaccine alone. While the vaccine regimen produced no clinical responses, IFN-α administration was associated with improved survival.
doi:10.1007/s00262-016-1893-7
PMCID: PMC5071149  PMID: 27581603
Vaccines; Carcinoembryonic Antigen (CEA); Colorectal Cancer; Immunotherapy; Interferon alpha-2b
3.  Malignant mesothelioma effusions are infiltrated by CD3+ T cells highly expressing PD-L1 and the PD-L1+ tumor cells within these effusions are susceptible to ADCC by the anti-PD-L1 antibody avelumab 
INTRODUCTION
The functional aspects of programmed death 1 (PD-1) and PD ligand 1 (PD-L1) immune checkpoints in malignant mesothelioma have not been studied.
METHODS
Tumor samples from 65 patients with mesothelioma were evaluated for PD-L1 expression by immunohistochemistry and its prognostic significance. Malignant effusions from patients with pleural and peritoneal mesothelioma were evaluated for PD-1+ and PD-L1+ infiltrating lymphocytes and their role in inducing tumor cell PD-L1 expression. Antibody dependent cellular cytotoxicity (ADCC) of avelumab, a fully humanized IgG1 anti PD-L1 antibody towards primary mesothelioma cell lines was evaluated in presence of autologous and allogeneic NK cells.
RESULTS
Of 65 pleural and peritoneal mesothelioma tumors examined, 41 (63%) were PD-L1 positive, which was associated with slightly inferior overall survival compared to patients with PD-L1 negative tumors (median 23.0 vs. 33.3 months; p=0.35). The frequency of PD-L1 expression was similar in pleural and peritoneal mesothelioma patients with 62% and 64% of samples positive, respectively. Of nine mesothelioma effusion samples evaluated, the fraction of cells expressing PD-L1 ranged from 12 to 83%. Of 7 patients with paired malignant effusion and peripheral blood mononuclear cells (PBMC) samples, PD-L1 expression was significantly higher on CD3+ T cells present in malignant effusions as compared with PBMC (p=0.016). In addition, CD14+PD-1+ cells were elevated in malignant effusions compared with PBMC (p=0.031). The lymphocytes present in malignant effusions recognized autologous tumor cells and induced IFN-γ-mediated PD-L1 expression on the tumor cell surface. Of the three primary mesothelioma cell lines tested, two were susceptible to avelumab mediated ADCC in presence of autologous NK cells.
CONCLUSION
The majority of pleural as well as peritoneal mesothelioma express PD-L1. Malignant effusions in this disease are characterized by presence of tumor cells and CD3+ T cells that highly express PD-L1. In addition, mesothelioma tumor cells are susceptible to ADCC by anti-PD-L1 antibody avelumab.
doi:10.1016/j.jtho.2016.07.033
PMCID: PMC5075512  PMID: 27544053
PD-1-PD-L1; mesothelioma; avelumab; ADCC
4.  Combination therapy with an OX40L fusion protein and a vaccine targeting the transcription factor twist inhibits metastasis in a murine model of breast cancer 
Oncotarget  2017;8(53):90825-90841.
OX40 is a costimulatory receptor that potentiates proliferation, survival, memory formation, and effector function of CD4+ and CD8+ T-cells, while overcoming the suppressive activity of regulatory T-cells (Tregs). Here, we explored the combination of an OX40L fusion protein (OX40L-FP) with a poxvirus-based cancer vaccine (MVA-Twist-TRICOM) to inhibit tumor metastasis in the 4T1 murine breast cancer model.
Contrary to the single agent treatments, the combination therapy significantly decreased the number of metastatic colonies per lung and prolonged survival. Depletion studies demonstrated that these effects were mediated by both CD4+ and CD8+ T-cells. The combination therapy a) increased the total number of T-cells in the CD4+Foxp3- population and the CD4+ central and effector memory subsets within the lung, spleen, and draining lymph node, b) enhanced infiltration of CD4+ T-cells into metastatic areas of the lung, and (c) increased the number of functional CD8+ T-cells that produced IFNγ and TNFα. The combination therapy also promoted the development of KLRG1-CD127+ memory precursor CD8+ T-cells, while reducing those with a KLRG1+ terminally differentiated phenotype. Moreover, the combination of OX40L-FP and vaccine induced greater CD4+ and CD8+ Twist-specific responses. In addition, Tregs isolated from mice receiving the combination were also less immunosuppressive in ex-vivo proliferation assays than those from the OX40L-FP and MVA-Twist-TRICOM monotherapy groups. Such results provide the rationale to combine co-stimulatory agonists with cancer vaccines for the treatment of tumor metastasis.
doi:10.18632/oncotarget.19967
PMCID: PMC5710887
OX40; cancer vaccines; combination immunotherapy; twist
5.  Enhanced immunotherapy by combining a vaccine with a novel murine GITR ligand fusion protein 
Oncotarget  2017;8(43):73469-73482.
Immunotherapy was significantly enhanced in a murine tumor model by combining a vaccine with a fusion protein designed to target the glucocorticoid-induced tumor necrosis factor (TNF) receptor related gene (GITR) on the surface of T cells. The recombinant poxvirus-based vaccine platform included Modified Vaccinia virus Ankara (rMVA) and fowlpox (rF) vectors as the driver immunogens both engineered to express the human carcinoembryonic antigen (CEA) and three murine costimulatory molecules B7.1, ICAM-1, LFA-3 (designated TRICOM). In previous studies, mice expressing human CEA as a transgene (CEA.Tg mice) vaccinated with rMVA/rF-CEA-TRICOM overcame CEA immune tolerance by inducing anti-CEA‒specific immunity and regression of CEA-expressing tumors. The murine GITR ligand fusion protein (mGITRL-FP) consisted of a mouse IgG2a Fc region, a yeast-derived coiled GCN4 pII and the extracellular GITR-binding domain of murine GITR ligand. The design maximized valency and the potential to agonize the GITR receptor. Combined treatment of the vaccine and mGITRL-FP mediated a more robust tumor regression, leading to sustained improvement in overall survival. The enhanced immunotherapeutic effect was linked to the generation of a strong CD8+ T cell antitumor immune response. A treatment schedule with mGITRL-FP administered prior to the priming rMVA-CEA-TRICOM vaccination was of paramount importance. The mechanism of action for the enhanced antitumor effects resided in the depletion of immune cells, particularly FoxP3+ regulatory T cells, that express high GITR levels following activation. The results provide evidence that targeting GITR with mGITRL-FP in concert with a cancer vaccine represents a potential novel approach to more effective immunotherapy.
doi:10.18632/oncotarget.20703
PMCID: PMC5650275
poxvirus vaccines; rMVA/rF-CEA-TRICOM; mGITRL-FP; CD4+FoxP3+ regulatory T cells; immunotherapy
6.  Analyses of functions of an anti-PD-L1/TGFβR2 bispecific fusion protein (M7824) 
Oncotarget  2017;8(43):75217-75231.
M7824 (MSB0011359C) is a novel first-in-class bifunctional fusion protein consisting of a fully human IgG1 anti-PD-L1 monoclonal antibody (with structural similarities to avelumab) linked to the extracellular domain of two TGFβ receptor 2 (TGFβR2) molecules serving as a TGFβ Trap. Avelumab has demonstrated clinical activity in a range of human cancers and has been approved by the Food and Drug Administration for the therapy of Merkel cell and bladder carcinomas. Preclinical studies have shown this anti-PD-L1 is capable of mediating antibody-dependent cell-mediated cytotoxicity (ADCC). In the studies reported here, it is shown that M7824 is also capable of mediating ADCC of a wide range of human carcinoma cells in vitro, employing natural killer (NK) cells as effectors, albeit not as potent as anti-PD-L1 employing some tumor cells as targets. The addition of the IL-15 superagonist fusion protein complex ALT-803 enhanced the ADCC capacity of both anti-PD-L1 and M7824, and to levels that both agents now demonstrated similar levels of ADCC of tumor cells. TGFβ is a known immunosuppressive entity. Studies reported here show TGFβ1 induced reduction of several NK activation markers as well as reduction of endogenous NK lytic activity and NK-mediated ADCC of tumor cells. These phenomena could be reduced or mitigated, however, by M7824, but not by anti-PD-L1. M7824, but not anti-PD-L1, was also shown to reduce the immunosuppressive activity of regulatory T cells on human CD4+ T-cell proliferation. These studies thus demonstrate the dual functionalities of M7824 and provide the rationale for its further clinical development.
doi:10.18632/oncotarget.20680
PMCID: PMC5650414
anti-PD-L1/TGFβR2; M7824; checkpoint inhibitors; immunotherapy; anti-PD-L1
7.  Analyses of Pre-therapy Peripheral Immunoscore and Response to Vaccine Therapy 
Cancer immunology research  2016;4(9):755-765.
Tumor immunoscore analyses, especially for primary colorectal cancer and melanoma lesions, provide valuable prognostic information. Metastatic lesions of many carcinoma types, however, are often not easily accessible. We hypothesized that immune cells in peripheral blood may differ among individual patients with metastatic disease, which, in turn, may influence their response to immunotherapy. We thus analyzed immune cell subsets within peripheral blood mononuclear cells to determine if a “peripheral immunoscore” could have any prognostic significance for patients before receiving immunotherapy. Patients with metastatic breast cancer were randomized to receive docetaxel ± PANVAC vaccine. In another trial, prostate cancer patients with metastatic bone lesions were randomized to receive a bone-seeking radionuclide ± PROSTVAC vaccine. Predefined analyses of “classic” immune cell types (CD4, CD8, natural killer cells, regulatory T cells, myeloid-derived suppressor cells, and ratios) revealed no differences in progression-free survival (PFS) for either arm in both trials. Predefined analyses of refined immune cell subsets for which a biologic function had been previously reported also showed no significant prognostic value in PFS for patients receiving either docetaxel or radionuclide alone; however, in patients receiving these agents in combination with vaccine, the peripheral immunoscore of refined subsets revealed statistically significant differences in PFS (P < 0.001) for breast cancer patients receiving docetaxel plus vaccine, and in prostate cancer patients receiving radionuclide plus vaccine (P = 0.004). Larger randomized studies will be required to validate these findings. These studies, however, provide the rationale for the evaluation of refined immune cell subsets to help determine which patients may benefit most from immunotherapy.
doi:10.1158/2326-6066.CIR-16-0037
PMCID: PMC5138028  PMID: 27485137
cancer vaccine; peripheral immunoscore; immune cell subsets; immunotherapy; combination therapies
8.  A novel bifunctional anti-PD-L1/TGF-β Trap fusion protein (M7824) efficiently reverts mesenchymalization of human lung cancer cells 
Oncoimmunology  2017;6(10):e1349589.
ABSTRACT
Mesenchymalization is a cellular and molecular program in which epithelial cells progressively lose their well-differentiated phenotype and adopt mesenchymal characteristics. Tumor mesenchymalization occurs during the progression of cancer to metastatic disease, and is also associated with resistance to multiple therapeutics, including killing by cytotoxic immune cells. Furthermore, tumor cells can evade immune destruction by upregulating the checkpoint molecule PD-L1, and emerging research has found higher PD-L1 expression in mesenchymalized tumors. Here, the association between TGF-β1-mediated mesenchymalization and PD-L1 was investigated in non-small cell lung cancer cells (NSCLC). TGF-β1 was found to upregulate PD-L1 gene transcription in a Smad2-dependent manner, and a positive association between PD-L1 and phosphorylated Smad2 was found in NSCLC tumors. The potential to target these 2 negative immune regulators with a single agent was investigated using M7824, a novel clinical-stage bifunctional agent that targets both PD-L1 and TGF-β. Treatment of NSCLC cells with M7824 in vitro and in vivo attenuated features of TGF-β1-mediated mesenchymalization, including mesenchymal marker expression, proliferation suppression, and chemoresistance. These findings demonstrate that upregulation of tumor cell PD-L1 is a novel mechanism of TGF-β1-induced immunosuppression in NSCLC, and that treatment with M7824 has the potential to simultaneously block both tumor mesenchymalization and PD-L1-dependent immunosuppression.
doi:10.1080/2162402X.2017.1349589
PMCID: PMC5665067
EMT; fusion protein; immunotherapy; NSCLC; PD-L1; TGF-β1
9.  The association of clinical outcome and peripheral T-cell subsets in metastatic colorectal cancer patients receiving first-line FOLFIRI plus bevacizumab therapy 
Oncoimmunology  2016;5(7):e1188243.
ABSTRACT
The first-line standard of care for patients with metastatic colorectal cancer (mCRC) is FOLFIRI (irinotecan, levo-leucovorin, 5-fluorouracil (5-FU)) plus bevacizumab. With the renewed interest in cancer immunotherapy with agents such as vaccines, checkpoint inhibitors and immune modulators, the possibility exists for the use of one or more of these immunotherapeutics in the first-line setting and thus in combination with the FOLFIRI and bevacizumab regimen. Studies were undertaken to study the effects of FOLFIRI and bevacizumab therapy on peripheral T-cell subsets, and to determine if there are any associations between these subsets and response to therapy. Peripheral blood mononuclear cell subsets of patients with mCRC (n = 23) were analyzed prior to and during therapy. While there were differences among patients, the majority of patients showed either a minimal change or an increase in CD4+ T cell to regulatory T cell (Treg) ratios during therapy, as well as either minimal change or a decrease in Treg suppressive activity during therapy. There was also an association (p = 0.036) between a decrease in Treg frequency during FOLFIRI therapy and overall survival, and an association (p = 0.037) between the frequency of Tregs prior to therapy and progression-free survival. Responders to the chemotherapy by RECIST criteria also had a greater decrease in Tregs during therapy vs. pre-therapy (p = 0.0064) as compared to non-responders. While the number of mCRC patients undergoing chemotherapy in this study is relatively small, it provides the rationale for the use of immunotherapeutics in this first-line metastatic setting.
doi:10.1080/2162402X.2016.1188243
PMCID: PMC5006891  PMID: 27622042
Chemotherapy; colorectal cancer; FOLFIRI; immunotherapy; peripheral T cells; Tregs
10.  Systemic Immunotherapy of Non–Muscle Invasive Mouse Bladder Cancer with Avelumab, an Anti–PD-L1 Immune Checkpoint Inhibitor 
Cancer immunology research  2016;4(5):452-462.
Bacillus Calmette-Guerin (BCG) is the standard of care for intravesical therapy for carcinoma in situ and non–muscle invasive, nonmetastatic human urothelial carcinoma. While the responsiveness to this immunotherapeutic is believed to be linked with (i) a high number of somatic mutations and (ii) a large number of tumor-infiltrating lymphocytes, recent findings of the roles that inhibitory immune receptors and their ligands play in tumor evasion may provide insights into the limitations of the effectiveness of BCG and offer new targets for immune-based therapy. In this study, an aggressive, bioluminescent orthotopic bladder cancer model, MB49 tumor cells transfected with luciferase (MB49luc), was used to study the antitumor effects of avelumab, an antibody to PD-L1. MB49luc murine tumor cells form multifocal tumors on the mucosal wall of the bladder reminiscent of non–muscle invasive, nonmetastatic urothelial carcinomas. MB49luc bladder tumors are highly positive for the expression of PD-L1 and avelumab administration induced significant (P<0.05) antitumor effects. These antitumor effects were more dependent on the presence of CD4 than CD8 T cells, as determined by in vivo immune cell depletions. The findings suggest that in this bladder tumor model, interruption of the immune suppressive PD-1/PD-L1 complex releases a local adaptive immune response that, in turn, reduces tumor growth. This bladder tumor model can be used to further identify host antitumor immune mechanisms and evaluate combinations of immune-based therapies for carcinoma in situ and non–muscle invasive, nonmetastatic urothelial carcinoma, to provide the rationale for subsequent clinical studies.
doi:10.1158/2326-6066.CIR-15-0176
PMCID: PMC4881865  PMID: 26921031
non–muscle invasive bladder cancer; immunotherapy; avelumab; anti-PD-L1
11.  Enhanced antitumor effects by combining an IL-12/anti-DNA fusion protein with avelumab, an anti-PD-L1 antibody 
Oncotarget  2017;8(13):20558-20571.
The combined therapeutic potential of an immunocytokine designed to deliver IL-12 to the necrotic regions of solid tumors with an anti-PD-L1 antibody that disrupts the immunosuppressive PD-1/PD-L1 axis yielded a combinatorial benefit in multiple murine tumor models. The murine version of the immunocytokine, NHS-muIL12, consists of an antibody (NHS76) recognizing DNA/DNA-histone complexes, fused with two molecules of murine IL-12 (NHS-muIL12). By its recognition of exposed DNA, NHS-muIL12 targets IL-12 to the necrotic portions of tumors; it has a longer plasma half-life and better antitumor efficacy against murine tumors than recombinant murine IL-12. It is shown here that NHS-muIL12, in an IFN-γ‒dependent mechanism, upregulates mPD-L1 expression on mouse tumors, which could be construed as an immunosuppressive action. Yet concurrent therapy with NHS-muIL12 and an anti-PD-L1 antibody resulted in additive/synergistic antitumor effects in PD-L1‒expressing subcutaneously transplanted tumors (MC38, MB49) and in an intravesical bladder tumor model (MB49). Antitumor efficacy correlated with (a) with a higher frequency of tumor antigen-specific splenic CD8+ T cells and (b) enhanced T cell activation over a wide range of NHS-muIL12 concentrations. These findings suggest that combining NHS-muIL12 and an anti-PD-L1 antibody enhances T cell activation and T cell effector functions within the tumor microenvironment, significantly improving overall tumor regression. These results should provide the rationale to examine the combination of these agents in clinical studies.
doi:10.18632/oncotarget.16137
PMCID: PMC5400526  PMID: 28423552
checkpoint inhibitor; PD-L1; immunocytokine; interleukin-12; immunotherapy
12.  Immunotherapy biomarkers 2016: overcoming the barriers 
This report summarizes the symposium, ‘Immunotherapy Biomarkers 2016: Overcoming the Barriers’, which was held on April 1, 2016 at the National Institutes of Health in Bethesda, Maryland. The symposium, cosponsored by the Society for Immunotherapy of Cancer (SITC) and the National Cancer Institute (NCI), focused on emerging immunotherapy biomarkers, new technologies, current hurdles to further progress, and recommendations for advancing the field of biomarker development.
doi:10.1186/s40425-017-0225-6
PMCID: PMC5359902
Biomarkers; Immunotherapy; Immune monitoring; High throughput; Baseline measures; Tumor microenvironment
13.  Safety, tumor trafficking and immunogenicity of chimeric antigen receptor (CAR)-T cells specific for TAG-72 in colorectal cancer 
Background
T cells engineered to express chimeric antigen receptors (CARs) have established efficacy in the treatment of B-cell malignancies, but their relevance in solid tumors remains undefined. Here we report results of the first human trials of CAR-T cells in the treatment of solid tumors performed in the 1990s.
Methods
Patients with metastatic colorectal cancer (CRC) were treated in two phase 1 trials with first-generation retroviral transduced CAR-T cells targeting tumor-associated glycoprotein (TAG)-72 and including a CD3-zeta intracellular signaling domain (CART72 cells). In trial C-9701 and C-9702, CART72 cells were administered in escalating doses up to 1010 total cells; in trial C-9701 CART72 cells were administered by intravenous infusion. In trial C-9702, CART72 cells were administered via direct hepatic artery infusion in patients with colorectal liver metastases. In both trials, a brief course of interferon-alpha (IFN-α) was given with each CART72 infusion to upregulate expression of TAG-72.
Results
Fourteen patients were enrolled in C-9701 and nine in C-9702. CART72 manufacturing success rate was 100% with an average transduction efficiency of 38%. Ten patients were treated in CC-9701 and 6 in CC-9702. Symptoms consistent with low-grade, cytokine release syndrome were observed in both trials without clear evidence of on target/off tumor toxicity. Detectable, but mostly short-term (≤14 weeks), persistence of CART72 cells was observed in blood; one patient had CART72 cells detectable at 48 weeks. Trafficking to tumor tissues was confirmed in a tumor biopsy from one of three patients. A subset of patients had 111Indium-labeled CART72 cells injected, and trafficking could be detected to liver, but T cells appeared largely excluded from large metastatic deposits. Tumor biomarkers carcinoembryonic antigen (CEA) and TAG-72 were measured in serum; there was a precipitous decline of TAG-72, but not CEA, in some patients due to induction of an interfering antibody to the TAG-72 binding domain of humanized CC49, reflecting an anti-CAR immune response. No radiologic tumor responses were observed.
Conclusion
These findings demonstrate the relative safety of CART72 cells. The limited persistence supports the incorporation of co-stimulatory domains in the CAR design and the use of fully human CAR constructs to mitigate immunogenicity.
doi:10.1186/s40425-017-0222-9
PMCID: PMC5360066
14.  Analyses of the peripheral immunome following multiple administrations of avelumab, a human IgG1 anti-PD-L1 monoclonal antibody 
Background
Multiple anti-PD-L1/PD-1 checkpoint monoclonal antibodies (MAb) have shown clear evidence of clinical benefit. All except one have been designed or engineered to omit the possibility to mediate antibody-dependent cell-mediated cytotoxicity (ADCC) as a second potential mode of anti-tumor activity; the reason for this is the concern of lysis of PD-L1 positive immune cells. Avelumab is a fully human IgG1 MAb which has been shown in prior in vitro studies to mediate ADCC versus a range of human tumor cells, and clinical studies have demonstrated anti-tumor activity versus a range of human cancers. This study was designed to investigate the effect on immune cell subsets in the peripheral blood of cancer patients prior to and following multiple administrations of avelumab.
Methods
One hundred twenty-three distinct immune cell subsets in the peripheral blood of cancer patients (n = 28) in a phase I trial were analyzed by flow cytometry prior to and following one, three, and nine cycles of avelumab. Changes in soluble (s) CD27 and sCD40L in plasma were also evaluated. In vitro studies were also performed to determine if avelumab would mediate ADCC of PBMC.
Results
No statistically significant changes in any of the 123 immune cell subsets analyzed were observed at any dose level, or number of doses, of avelumab. Increases in the ratio of sCD27:sCD40L were observed, suggesting potential immune activation. Controlled in vitro studies also showed lysis of tumor cells by avelumab versus no lysis of PBMC from five donors.
Conclusions
These studies demonstrate the lack of any significant effect on multiple immune cell subsets, even those expressing PD-L1, following multiple cycles of avelumab. These results complement prior studies showing anti-tumor effects of avelumab and comparable levels of adverse events with avelumab versus other anti-PD-1/PD-L1 MAbs. These studies provide the rationale to further exploit the potential ADCC mechanism of action of avelumab as well as other human IgG1 checkpoint inhibitors.
Trial registration
ClinicalTrials.gov identifier: NCT01772004 (first received: 1/14/13; start date: January 2013) and NCT00001846 (first received date: 11/3/99; start date: August 1999).
Electronic supplementary material
The online version of this article (doi:10.1186/s40425-017-0220-y) contains supplementary material, which is available to authorized users.
doi:10.1186/s40425-017-0220-y
PMCID: PMC5320726
Avelumab; Anti-PD-L1; Checkpoint inhibitor; Immunotherapy; Peripheral immunome; Immune subsets; ADCC; Antibody-dependent cell-mediated cytotoxicity
15.  Near infrared photoimmunotherapy with avelumab, an anti-programmed death-ligand 1 (PD-L1) antibody 
Oncotarget  2016;8(5):8807-8817.
Near Infrared-Photoimmunotherapy (NIR-PIT) is a highly selective tumor treatment that employs an antibody-photo-absorber conjugate (APC). Programmed cell death protein-1 ligand (PD-L1) is emerging as a molecular target. Here, we describe the efficacy of NIR-PIT, using fully human IgG1 anti-PD-L1 monoclonal antibody (mAb), avelumab, conjugated to the photo-absorber, IR700DX, in a PD-L1 expressing H441 cell line, papillary adenocarcinoma of lung. Avelumab-IR700 showed specific binding and cell-specific killing was observed after exposure of the cells to NIR in vitro. In the in vivo study, avelumab-IR700 showed high tumor accumulation and high tumor-background ratio. Tumor-bearing mice were separated into 4 groups: (1) no treatment; (2) 100 μg of avelumab-IR700 i.v.; (3) NIR light exposure only, NIR light was administered; (4) 100 μg of avelumab-IR700 i.v., NIR light was administered. Tumor growth was significantly inhibited by NIR-PIT treatment compared with the other groups (p < 0.001), and significantly prolonged survival was achieved (p < 0.01 vs other groups). In conclusion, the anti-PD-L1 antibody, avelumab, is suitable as an APC for NIR-PIT. Furthermore, NIR-PIT with avelumab-IR700 is a promising candidate of the treatment of PD-L1-expressing tumors that could be readily translated to humans.
doi:10.18632/oncotarget.12410
PMCID: PMC5341755  PMID: 27716622
near infrared photoimmunotherapy; PD-L1; lung cancer
16.  An NK cell line (haNK) expressing high levels of granzyme and engineered to express the high affinity CD16 allele 
Oncotarget  2016;7(52):86359-86373.
Natural killer (NK) cells are known to play a role in mediating innate immunity, in enhancing adaptive immune responses, and have been implicated in mediating anti-tumor responses via antibody-dependent cell-mediated cytotoxicity (ADCC) by reactivity of CD16 with the Fc region of human IgG1 antibodies. The NK-92 cell line, derived from a lymphoma patient, has previously been well characterized and adoptive transfer of irradiated NK-92 cells has demonstrated safety and shown preliminary evidence of clinical benefit in cancer patients. The NK-92 cell line, devoid of CD16, has now been engineered to express the high affinity (ha) CD16 V158 FcγRIIIa receptor, as well as engineered to express IL-2; IL-2 has been shown to replenish the granular stock of NK cells, leading to enhanced perforin- and granzyme-mediated lysis of tumor cells. The studies reported here show high levels of granzyme in haNK cells, and demonstrate the effects of irradiation of haNK cells on multiple phenotypic markers, viability, IL-2 production, and lysis of a spectrum of human tumor cells. Studies also compare endogenous irradiated haNK lysis of tumor cells with that of irradiated haNK-mediated ADCC using cetuximab, trastuzumab and pertuzumab monoclonal antibodies. These studies thus provide the rationale for the potential use of irradiated haNK cells in adoptive transfer studies for a range of human tumor types. Moreover, since only approximately 10% of humans are homozygous for the high affinity V CD16 allele, these studies also provide the rationale for the use of irradiated haNK cells in combination with IgG1 anti-tumor monoclonal antibodies.
doi:10.18632/oncotarget.13411
PMCID: PMC5341330  PMID: 27861156
ADCC; NK lysis; immunotherapy; high affinity CD16; cetuximab
17.  31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016): late breaking abstracts 
Althammer, Sonja | Steele, Keith | Rebelatto, Marlon | Tan, Tze Heng | Wiestler, Tobias | Schmidt, Guenter | Higgs, Brandon | Li, Xia | Shi, Li | Jin, Xiaoping | Antal, Joyce | Gupta, Ashok | Ranade, Koustubh | Binning, Gerd | Bellmunt, Joaquim | de Wit, Ronald | Vaughn, David J. | Fradet, Yves | Lee, Jae Lyun | Fong, Lawrence | Vogelzang, Nicholas J. | Climent, Miguel A. | Petrylak, Daniel P. | Choueiri, Toni K. | Necchi, Andrea | Gerritsen, Winald | Gurney, Howard | Quinn, David I. | Culine, Stéphane | Sternberg, Cora N. | Mai, Yabing | Puhlmann, Markus | Perini, Rodolfo F. | Bajorin, Dean F. | Sharma, Padmanee | Callahan, Margaret K. | Calvo, Emiliano | Kim, Joseph W. | de Braud, Filipo | Ott, Patrick A. | Bono, Petri | Pillai, Rathi N. | Morse, Michael | Le, Dung T. | Taylor, Matthew | Spilliopoulou, Pavlina | Bendell, Johanna | Jaeger, Dirk | Chan, Emily | Antonia, Scott J. | Ascierto, Paolo A. | Hennicken, Delphine | Tschaika, Marina | Azrilevich, Alex | Rosenberg, Jonathan | Levy, Ofer | Chan, Christopher | Cojocaru, Gady | Liang, Spencer | Ophir, Eran | Ganguly, Sudipto | Toporik, Amir | Kotturi, Maya | Kfir, Tal Fridman | Murter, Benjamin M. | Logronio, Kathryn | Dassa, Liat | Leung, Ling | Greenwald, Shirley | Azulay, Meir | Kumar, Sandeep | Alteber, Zoya | Pan, Xiaoyu | Machlenkin, Arthur | Benita, Yair | Drake, Andrew W. | Chajut, Ayelet | Salomon, Ran | Vankin, Ilan | Safyon, Einav | Hunter, John | Levine, Zurit | White, Mark | Leidner, Rom | Kang, Hyunseok | Haddad, Robert | Segal, Neil H. | Wirth, Lori J. | Ferris, Robert L. | Hodi, F. Stephen | Sanborn, Rachel E. | Gajewski, Thomas F. | Sharfman, William | McDonald, Dan | Srivastava, Shivani | Gu, Xuemin | Phillips, Penny | Passey, Chaitali | Seiwert, Tanguy | Habtetsion, Tsadik | Zhou, Gang | Sakellariou-Thompson, Donastas | Haymaker, Cara | Creasy, Caitlin | Hurd, Mark | Uraoka, Naohiro | Canales, Jaime Rodriguez | Koptez, Scott | Hwu, Patrick | Maitra, Anirban | Bernatchez, Chantale | Coyle, Scott M. | Roybel, Kole T. | Rupp, Levi J. | Santoro, Stephen P. | Secrest, Stephanie | Spelman, Michael | Ho, Hanson | Gomes, Tina | Tse, Tiffany | Yung-Wu, Chia | Taunton, Jack | Lim, Wendell | Emtage, Peter | Moudgil, Tarsem | Ballesteros-Merino, Carmen | Hilton, Traci | Paustian, Christopher | Leidner, Rom | Page, David | Urba, Walter | Fox, Bernard | Bell, Bryan | Patel, Ashish | Olafsen, Tove | Satpayev, Daulet | Torgov, Michael | Marchioni, Filippo | Romero, Jason | Jiang, Ziyue Karen | Zamilpa, Charles | Keppler, Jennifer S. | Mascioni, Alessandro | Jia, Fang | Lee, Chen-Yu | Gudas, Jean | Sullivan, Ryan J. | Hoshida, Yujin | Logan, Theodore | Khushalani, Nikhil | Giobbie-Hurder, Anita | Margolin, Kim | Roder, Joanna | Bhatt, Rupal | Koon, Henry | Olencki, Thomas | Hutson, Thomas | Curti, Brendan | Blackmon, Shauna | Mier, James W. | Puzanov, Igor | Roder, Heinrich | Stewart, John | Amin, Asim | Ernstoff, Marc S. | Clark, Joseph I. | Atkins, Michael B. | Kaufman, Howard L. | Sosman, Jeffrey | Signoretti, Sabina | McDermott, David F. | Anderson, Abraham A. | Puzanov, Igor | Milhem, Mohammed M. | Andtbacka, Robert H. I. | Minor, David | Gorski, Kevin S. | Baker, Daniel M. | Hamid, Omid | Kaufman, Howard L. | Akporiaye, Emmanuel | Curti, Brendan | Koguchi, Yoshinobu | Leidner, Rom | Sutcliffe, Kim | Conder, Kristie | Urba, Walter | Marron, Thomas | Bhardwaj, Nina | Hammerich, Linda | George, Fiby | Kim-Schulze, Seunghee | Keler, Tibor | Davis, Tom | Crowley, Elizabeth | Salazar, Andres | Brody, Joshua | Monjazeb, Arta | Daly, Megan E. | Riess, Jonathan | Li, Tianhong | Murphy, William J. | Kelly, Karen | Hu, Zhiwei | Shen, Rulong | Campbell, Amanda | McMichael, Elizabeth | Yu, Lianbo | Ramaswam, Bhuvaneswari | London, Cheryl A. | Xu, Tian | Carson, William | Kokolus, Kathleen M. | Repasky, Elizabeth A. | Schell, Todd D. | Drabick, Joseph D. | Messenheimer, David J. | Jensen, Shawn | Fox, Bernard | Rubinstein, Mark | Andrijauskaite, Kristina | Swiderska-syn, Marzena | Lind, Kristin | Choppin, Agnes | Roell, Marina K. | Wrangle, John | Andrijauskaite, Kristina | Swiderska-syn, Marzena | Rhode, Peter | Wong, Hing | Rubinstein, Mark | Ahmad, Shamim | Webb, Mason | Abu-Eid, Rasha | Shrimali, Rajeev | Verma, Vivek | Doroodchi, Atbin | Berrong, Zuzana | Yashar, David | Samara, Raed | Mkrtichyan, Mikayel | Khleif, Samir | Powell, Steven | Gitau, Mark | Sumey, Christopher | Terrell, Andrew | Lohr, Michele | Nowak, Ryan K. | McGraw, Steven | Jensen, Ash | Blanchard, Miran | Gold, Kathryn A. | Cohen, Ezra E. W. | Ellison, Christie | Black, Lora | Lee, John | Spanos, William Chad | Wennerberg, Erik | Schwitzer, Emily | Lhuillier, Claire | Koelwyn, Graeme | Hiner, Rebecca | Jones, Lee | Demaria, Sandra | Amanda, Vandeveer | Greiner, John W. | Schlom, Jeffrey | Bookstaver, Michelle | Jewell, Christopher M. | Paustian, Christopher | Gunderson, Andrew | Boulmay, Brian | Li, Rui | Spieler, Bradley | Happel, Kyle | Moudgil, Tarsem | Feng, Zipei | Ballesteros-Merino, Carmen | Dubay, Christopher | Fisher, Brenda | Koguchi, Yoshinobu | Aung, Sandra | Mederos, Eileen | Bifulco, Carlo B. | McNamara, Michael | Bahjat, Keith | Redmond, William | Ochoa, Augusto | Hu, Hong-Ming | Mehta, Adi | Lund-Johansen, Fridtjof | Fox, Bernard | Urba, Walter | Sanborn, Rachel E. | Hilton, Traci | Bedu-Addo, Frank | Conn, Greg | King, Michael | Dutta, Panna | Shepard, Robert | Einstein, Mark | Adams, Sylvia | Wang, Ena | Jin, Ping | Novik, Yelena | Morrison, Debra | Oratz, Ruth | Marincola, Franco M. | Stroncek, David | Goldberg, Judith | Demaria, Sandra | Formenti, Silvia C. | Galon, Jérôme | Mlecnik, Bernhard | Marliot, Florence | Ou, Fang-Shu | Bifulco, Carlo B. | Lugli, Alessandro | Zlobec, Inti | Rau, Tilman T. | Nagtegaal, Iris D. | Vink-Borger, Elisa | Hartmann, Arndt | Geppert, Carol | Roehrl, Michael H. | Bavi, Prashant | Ohashi, Pamela S. | Wang, Julia Y. | Nguyen, Linh T. | Han, SeongJun | MacGregor, Heather L. | Hafezi-Bakhtiari, Sara | Wouters, Bradley G. | Kawakami, Yutaka | Papivanova, Boryana | Xu, Mingli | Fujita, Tomonobu | Hazama, Shoichi | Suzuki, Nobuaki | Nagano, Hiroaki | Okuno, Kiyotaka | Itoh, Kyogo | Zavadova, Eva | Vocka, Michal | Spacek, Jan | Petruzelka, Lubos | Konopasek, Bohuslav | Dundr, Pavel | Skalova, Helena | Torigoe, Toshihiko | Sato, Noriyuki | Furuhata, Tomohisa | Takemasa, Ichiro | Van den Eynde, Marc | Jouret-Mourin, Anne | Machiels, Jean-Pascal | Fredriksen, Tessa | Lafontaine, Lucie | Buttard, Bénédicte | Church, Sarah | Maby, Pauline | Angell, Helen | Angelova, Mihaela | Vasaturo, Angela | Bindea, Gabriela | Berger, Anne | Lagorce, Christine | Patel, Prabhu S. | Vora, Hemangini H. | Shah, Birva | Patel, Jayendrakumar B. | Rajvik, Kruti N. | Pandya, Shashank J. | Shukla, Shilin N. | Wang, Yili | Zhang, Guanjun | Masucci, Giuseppe V. | Andersson, Emilia K. | Grizzi, Fabio | Laghi, Luigi | Botti, Gerardo | Tatangelo, Fabiana | Delrio, Paolo | Cilberto, Gennaro | Ascierto, Paolo A. | Marincola, Franco | Sargent, Daniel J. | Fox, Bernard A. | Algazi, Alain | Tsai, Katy | Rosenblum, Michael | Nandoskar, Prachi | Andtbacka, Robert H. I. | Li, Amy | Nonomura, John | Takamura, Kathryn | Dwyer, Mary | Browning, Erica | Talia, Reneta | Twitty, Chris | Gargosky, Sharron | Campbell, Jean | Ballesteros-Merino, Carmen | Bifulco, Carlo B. | Fox, Bernard | Le, Mai | Pierce, Robert H. | Daud, Adil | Gartrell, Robyn | Marks, Douglas | Stack, Edward | Lu, Yan | Izaki, Daisuke | Beck, Kristen | Jia, Dan Tong | Armenta, Paul | White-Stern, Ashley | Fu, Yichun | Blake, Zoe | Kaufman, Howard L. | Taback, Bret | Horst, Basil | Saenger, Yvonne M. | Leonardo, Steven | Gorden, Keith | Fulton, Ross B. | Fraser, Kathryn | Kangas, Takashi O. | Walsh, Richard | Ertelt, Kathleen | Graff, Jeremy | Uhlik, Mark | Sims, Jennifer S. | Lei, Liang | Tsujiuchi, Takashi | Bruce, Jeffrey N. | Canoll, Peter | Tolcher, Anthony W | Alley, Evan W | Chichili, Gurunadh | Canoll, Jan E | Moore, Paul | Bonvini, Ezio | Johnson, Syd | Shankar, Sadhna | Vasselli, James | Wigginton, Jon | Powderly, John
doi:10.1186/s40425-016-0191-4
PMCID: PMC5260784
18.  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
19.  Phase I trial of a yeast-based therapeutic cancer vaccine (GI-6301) targeting the transcription factor brachyury 
Cancer immunology research  2015;3(11):1248-1256.
The nuclear transcription factor brachyury has previously been shown to be a strong mediator of the epithelial-to-mesenchymal transition (EMT) in human carcinoma cells and a strong negative prognostic factor in several tumor types. Brachyury is overexpressed in a range of human carcinoma as well as in chordoma, a rare tumor for which there is no standard systemic therapy. Preclinical studies have shown a recombinant Saccharomyces cerevisiae (yeast) vaccine encoding brachyury (GI-6301) can activate human T cells in vitro. A Phase I dose escalation (3+3 design) trial enrolled 34 patients at 4 dose levels (3, 3, 16, and 11 patients, respectively, at 4, 16, 40, and 80 yeast units (YU)). Expansion cohorts were enrolled at 40 and 80 YU dose levels for analysis of immune response and clinical activity. We observed brachyury-specific T-cell immune responses in the majority of evaluable patients despite most having been heavily pretreated. No evidence of autoimmunity or other serious adverse events were observed. Two chordoma patients showed evidence of disease control (one mixed response and one partial response). A patient with colorectal carcinoma, who enrolled on study with a large progressing pelvic mass and rising CEA, remains on study for greater than 1 year with stable disease, evidence of decreased tumor density and decreased serum CEA. This study is the first-in-human to demonstrate the safety and immunogenicity of this therapeutic cancer vaccine and provides rationale for exploration in Phase II studies. A randomized Phase II chordoma study is enrolling.
doi:10.1158/2326-6066.CIR-15-0119
PMCID: PMC4636967  PMID: 26130065
Chordoma; Immunotherapy; Epithelial to mesenchymal transition (EMT); Tarmogen; Therapeutic vaccine
20.  Samarium-153-EDTMP (Quadramet®) with or without vaccine in metastatic castration-resistant prostate cancer: A randomized Phase 2 trial 
Oncotarget  2016;7(42):69014-69023.
PSA-TRICOM is a therapeutic vaccine in late stage clinical testing in metastatic castration-resistant prostate cancer (mCRPC). Samarium-153-ethylene diamine tetramethylene phosphonate (Sm-153-EDTMP; Quadramet®), a radiopharmaceutical, binds osteoblastic bone lesions and emits beta particles causing local tumor cell destruction. Preclinically, Sm-153-EDTMP alters tumor cell phenotype facilitating immune-mediated killing. This phase 2 multi-center trial randomized patients to Sm-153-EDTMP alone or with PSA-TRICOM vaccine. Eligibility required mCRPC, bone metastases, prior docetaxel and no visceral disease. The primary endpoint was the proportion of patients without radiographic disease progression at 4 months. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and immune responses. Forty-four patients enrolled. Eighteen and 21 patients were evaluable for the primary endpoint in Sm-153-EDTMP alone and combination arms, respectively. There was no statistical difference in the primary endpoint, with two of 18 (11.1%) and five of 21 (23.8%) in Sm-153-EDTMP alone and combination arms, respectively, having stable disease at approximately the 4-month evaluation time point (P = 0.27). Median PFS was 1.7 vs. 3.7 months in the Sm-153-EDTMP alone and combination arms (P = 0.041, HR = 0.51, P = 0.046). No patient in the Sm-153-EDTMP alone arm achieved prostate-specific antigen (PSA) decline > 30% compared with four patients (of 21) in the combination arm, including three with PSA decline > 50%. Toxicities were similar between arms and related to number of Sm-153-EDTMP doses administered. These results provide the rationale for clinical evaluation of new radiopharmaceuticals, such as Ra-223, in combination with PSA-TRICOM.
doi:10.18632/oncotarget.10883
PMCID: PMC5340090  PMID: 27486817
therapeutic vaccine; radionuclide; prostate cancer; Quadramet®; cancer immunotherapy
21.  NUCLEAR BRACHYURY EXPRESSION IS CONSISTENT IN CHORDOMA, COMMON IN GERM CELL TUMORS AND SMALL CELL CARCINOMAS AND RARE IN OTHER CARCINOMAS AND SARCOMAS. AN IMMUNOHISTOCHEMICAL STUDY OF 5229 CASES 
Brachyury is a transcription factor of the T-box family typically expressed in notochord and chordoma. Some studies report brachyury as highly specific for chordoma, whereas others have concluded that brachyury is expressed in many types of common carcinomas by RT-PCR and immunohistochemistry and could be involved in the epithelial-mesenchymal transition and metastatic process. In this study, we immunohistochemically evaluated 5229 different tumors for nuclear brachyury expression using a new rabbit monoclonal antibody and automated immunostaining (Leica Bond Max). Only nuclear labeling was scored, and antibody dilution of 1:2000 was used. In normal tissues, only rare cells in seminiferous tubules were labeled; all other organs were negative. All chordomas (75/76), except a sarcomatous one, were positive, whereas chondrosarcomas were negative. Among epithelial tumors, positivity was often detected in embryonal carcinoma (74%) and seminoma (45%). Pulmonary small cell carcinoma was often positive (41%), whereas pulmonary and pancreatic adenocarcinomas only rarely showed nuclear brachyury-positivity (3–4%). Common carcinomas such as ductal carcinomas of breast, or adenocarcinomas of the prostate only exceptionally showed nuclear positivity (< 1%). No colorectal, hepatocellular, renal cell, squamous cell, thyroid or urothelial carcinoma, or mesothelioma showed nuclear brachyury-positivity. Among mesenchymal and neuroectodermal tumors, only isolated cases of melanoma, malignant peripheral nerve sheath tumor, rhabdomyosarcoma, synovial sarcoma, and follicular lymphoma showed nuclear expression. However, as shown previously with lung carcinoma, experiments with lower antibody dilutions (1:200–1:500) showed weak cytoplasmic and nuclear labeling in breast cancers. In addition to chordoma, we show here for the first time that nuclear brachyury expression is prevalent in embryonal carcinoma, seminoma, and small cell carcinoma of the lung but very rare in common carcinomas, sarcomas, and melanoma. With these reservations, we have demonstrated the presence of nuclear brachyury immunoreactivity to be a sensitive and fairly specific marker for chordoma.
doi:10.1097/PAS.0000000000000462
PMCID: PMC4567944  PMID: 26099010
Brachyury; chordoma; seminoma; germ cell tumor; small cell carcinoma
22.  Antibody-dependent cellular cytotoxicity (ADCC) activity of a novel anti-PD-L1 antibody avelumab (MSB0010718C) on human tumor cells 
Cancer immunology research  2015;3(10):1148-1157.
Several anti-PD1/PD-L1 monoclonal antibodies (MAb) are currently providing evidence of clinical benefit in subsets of cancer patients. The mode of action of these MAbs is to inhibit PD1 on immune cells interacting with PD-L1 on tumor cells. These MAbs are either designed or engineered to eliminate antibody-dependent cell-mediated cytotoxicity (ADCC), which, however, has been implicated as an important mechanism in several highly effective MAb-mediated cancer therapies. A fully human anti-PD-L1 MAb would potentially be able to block PD-L1/PD1 interactions and also mediate the ADCC lysis of tumor cells. MSB0010718C (designated avelumab) is a fully human IgG1 anti-PD-L1 MAb. The studies reported here demonstrate (a) the ability of avelumab to lyse a range of human tumor cells in the presence of PBMC or NK effectors; (b) IFNγ can enhance tumor cell PD-L1 expression and in some cases enhance ADCC tumor cell lysis; (c) purified NK cells are potent effectors for avelumab; (d) similar levels of avelumab-mediated ADCC lysis of tumor cells are seen using purified NK as effectors from either healthy donors or cancer patients; (e) very low levels of avelumab-mediated lysis are seen using whole PBMCs as targets; this finding complements results seen in analyses of PBMC subsets of patients receiving avelumab; and (f) the addition of IL12 to NK cells greatly enhances avelumab-mediated ADCC. These studies thus provide an additional mode of action for an anti-PD-L1 MAb and support the rationale for further studies to enhance avelumab-mediated ADCC activity.
doi:10.1158/2326-6066.CIR-15-0059
PMCID: PMC4739754  PMID: 26014098
checkpoint inhibitor; anti-PD-L1; antibody-dependent cellular cytotoxicity
23.  The IDO1 selective inhibitor epacadostat enhances dendritic cell immunogenicity and lytic ability of tumor antigen-specific T cells 
Oncotarget  2016;7(25):37762-37772.
Epacadostat is a novel inhibitor of indoleamine-2,3-dioxygenase-1 (IDO1) that suppresses systemic tryptophan catabolism and is currently being evaluated in ongoing clinical trials. We investigated the effects of epacadostat on (a) human dendritic cells (DCs) with respect to maturation and ability to activate human tumor antigen-specific cytotoxic T-cell (CTL) lines, and subsequent T-cell lysis of tumor cells, (b) human regulatory T cells (Tregs), and (c) human peripheral blood mononuclear cells (PBMCs) in vitro. Simultaneous treatment with epacadostat and IFN-γ plus lipopolysaccharide (LPS) did not change the phenotype of matured human DCs, and as expected decreased the tryptophan breakdown and kynurenine production. Peptide-specific T-cell lines stimulated with DCs pulsed with peptide produced significantly more IFN-γ, TNFα, GM-CSF and IL-8 if the DCs were treated with epacadostat. These T cells also displayed higher levels of tumor cell lysis on a per cell basis. Epacadostat also significantly decreased Treg proliferation induced by IDO production from IFN-γ plus LPS matured human DCs, although the Treg phenotype did not change. Multicolor flow cytometry was performed on human PBMCs treated with epacadostat; analysis of 123 discrete immune cell subsets revealed no changes in major immune cell types, an increase in activated CD83+ conventional DCs, and a decrease in immature activated Tim3+ NK cells. These studies show for the first time several effects of epacadostat on human DCs, and subsequent effects on CTL and Tregs, and provide a rationale as to how epacadostat could potentially increase the efficacy of immunotherapeutics, including cancer vaccines.
doi:10.18632/oncotarget.9326
PMCID: PMC5122347  PMID: 27192116
IDO inhibitor; dendritic cells; T cells; indoleamine-2; 3-dioxygenase (IDO); Tregs
24.  Enhanced killing of chordoma cells by antibody-dependent cell-mediated cytotoxicity employing the novel anti-PD-L1 antibody avelumab 
Oncotarget  2016;7(23):33498-33511.
Chordoma, a rare bone tumor derived from the notochord, has been shown to be resistant to conventional therapies. Checkpoint inhibition has shown great promise in immune-mediated therapy of diverse cancers. The anti-PD-L1 mAb avelumab is unique among checkpoint inhibitors in that it is a fully human IgG1 capable of mediating antibody-dependent cell-mediated cytotoxicity (ADCC) of PD-L1-expressing tumor cells. Here, we investigated avelumab as a potential therapy for chordoma. We examined 4 chordoma cell lines, first for expression of PD-L1, and in vitro for ADCC killing using NK cells and avelumab. PD-L1 expression was markedly upregulated by IFN-γ in all 4 chordoma cell lines, which significantly increased sensitivity to ADCC. Brachyury is a transcription factor that is uniformly expressed in chordoma. Clinical trials are ongoing in which chordoma patients are treated with brachyury-specific vaccines. Co-incubating chordoma cells with brachyury-specific CD8+ T cells resulted in significant upregulation of PD-L1 on the tumor cells, mediated by the CD8+ T cells' IFN-γ production, and increased sensitivity of chordoma cells to avelumab-mediated ADCC. Residential cancer stem cell subpopulations of chordoma cells were also killed by avelumab-mediated ADCC to the same degree as non-cancer stem cell populations. These findings suggest that as a monotherapy for chordoma, avelumab may enable endogenous NK cells, while in combination with T-cell immunotherapy, such as a vaccine, avelumab may enhance NK-cell killing of chordoma cells via ADCC.
doi:10.18632/oncotarget.9256
PMCID: PMC5085098  PMID: 27172898
chordoma; programmed death-ligand 1 (PD-L1); antibody-dependent cell-mediated cytotoxicity (ADCC); cancer stem cells; immunotherapy
25.  A fully human IgG1 anti-PD-L1 MAb in an in vitro assay enhances antigen-specific T-cell responses 
Monoclonal antibodies (MAbs) that interfere with checkpoint molecules are being investigated for the treatment of infectious diseases and cancer, with the aim of enhancing the function of an impaired immune system. Avelumab (MSB0010718C) is a fully human IgG1 MAb targeting programmed death-ligand 1 (PD-L1), which differs from other checkpoint-blocking antibodies in its ability to mediate antibody-dependent cell-mediated cytotoxicity. These studies were conducted to define whether avelumab could enhance the detection of antigen-specific immune response in in vitro assays. Peripheral blood mononuclear cells from 17 healthy donors were stimulated in vitro, with and without avelumab, with peptide pools encoding for cytomegalovirus, Epstein–Barr virus, influenza and tetanus toxin or the negative peptide control encoding for human leukocyte antigen. These studies show for the first time that the addition of avelumab to an antigen-specific IVS assay (a) increased the frequency of activated antigen-specific CD8+ T lymphocytes, and did so to a greater extent than that seen with commercially available PD-L1-blocking antibodies, (b) reduced CD4+ T-cell proliferation and (c) induced a switch in the production of Th2 to Th1 cytokines. Moreover, there was an inverse correlation between the enhancement of CD8+ T-cell activation and reduction in CD4+ T-cell proliferation induced by avelumab. These findings provide the rationale for the use of avelumab anti-PD-L1 in in vitro assays to monitor patient immune responses to immunotherapies.
doi:10.1038/cti.2016.27
PMCID: PMC4910121  PMID: 27350882

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