Volume 4 Supplement 1

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016)

Open Access

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016): part two

National Harbor, MD, USA. 9-13 November 2016
  • Casey Ager1Email author,
  • Matthew Reilley2,
  • Courtney Nicholas1,
  • Todd Bartkowiak1,
  • Ashvin Jaiswal1,
  • Michael Curran1,
  • Tina C. Albershardt3Email author,
  • Anshika Bajaj3,
  • Jacob F. Archer3,
  • Rebecca S. Reeves3,
  • Lisa Y. Ngo3,
  • Peter Berglund3,
  • Jan ter Meulen3,
  • Caroline Denis4,
  • Hormas Ghadially5,
  • Thomas Arnoux4,
  • Fabien Chanuc4,
  • Nicolas Fuseri4,
  • Robert W. Wilkinson5,
  • Nicolai Wagtmann4,
  • Yannis Morel4,
  • Pascale Andre4Email author,
  • Michael B. Atkins6Email author,
  • Matteo S. Carlino7,
  • Antoni Ribas8,
  • John A. Thompson9,
  • Toni K. Choueiri10,
  • F. Stephen Hodi10,
  • Wen-Jen Hwu11,
  • David F. McDermott12,
  • Victoria Atkinson13,
  • Jonathan S. Cebon14,
  • Bernie Fitzharris15,
  • Michael B. Jameson16,
  • Catriona McNeil17,
  • Andrew G. Hill18,
  • Eric Mangin19,
  • Malidi Ahamadi19,
  • Marianne van Vugt20,
  • Mariëlle van Zutphen20,
  • Nageatte Ibrahim19,
  • Georgina V. Long21,
  • Robyn Gartrell22,
  • Zoe Blake22Email author,
  • Ines Simoes23,
  • Yichun Fu22,
  • Takuro Saito24,
  • Yingzhi Qian22,
  • Yan Lu22,
  • Yvonne M. Saenger25,
  • Sadna Budhu26Email author,
  • Olivier De Henau26,
  • Roberta Zappasodi26,
  • Kyle Schlunegger27,
  • Bruce Freimark27,
  • Jeff Hutchins27,
  • Christopher A. Barker26,
  • Jedd D. Wolchok26,
  • Taha Merghoub26,
  • Elena Burova28Email author,
  • Omaira Allbritton28,
  • Peter Hong28,
  • Jie Dai28,
  • Jerry Pei28,
  • Matt Liu28,
  • Joel Kantrowitz28,
  • Venus Lai28,
  • William Poueymirou28,
  • Douglas MacDonald28,
  • Ella Ioffe28,
  • Markus Mohrs28,
  • William Olson28,
  • Gavin Thurston28,
  • Cristian Capasso29Email author,
  • Federica Frascaro30,
  • Sara Carpi31,
  • Siri Tähtinen29,
  • Sara Feola32,
  • Manlio Fusciello29,
  • Karita Peltonen29,
  • Beatriz Martins29,
  • Madeleine Sjöberg29,
  • Sari Pesonen33,
  • Tuuli Ranki33,
  • Lukasz Kyruk29,
  • Erkko Ylösmäki29,
  • Vincenzo Cerullo29,
  • Fabio Cerignoli34Email author,
  • Biao Xi34,
  • Garret Guenther34,
  • Naichen Yu34,
  • Lincoln Muir34,
  • Leyna Zhao34,
  • Yama Abassi34,
  • Víctor Cervera-Carrascón35Email author,
  • Mikko Siurala35,
  • João Santos35,
  • Riikka Havunen36,
  • Suvi Parviainen35,
  • Akseli Hemminki35,
  • Angus Dalgleish37Email author,
  • Satvinder Mudan38,
  • Mark DeBenedette39Email author,
  • Ana Plachco39,
  • Alicia Gamble39,
  • Elizabeth W. Grogan39,
  • John Krisko39,
  • Irina Tcherepanova39,
  • Charles Nicolette39,
  • Pooja Dhupkar40Email author,
  • Ling Yu40,
  • Eugenie S. Kleinerman40,
  • Nancy Gordon40,
  • Italia Grenga41,
  • Lauren Lepone41,
  • Sofia Gameiro41,
  • Karin M. Knudson41,
  • Massimo Fantini41,
  • Kwong Tsang41,
  • James Hodge41,
  • Renee Donahue41Email author,
  • Jeffrey Schlom41,
  • Elizabeth Evans42Email author,
  • Holm Bussler42,
  • Crystal Mallow42,
  • Christine Reilly42,
  • Sebold Torno42,
  • Maria Scrivens42,
  • Cathie Foster42,
  • Alan Howell42,
  • Leslie Balch42,
  • Alyssa Knapp42,
  • John E. Leonard42,
  • Mark Paris42,
  • Terry Fisher42,
  • Siwen Hu-Lieskovan43,
  • Antoni Ribas43,
  • Ernest Smith42,
  • Maurice Zauderer42,
  • William Fogler44Email author,
  • Marilyn Franklin45,
  • Matt Thayer45,
  • Dan Saims45,
  • John L. Magnani44,
  • Jian Gong46,
  • Michael Gray46,
  • Jeff Hutchins46,
  • Bruce Freimark46Email author,
  • George Fromm47Email author,
  • Suresh de Silva47,
  • Louise Giffin47,
  • Xin Xu47,
  • Jason Rose47,
  • Taylor H. Schreiber47,
  • Massimo Fantini48,
  • Sofia R. Gameiro48,
  • Karin M. Knudson48,
  • Paul E. Clavijo49,
  • Clint T. Allen49,
  • Renee Donahue48,
  • Lauren Lepone48,
  • Italia Grenga48,
  • James W. Hodge48,
  • Kwong Y. Tsang48,
  • Jeffrey Schlom48,
  • Michael Gray50Email author,
  • Jian Gong50,
  • Jeff Hutchins50,
  • Bruce Freimark50,
  • Jane Grogan51Email author,
  • Nicholas Manieri51,
  • Eugene Chiang51,
  • Patrick Caplazi51,
  • Mahesh Yadav51,
  • Patrick Hagner52Email author,
  • Hsiling Chiu52,
  • Michelle Waldman52,
  • Anke Klippel52,
  • Anjan Thakurta52,
  • Michael Pourdehnad53,
  • Anita Gandhi52,
  • Ian Henrich54Email author,
  • Laura Quick55,
  • Rob Young55,
  • Margaret Chou55,
  • Andrew Hotson56Email author,
  • Stephen Willingham56,
  • Po Ho56,
  • Carmen Choy56,
  • Ginna Laport56,
  • Ian McCaffery56,
  • Richard Miller56,
  • Kimberly A. Tipton57,
  • Kenneth R. Wong57,
  • Victoria Singson57,
  • Chihunt Wong57,
  • Chanty Chan57,
  • Yuanhiu Huang57,
  • Shouchun Liu57,
  • Jennifer H. Richardson57,
  • W. Michael Kavanaugh57,
  • James West57,
  • Bryan A. Irving57Email author,
  • Kimberly A. Tipton58,
  • Kenneth R. Wong58,
  • Victoria Singson58,
  • Chihunt Wong58,
  • Chanty Chan58,
  • Yuanhiu Huang58,
  • Shouchun Liu58,
  • Jennifer H. Richardson58,
  • W. Michael Kavanaugh58,
  • James West58,
  • Bryan A. Irving58Email author,
  • Ritika Jaini59Email author,
  • Matthew Loya59,
  • Charis Eng59,
  • Melissa L. Johnson60Email author,
  • Alex A. Adjei61,
  • Mateusz Opyrchal62,
  • Suresh Ramalingam63,
  • Pasi A. Janne64,
  • George Dominguez65,
  • Dmitry Gabrilovich65,
  • Laura de Leon66,
  • Jeannette Hasapidis66,
  • Scott J. Diede67,
  • Peter Ordentlich66,
  • Scott Cruickshank66,
  • Michael L. Meyers68,
  • Matthew D. Hellmann69,
  • Pawel Kalinski70, 71Email author,
  • Amer Zureikat72,
  • Robert Edwards73,
  • Ravi Muthuswamy73,
  • Nataša Obermajer74,
  • Julie Urban73,
  • Lisa H. Butterfield72,
  • William Gooding72,
  • Herbert Zeh72,
  • David Bartlett74,
  • Olga Zubkova75Email author,
  • Larissa Agapova75,
  • Marina Kapralova75,
  • Liudmila Krasovskaia75,
  • Armen Ovsepyan76,
  • Maxim Lykov76,
  • Artem Eremeev75,
  • Vladimir Bokovanov75,
  • Olga Grigoryeva75,
  • Andrey Karpov75,
  • Sergey Ruchko75,
  • Charles Nicolette77,
  • Alexandr Shuster76,
  • Danny N. Khalil78Email author,
  • Luis Felipe Campesato78,
  • Yanyun Li79,
  • Taha Merghoub79,
  • Jedd D. Wolchok80,
  • Adam S. Lazorchak81Email author,
  • Troy D. Patterson81,
  • Yueyun Ding81,
  • Pottayil Sasikumar82,
  • Naremaddepalli Sudarshan82,
  • Nagaraj Gowda82,
  • Raghuveer Ramachandra82,
  • Dodheri Samiulla82,
  • Sanjeev Giri82,
  • Rajesh Eswarappa82,
  • Murali Ramachandra82,
  • David Tuck81,
  • Timothy Wyant81,
  • Jasmin Leshem83Email author,
  • Xiu-fen Liu83,
  • Tapan Bera83,
  • Masaki Terabe83,
  • Birgit Bossenmaier84,
  • Gerhard Niederfellner84,
  • Yoram Reiter85,
  • Ira Pastan83,
  • Leiming Xia86,
  • Yang Xia86,
  • Yangyang Hu86,
  • Yi Wang87,
  • Yangyi Bao87,
  • Fu Dai87,
  • Shiang Huang88,
  • Elaine Hurt89,
  • Robert E. Hollingsworth89,
  • Lawrence G. Lum90,
  • Alfred E. Chang86,
  • Max S. Wicha91,
  • Qiao Li92Email author,
  • Thomas Mace93Email author,
  • Neil Makhijani93,
  • Erin Talbert93,
  • Gregory Young93,
  • Denis Guttridge93,
  • Darwin Conwell93,
  • Gregory B. Lesinski93,
  • Rodney JM Macedo Gonzales94Email author,
  • Austin P. Huffman94,
  • Ximi K. Wang94,
  • Ran Reshef94,
  • Andy MacKinnon95Email author,
  • Jason Chen95,
  • Matt Gross95,
  • Gisele Marguier95,
  • Peter Shwonek95,
  • Natalija Sotirovska95,
  • Susanne Steggerda95,
  • Francesco Parlati95,
  • Amani Makkouk96Email author,
  • Mark K. Bennett96,
  • Jason Chen96,
  • Ethan Emberley96,
  • Matt Gross96,
  • Tony Huang96,
  • Weiqun Li96,
  • Andy MacKinnon96,
  • Gisele Marguier96,
  • Silinda Neou96,
  • Alison Pan96,
  • Jing Zhang96,
  • Winter Zhang96,
  • Francesco Parlati96,
  • Netonia Marshall97Email author,
  • Thomas U. Marron97,
  • Judith Agudo97,
  • Brian Brown97,
  • Joshua Brody97,
  • Christopher McQuinn98Email author,
  • Thomas Mace98,
  • Matthew Farren98,
  • Hannah Komar98,
  • Reena Shakya98,
  • Gregory Young98,
  • Thomas Ludwug98,
  • Gregory B. Lesinski98,
  • Y. Maurice Morillon99Email author,
  • Scott A. Hammond100,
  • Jeffrey Schlom99,
  • John W. Greiner99,
  • Pulak R. Nath101Email author,
  • Anthony L. Schwartz101,
  • Dragan Maric102,
  • David D. Roberts101,
  • Nataša Obermajer103Email author,
  • David Bartlett103,
  • Pawel Kalinski104, 105,
  • Aung Naing106,
  • Kyriakos P. Papadopoulos107,
  • Karen A. Autio108,
  • Deborah J. Wong109,
  • Manish Patel110,
  • Gerald Falchook111,
  • Shubham Pant112,
  • Patrick A. Ott113,
  • Melinda Whiteside114,
  • Amita Patnaik107,
  • John Mumm114,
  • Filip Janku106,
  • Ivan Chan114,
  • Todd Bauer106, 107,
  • Rivka Colen106,
  • Peter VanVlasselaer114,
  • Gail L. Brown114,
  • Nizar M. Tannir106,
  • Martin Oft114Email author,
  • Jeffrey Infante115,
  • Evan Lipson116Email author,
  • Ajay Gopal117,
  • Sattva S. Neelapu118,
  • Philippe Armand119,
  • Stephen Spurgeon120,
  • John P. Leonard121,
  • F. Stephen Hodi119,
  • Rachel E. Sanborn122,
  • Ignacio Melero123,
  • Thomas F. Gajewski124,
  • Matthew Maurer125,
  • Serena Perna126,
  • Andres A. Gutierrez127,
  • Raphael Clynes126,
  • Priyam Mitra126,
  • Satyendra Suryawanshi126,
  • Douglas Gladstone123,
  • Margaret K. Callahan127,
  • James Crooks128,
  • Sheila Brown128,
  • Audrey Gauthier129,
  • Marc Hillairet de Boisferon129,
  • Andrew MacDonald128,
  • Laura Rosa Brunet130Email author,
  • William T. Rothwell131Email author,
  • Peter Bell131,
  • James M. Wilson131,
  • Fumi Sato-Kaneko132Email author,
  • Shiyin Yao132,
  • Shannon S. Zhang133,
  • Dennis A. Carson132,
  • Cristina Guiducci133,
  • Robert L. Coffman133,
  • Kazutaka Kitaura134,
  • Takaji Matsutani134,
  • Ryuji Suzuki134,
  • Tomoko Hayashi132,
  • Ezra E. W. Cohen132,
  • David Schaer135Email author,
  • Yanxia Li135,
  • Julie Dobkin135,
  • Michael Amatulli135,
  • Gerald Hall135,
  • Thompson Doman136,
  • Jason Manro136,
  • Frank Charles Dorsey136,
  • Lillian Sams136,
  • Rikke Holmgaard135,
  • Krishnadatt Persaud135,
  • Dale Ludwig135,
  • David Surguladze135,
  • John S. Kauh137,
  • Ruslan Novosiadly135,
  • Michael Kalos135,
  • Kyla Driscoll135,
  • Hardev Pandha138,
  • Christy Ralph139,
  • Kevin Harrington140,
  • Brendan Curti141,
  • Rachel E. Sanborn142,
  • Wallace Akerley143,
  • Sumati Gupta143,
  • Alan Melcher144,
  • David Mansfield144,
  • David R. Kaufman145,
  • Emmett Schmidt145,
  • Mark Grose145,
  • Bronwyn Davies146,
  • Roberta Karpathy146,
  • Darren Shafren146Email author,
  • Katerina Shamalov147Email author,
  • Cyrille Cohen147,
  • Naveen Sharma148,
  • James Allison148,
  • Tala Shekarian149Email author,
  • Sandrine Valsesia-Wittmann150,
  • Christophe Caux149,
  • Aurelien Marabelle151,
  • Brian M. Slomovitz152Email author,
  • Kathleen M. Moore153,
  • Hagop Youssoufian154,
  • Marshall Posner155,
  • Poonam Tewary156Email author,
  • Alan D. Brooks157,
  • Ya-Ming Xu158,
  • Kithsiri Wijeratne158,
  • Leslie A. A. Gunatilaka159,
  • Thomas J. Sayers156,
  • John P. Vasilakos160Email author,
  • Tesha Alston160,
  • Simon Dovedi161,
  • James Elvecrog160,
  • Iwen Grigsby160,
  • Ronald Herbst162,
  • Karen Johnson160,
  • Craig Moeckly160,
  • Stefanie Mullins161,
  • Kristen Siebenaler160,
  • Julius SternJohn160,
  • Ashenafi Tilahun160,
  • Mark A. Tomai160,
  • Katharina Vogel161,
  • Robert W. Wilkinson161,
  • Eveline E. Vietsch163,
  • Anton Wellstein163Email author,
  • Martin Wythes164Email author,
  • Stefano Crosignani165,
  • Joseph Tumang164,
  • Shilpa Alekar164,
  • Patrick Bingham164,
  • Sandra Cauwenberghs165,
  • Jenny Chaplin164,
  • Deepak Dalvie164,
  • Sofie Denies165,
  • Coraline De Maeseneire165,
  • JunLi Feng164,
  • Kim Frederix165,
  • Samantha Greasley164,
  • Jie Guo164,
  • James Hardwick164,
  • Stephen Kaiser164,
  • Katti Jessen164,
  • Erick Kindt164,
  • Marie-Claire Letellier165,
  • Wenlin Li164,
  • Karen Maegley164,
  • Reece Marillier165,
  • Nichol Miller164,
  • Brion Murray164,
  • Romain Pirson165,
  • Julie Preillon166,
  • Virginie Rabolli165,
  • Chad Ray164,
  • Kevin Ryan164,
  • Stephanie Scales164,
  • Jay Srirangam164,
  • Jim Solowiej164,
  • Al Stewart164,
  • Nicole Streiner164,
  • Vince Torti164,
  • Konstantinos Tsaparikos164,
  • Xianxian Zheng164,
  • Gregory Driessens165,
  • Bruno Gomes165,
  • Manfred Kraus164,
  • Chunxiao Xu167Email author,
  • Yanping Zhang168,
  • Giorgio Kradjian168,
  • Guozhong Qin168,
  • Jin Qi168,
  • Xiaomei Xu168,
  • Bo Marelli168,
  • Huakui Yu168,
  • Wilson Guzman168,
  • Rober Tighe168,
  • Rachel Salazar168,
  • Kin-Ming Lo168,
  • Jessie English168,
  • Laszlo Radvanyi168,
  • Yan Lan168,
  • Roberta Zappasodi169Email author,
  • Sadna Budhu169,
  • Matthew D. Hellmann170,
  • Michael Postow170,
  • Yasin Senbabaoglu169,
  • Billel Gasmi169,
  • Hong Zhong169,
  • Yanyun Li169,
  • Cailian Liu169,
  • Daniel Hirschhorhn-Cymerman169,
  • Jedd D. Wolchok170,
  • Taha Merghoub169,
  • Yuanyuan Zha171Email author,
  • Gregory Malnassy172,
  • Noreen Fulton172,
  • Jae-Hyun Park172,
  • Wendy Stock173,
  • Yusuke Nakamura172,
  • Thomas F. Gajewski174,
  • Hongtao Liu174,
  • Xiaoming Ju175,
  • Rachelle Kosoff175,
  • Kimberly Ramos175,
  • Brandon Coder175,
  • Robert Petit175,
  • Michael Princiotta175,
  • Kyle Perry175,
  • Jun Zou175Email author,
  • Ainhoa Arina176Email author,
  • Christian Fernandez176,
  • Wenxin Zheng176,
  • Michael A. Beckett176,
  • Helena J. Mauceri176,
  • Yang-Xin Fu177,
  • Ralph R. Weichselbaum176,
  • Mark DeBenedette178Email author,
  • Whitney Lewis178,
  • Alicia Gamble178,
  • Charles Nicolette178,
  • Yanyan Han179Email author,
  • Yeting Wu180,
  • Chou Yang180,
  • Jing Huang180,
  • Dongyun Wu181,
  • Jin Li181,
  • Xiaoling Liang179,
  • Xiangjun Zhou181,
  • Jinlin Hou180,
  • Raffit Hassan182,
  • Thierry Jahan183,
  • Scott J. Antonia184,
  • Hedy L. Kindler185,
  • Evan W. Alley186,
  • Somayeh Honarmand187Email author,
  • Weiqun Liu187,
  • Meredith L. Leong187,
  • Chan C. Whiting187,
  • Nitya Nair187,
  • Amanda Enstrom187,
  • Edward E. Lemmens187,
  • Takahiro Tsujikawa188,
  • Sushil Kumar188,
  • Lisa M. Coussens188,
  • Aimee L. Murphy187,
  • Dirk G. Brockstedt187,
  • Sven D. Koch189Email author,
  • Martin Sebastian190,
  • Christian Weiss191,
  • Martin Früh192,
  • Miklos Pless193,
  • Richard Cathomas194,
  • Wolfgang Hilbe195,
  • Georg Pall196,
  • Thomas Wehler197,
  • Jürgen Alt197,
  • Helge Bischoff198,
  • Michael Geissler199,
  • Frank Griesinger200,
  • Jens Kollmeier201,
  • Alexandros Papachristofilou202,
  • Fatma Doener189,
  • Mariola Fotin-Mleczek189,
  • Madeleine Hipp189,
  • Henoch S. Hong189,
  • Karl-Josef Kallen189,
  • Ute Klinkhardt203,
  • Claudia Stosnach203,
  • Birgit Scheel189,
  • Andreas Schroeder203,
  • Tobias Seibel203,
  • Ulrike Gnad-Vogt203,
  • Alfred Zippelius202,
  • Ha-Ram Park204Email author,
  • Yong-Oon Ahn204,
  • Tae Min Kim205,
  • Soyeon Kim204,
  • Seulki Kim204,
  • Yu Soo Lee204,
  • Bhumsuk Keam205,
  • Dong-Wan Kim205,
  • Dae Seog Heo205,
  • Shari Pilon-Thomas206Email author,
  • Amy Weber206,
  • Jennifer Morse206,
  • Krithika Kodumudi206,
  • Hao Liu206,
  • John Mullinax206,
  • Amod A. Sarnaik206,
  • Luke Pike207,
  • Andrew Bang208,
  • Patrick A. Ott209,
  • Tracy Balboni207,
  • Allison Taylor207,
  • Alexander Spektor207,
  • Tyler Wilhite207,
  • Monica Krishnan207,
  • Daniel Cagney207,
  • Brian Alexander207,
  • Ayal Aizer207,
  • Elizabeth Buchbinder207,
  • Mark Awad207,
  • Leena Ghandi207,
  • F. Stephen Hodi209,
  • Jonathan Schoenfeld207Email author,
  • Anthony L. Schwartz210Email author,
  • Pulak R. Nath210,
  • Elizabeth Lessey-Morillon210,
  • Lisa Ridnour211,
  • David D. Roberts212,
  • Neil H. Segal213Email author,
  • Manish Sharma214,
  • Dung T. Le215,
  • Patrick A. Ott216,
  • Robert L. Ferris217,
  • Andrew D. Zelenetz213,
  • Sattva S. Neelapu218,
  • Ronald Levy219,
  • Izidore S. Lossos220,
  • Caron Jacobson216,
  • Radhakrishnan Ramchandren221,
  • John Godwin222,
  • A. Dimitrios Colevas219,
  • Roland Meier223,
  • Suba Krishnan223,
  • Xuemin Gu223,
  • Jaclyn Neely223,
  • Satyendra Suryawanshi223,
  • John Timmerman224,
  • Claire I. Vanpouille-Box225Email author,
  • Silvia C. Formenti225,
  • Sandra Demaria225,
  • Erik Wennerberg226Email author,
  • Aranzazu Mediero227,
  • Bruce N. Cronstein226,
  • Silvia C. Formenti228,
  • Sandra Demaria228,
  • Michael P. Gustafson229Email author,
  • AriCeli DiCostanzo229,
  • Courtney Wheatley229,
  • Chul-Ho Kim229,
  • Svetlana Bornschlegl229,
  • Dennis A. Gastineau229,
  • Bruce D. Johnson229,
  • Allan B. Dietz229,
  • Cameron MacDonald230Email author,
  • Mark Bucsek230,
  • Guanxi Qiao230,
  • Bonnie Hylander230,
  • Elizabeth Repasky230,
  • William J. Turbitt231Email author,
  • Yitong Xu231,
  • Andrea Mastro231,
  • Connie J. Rogers231,
  • Sita Withers232Email author,
  • Ziming Wang232,
  • Lam T. Khuat232,
  • Cordelia Dunai232,
  • Bruce R. Blazar233,
  • Dan Longo234,
  • Robert Rebhun232,
  • Steven K. Grossenbacher232,
  • Arta Monjazeb232,
  • William J. Murphy232,
  • Scott Rowlinson235,
  • Giulia Agnello235Email author,
  • Susan Alters235,
  • David Lowe235,
  • Nicole Scharping236,
  • Ashley V. Menk237Email author,
  • Ryan Whetstone236,
  • Xue Zeng236,
  • Greg M. Delgoffe236,
  • Patricia M. Santos237Email author,
  • Ashley V. Menk237,
  • Jian Shi237,
  • Greg M. Delgoffe236,
  • Lisa H. Butterfield237,
  • Ryan Whetstone236Email author,
  • Ashley V. Menk237,
  • Nicole Scharping236,
  • Greg Delgoffe236,
  • Misako Nagasaka238Email author,
  • Ammar Sukari238,
  • Miranda Byrne-Steele239Email author,
  • Wenjing Pan239,
  • Xiaohong Hou239,
  • Brittany Brown239,
  • Mary Eisenhower239,
  • Jian Han239,
  • Natalie Collins240Email author,
  • Robert Manguso240,
  • Hans Pope240,
  • Yashaswi Shrestha241,
  • Jesse Boehm241,
  • W. Nicholas Haining240,
  • Kyle R. Cron242Email author,
  • Ayelet Sivan242,
  • Keston Aquino-Michaels242,
  • Thomas F. Gajewski243,
  • Marco Orecchioni244,
  • Davide Bedognetti245,
  • Wouter Hendrickx245,
  • Claudia Fuoco126,
  • Filomena Spada246,
  • Francesco Sgarrella244,
  • Gianni Cesareni246,
  • Francesco Marincola247,
  • Kostas Kostarelos248,
  • Alberto Bianco249,
  • Lucia Delogu244Email author,
  • Wouter Hendrickx250Email author,
  • Jessica Roelands250,
  • Sabri Boughorbel250,
  • Julie Decock251,
  • Scott Presnell252,
  • Ena Wang254,
  • Franco M. Marincola250,
  • Peter Kuppen253,
  • Michele Ceccarelli254,
  • Darawan Rinchai250,
  • Damien Chaussabel250,
  • Lance Miller255,
  • Davide Bedognetti250,
  • Andrew Nguyen256Email author,
  • J. Zachary Sanborn257,
  • Charles Vaske257,
  • Shahrooz Rabizadeh257,
  • Kayvan Niazi257,
  • Steven Benz257,
  • Shashank Patel258Email author,
  • Nicholas Restifo258,
  • James White259,
  • Sam Angiuoli259,
  • Mark Sausen259,
  • Sian Jones259,
  • Maria Sevdali259Email author,
  • John Simmons259,
  • Victor Velculescu259,
  • Luis Diaz259,
  • Theresa Zhang259,
  • Jennifer S. Sims260Email author,
  • Sunjay M. Barton260,
  • Robyn Gartrell260,
  • Angela Kadenhe-Chiweshe260,
  • Filemon Dela Cruz260,
  • Andrew T. Turk260,
  • Yan Lu260,
  • Christopher F. Mazzeo261,
  • Andrew L. Kung260,
  • Jeffrey N. Bruce260,
  • Yvonne M. Saenger262,
  • Darrell J. Yamashiro260,
  • Eileen P. Connolly260,
  • Jason Baird263Email author,
  • Marka Crittenden264,
  • David Friedman263,
  • Hong Xiao265,
  • Rom Leidner263,
  • Bryan Bell263,
  • Kristina Young264,
  • Michael Gough264,
  • Zhen Bian266Email author,
  • Koby Kidder266,
  • Yuan Liu266,
  • Emily Curran267Email author,
  • Xiufen Chen268,
  • Leticia P. Corrales267,
  • Justin Kline269,
  • Cordelia Dunai270Email author,
  • Ethan G. Aguilar270,
  • Lam T. Khuat270,
  • William J. Murphy270,
  • Jennifer Guerriero271Email author,
  • Alaba Sotayo271,
  • Holly Ponichtera272,
  • Alexandra Pourzia271,
  • Sara Schad271,
  • Ruben Carrasco271,
  • Suzan Lazo271,
  • Roderick Bronson273,
  • Anthony Letai271,
  • Richard S. Kornbluth274Email author,
  • Sachin Gupta275,
  • James Termini275,
  • Elizabeth Guirado275,
  • Geoffrey W. Stone275,
  • Christina Meyer276Email author,
  • Laura Helming277,
  • Joseph Tumang278,
  • Nicholas Wilson279,
  • Robert Hofmeister280,
  • Laszlo Radvanyi276,
  • Natalie J. Neubert281,
  • Laure Tillé281,
  • David Barras282,
  • Charlotte Soneson282,
  • Petra Baumgaertner281,
  • Donata Rimoldi281,
  • David Gfeller281,
  • Mauro Delorenzi282,
  • Silvia A. Fuertes Marraco281,
  • Daniel E. Speiser281Email author,
  • Tara S. Abraham283Email author,
  • Bo Xiang283,
  • Michael S. Magee283,
  • Scott A. Waldman283,
  • Adam E. Snook283,
  • Wojciech Blogowski284Email author,
  • Ewa Zuba-Surma285,
  • Marta Budkowska286,
  • Daria Salata286,
  • Barbara Dolegowska287,
  • Teresa Starzynska288,
  • Leo Chan289Email author,
  • Srinivas Somanchi290,
  • Kelsey McCulley289,
  • Dean Lee291,
  • Nico Buettner292,
  • Feng Shi293,
  • Paisley T. Myers294,
  • Stuart Curbishley295,
  • Sarah A. Penny295,
  • Lora Steadman295,
  • David Millar293,
  • Ellen Speers294,
  • Nicola Ruth295,
  • Gabriel Wong295,
  • Robert Thimme292,
  • David Adams295,
  • Mark Cobbold293Email author,
  • Remy Thomas296,
  • Wouter Hendrickx297,
  • Mariam Al-Muftah296,
  • Julie Decock296Email author,
  • Michael KK Wong298,
  • Michael Morse299,
  • David F. McDermott300,
  • Joseph I. Clark301,
  • Howard L. Kaufman302,
  • Gregory A. Daniels303,
  • Hong Hua304Email author,
  • Tharak Rao304,
  • Janice P. Dutcher305,
  • Kai Kang306Email author,
  • Yogen Saunthararajah307,
  • Vamsidhar Velcheti307,
  • Vikas Kumar308Email author,
  • Firoz Anwar309,
  • Amita Verma308,
  • Zinal Chheda310,
  • Gary Kohanbash310,
  • John Sidney311,
  • Kaori Okada310,
  • Shruti Shrivastav310,
  • Diego A. Carrera310,
  • Shuming Liu310,
  • Naznin Jahan310,
  • Sabine Mueller310,
  • Ian F. Pollack312,
  • Angel M. Carcaboso313,
  • Alessandro Sette311,
  • Yafei Hou310,
  • Hideho Okada310,
  • Jessica J. Field314,
  • Weiping Zeng314,
  • Vincent FS Shih314,
  • Che-Leung Law314,
  • Peter D. Senter314,
  • Shyra J. Gardai314,
  • Nicole M. Okeley314Email author,
  • Sarah A. Penny315Email author,
  • Jennifer G. Abelin316,
  • Abu Z. Saeed315,
  • Stacy A. Malaker317,
  • Paisley T. Myers316,
  • Jeffrey Shabanowitz316,
  • Stephen T. Ward315,
  • Donald F. Hunt316,
  • Mark Cobbold318,
  • Pam Profusek319Email author,
  • Laura Wood319,
  • Dale Shepard319,
  • Petros Grivas319,
  • Kerstin Kapp320,
  • Barbara Volz320,
  • Detlef Oswald320,
  • Burghardt Wittig321,
  • Manuel Schmidt320Email author,
  • Julian P. Sefrin322Email author,
  • Lars Hillringhaus322,
  • Valeria Lifke322,
  • Alexander Lifke322,
  • Anna Skaletskaya323,
  • Jose Ponte323,
  • Thomas Chittenden323,
  • Yulius Setiady323Email author,
  • Sandrine Valsesia-Wittmann324Email author,
  • Eva Sivado324,
  • Vincent Thomas325,
  • Meddy El Alaoui324,
  • Sébastien Papot326,
  • Charles Dumontet327,
  • Mike Dyson328,
  • John McCafferty328,
  • Said El Alaoui325,
  • Amita Verma329Email author,
  • Vikas Kumar329,
  • Praveen K. Bommareddy330Email author,
  • Howard L. Kaufman331,
  • Andrew Zloza331,
  • Frederick Kohlhapp330,
  • Ann W. Silk330,
  • Sachin Jhawar330,
  • Tomas Paneque332,
  • Praveen K. Bommareddy333Email author,
  • Frederick Kohlhapp333,
  • Jenna Newman333,
  • Pedro Beltran333,
  • Andrew Zloza334,
  • Howard L. Kaufman334,
  • Felicia Cao335Email author,
  • Bang-Xing Hong335,
  • Tania Rodriguez-Cruz335,
  • Xiao-Tong Song335,
  • Stephen Gottschalk335,
  • Hugo Calderon336,
  • Sam Illingworth336,
  • Alice Brown336,
  • Kerry Fisher336,
  • Len Seymour337,
  • Brian Champion336Email author,
  • Emma Eriksson338Email author,
  • Jessica Wenthe338,
  • Ann-Charlotte Hellström338,
  • Gabriella Paul-Wetterberg338,
  • Angelica Loskog339,
  • Emma Eriksson340Email author,
  • Ioanna Milenova341,
  • Jessica Wenthe340,
  • Magnus Ståhle340,
  • Justyna Jarblad-Leja342,
  • Gustav Ullenhag343,
  • Anna Dimberg340,
  • Rafael Moreno344,
  • Ramon Alemany344,
  • Angelica Loskog345,
  • Emma Eriksson346Email author,
  • Ioanna Milenova347,
  • Rafael Moreno348,
  • Ramon Alemany348,
  • Angelica Loskog349,
  • Sachin Jhawar350Email author,
  • Sharad Goyal351,
  • Praveen K. Bommareddy350,
  • Tomas Paneque352,
  • Howard L. Kaufman351,
  • Andrew Zloza351,
  • Howard L. Kaufman353Email author,
  • Ann Silk353,
  • Janice Mehnert353,
  • Nashat Gabrail354,
  • Jennifer Bryan353,
  • Daniel Medina353,
  • Praveen K. Bommareddy353,
  • Darren Shafren355,
  • Mark Grose355,
  • Andrew Zloza353,
  • Leah Mitchell356Email author,
  • Kader Yagiz356,
  • Fernando Lopez356,
  • Daniel Mendoza356,
  • Anthony Munday356,
  • Harry Gruber356,
  • Douglas Jolly356,
  • Steven Fuhrmann357,
  • Sasa Radoja357,
  • Wei Tan357,
  • Aldo Pourchet358,
  • Alan Frey358,
  • Ian Mohr358,
  • Matthew Mulvey357Email author,
  • Tuuli Ranki359Email author,
  • Sari Pesonen359,
  • Cristian Capasso360,
  • Erkko Ylösmäki360,
  • Vincenzo Cerullo360,
  • Robert H. I. Andtbacka361,
  • Merrick Ross362,
  • Sanjiv Agarwala363,
  • Kenneth Grossmann361,
  • Matthew Taylor364,
  • John Vetto365,
  • Rogerio Neves366,
  • Adil Daud367,
  • Hung Khong361,
  • Stephanie M. Meek368,
  • Richard Ungerleider369,
  • Scott Welden369Email author,
  • Maki Tanaka370,
  • Matthew Williams371,
  • Robert H. I. Andtbacka372,
  • Brendan Curti373,
  • Sigrun Hallmeyer374,
  • Bernard Fox4,
  • Zipei Feng373,
  • Christopher Paustian373,
  • Carlo Bifulco375,
  • Mark Grose376,
  • Darren Shafren376Email author,
  • Sadia Zafar377Email author,
  • Suvi Parviainen377,
  • Mikko Siurala377,
  • Otto Hemminki377,
  • Riikka Havunen377,
  • Siri Tähtinen377,
  • Simona Bramante377,
  • Lotta Vassilev377,
  • Hongjie Wang378,
  • Andre Lieber378,
  • Silvio Hemmi379,
  • Tanja de Gruijl380,
  • Anna Kanerva377,
  • Akseli Hemminki377,
  • Tameem Ansari381Email author,
  • Srividya Sundararaman381,
  • Diana Roen381,
  • Paul Lehmann381,
  • Anja C. Bloom382Email author,
  • Lewis H. Bender383,
  • Ian B. Walters383,
  • Masaki Terabe382,
  • Jay A. Berzofsky382,
  • Fanny Chapelin384Email author,
  • Hideho Okada385,
  • Eric T. Ahrens384,
  • Jeff DeFalco386,
  • Michael Harbell386,
  • Amy Manning-Bog386,
  • Alexander Scholz386,
  • Danhui Zhang386,
  • Gilson Baia386,
  • Yann Chong Tan386,
  • Jeremy Sokolove387,
  • Dongkyoon Kim386,
  • Kevin Williamson386,
  • Xiaomu Chen386,
  • Jillian Colrain386,
  • Gregg Espiritu Santo386,
  • Ngan Nguyen386,
  • Wayne Volkmuth386,
  • Norman Greenberg386Email author,
  • William Robinson2,
  • Daniel Emerling386,
  • Charles G. Drake388Email author,
  • Daniel P. Petrylak389,
  • Emmanuel S. Antonarakis388,
  • Adam S. Kibel390,
  • Nancy N. Chang391,
  • Tuyen Vu391,
  • Dwayne Campogan391,
  • Heather Haynes391,
  • James B. Trager391,
  • Nadeem A. Sheikh391,
  • David I. Quinn392,
  • Peter Kirk394Email author,
  • Murali Addepalli394,
  • Thomas Chang394,
  • Ping Zhang394,
  • Marina Konakova394,
  • Katsunobu Hagihara395,
  • Steven Pai396,
  • Laurie VanderVeen394,
  • Palakshi Obalapur394,
  • Peiwen Kuo394,
  • Phi Quach394,
  • Lawrence Fong396,
  • Deborah H. Charych394,
  • Jonathan Zalevsky394,
  • John L. Langowski397Email author,
  • Murali Addepalli397,
  • Yolanda Kirksey397,
  • Ravi Nutakki397,
  • Shalini Kolarkar397,
  • Rhoneil Pena397,
  • Ute Hoch397,
  • Jonathan Zalevsky397,
  • Stephen K. Doberstein397,
  • Deborah H. Charych397,
  • John Cha398,
  • Zach Mallon398,
  • Myra Perez398,
  • Amanda McDaniel398,
  • Snjezana Anand398,
  • Darrin Uecker398,
  • Richard Nuccitelli398Email author,
  • Amanda McDaniel399,
  • Snjezana Anand399,
  • John Cha399,
  • Darrin Uecker399,
  • Richard Nuccitelli399Email author,
  • Nataša Obermajer400Email author,
  • Julie Urban401,
  • Eva Wieckowski401,
  • Ravikumar Muthuswamy401,
  • Roshni Ravindranathan401,
  • David Bartlett400,
  • Pawel Kalinski402, 403,
  • Ariana N. Renrick404Email author,
  • Menaka Thounaojam405,
  • Portia Thomas404,
  • Samuel Pellom404,
  • Anil Shanker406,
  • Samuel Pellom407,
  • Menaka Thounaojam408,
  • Duafalia Dudimah409,
  • Alan Brooks410,
  • Thomas J. Sayers411,
  • Anil Shanker409Email author,
  • Yu-Lin Su412Email author,
  • Tomasz Adamus413,
  • Qifang Zhang413,
  • Sergey Nechaev413,
  • Marcin Kortylewski413,
  • Spencer Wei414Email author,
  • James Allison414,
  • Clark Anderson415Email author,
  • Chad Tang415,
  • Jonathan Schoenhals415,
  • Efrosini Tsouko415,
  • John Heymach415,
  • Patricia de Groot415,
  • Joe Chang415,
  • Kenneth R. Hess415,
  • Adi Diab415,
  • Padmanee Sharma415,
  • James Allison415,
  • Aung Naing415,
  • David Hong415,
  • James Welsh415,
  • Tina C. Albershardt416Email author,
  • Andrea J. Parsons416,
  • Jardin Leleux416,
  • Rebecca S. Reeves416,
  • Jan ter Meulen416,
  • Peter Berglund416,
  • Stephane Ascarateil417Email author,
  • Marie Eve Koziol418,
  • Sarah A. Penny419,
  • Stacy A. Malaker420,
  • Lora Steadman419,
  • Paisley T. Myers421,
  • Dina Bai421,
  • Jeffrey Shabanowitz421,
  • Donald F. Hunt421,
  • Mark Cobbold422Email author,
  • Peihong Dai423,
  • Weiyi Wang423,
  • Ning Yang423,
  • Stewart Shuman423,
  • Taha Merghoub424,
  • Jedd D. Wolchok425,
  • Liang Deng425Email author,
  • Patrick Dillon426Email author,
  • Gina Petroni426,
  • David Brenin426,
  • Kim Bullock426,
  • Walter Olson426,
  • Mark E. Smolkin427,
  • Kelly Smith426,
  • Carmel Nail426,
  • Craig L. SlingluffJr428,
  • Meenu Sharma429,
  • Faisal Fa’ak430Email author,
  • Louise Janssen429,
  • Hiep Khong429,
  • Zhilan Xiao429,
  • Yared Hailemichael430,
  • Manisha Singh429,
  • Christina Vianden429,
  • Adi Diab429,
  • Jonathan Zalevsky431,
  • Ute Hoch431,
  • Willem W. Overwijk429,
  • Andrea Facciabene432Email author,
  • Pierini Stefano432,
  • Fang Chongyung432,
  • Stavros Rafail432,
  • Yared Hailemichael433Email author,
  • Michael Nielsen433,
  • Faisal Fa’ak433,
  • Peter Vanderslice434,
  • Darren G. Woodside435,
  • Robert V. Market435,
  • Ronald J. Biediger435,
  • Upendra K. Marathi436,
  • Willem W. Overwijk433,
  • Kevin Hollevoet437Email author,
  • Nick Geukens437,
  • Paul Declerck437,
  • Nathalie Joly438,
  • Laura McIntosh438Email author,
  • Eustache Paramithiotis438,
  • Magnus Rizell439,
  • Malin Sternby439,
  • Bengt Andersson440,
  • Alex Karlsson-Parra441Email author,
  • Rui Kuai442Email author,
  • Lukasz Ochyl442,
  • Anna Schwendeman442,
  • James Moon442,
  • Weiwen Deng443,
  • Thomas E. Hudson443,
  • Edward E. Lemmens443,
  • Bill Hanson443,
  • Chris S. Rae443,
  • Joel Burrill443,
  • Justin Skoble443,
  • George Katibah443,
  • Aimee L. Murphy443,
  • Michele deVries443,
  • Dirk G. Brockstedt443,
  • Meredith L. Leong443Email author,
  • Peter Lauer443,
  • Thomas W. Dubensky443,
  • Chan C. Whiting443,
  • Xin Chen444,
  • Yangyang Hu445,
  • Yang Xia445,
  • Li Zhou444,
  • Yangyi Bao446,
  • Shiang Huang447,
  • Xiubao Ren448,
  • Elaine Hurt449,
  • Robert E. Hollingsworth449,
  • Alfred E. Chang445,
  • Max S. Wicha450,
  • Qiao Li451Email author,
  • Charu Aggarwal452,
  • Drishty Mangrolia453Email author,
  • Roger Cohen452,
  • Gregory Weinstein454,
  • Matthew Morrow453,
  • Joshua Bauml452,
  • Kim Kraynyak453,
  • Jean Boyer455,
  • Jian Yan453,
  • Jessica Lee453,
  • Laurent Humeau445,
  • Sandra Oyola453,
  • Susan Duff453,
  • David Weiner456,
  • Zane Yang453,
  • Mark Bagarazzi453,
  • Douglas G. McNeel457Email author,
  • Jens Eickhoff458,
  • Robert Jeraj458,
  • Mary Jane Staab457,
  • Jane Straus457,
  • Brian Rekoske458,
  • Glenn Liu457,
  • Marit Melssen459Email author,
  • Gina Petroni459,
  • William Grosh459,
  • Nikole Varhegyi459,
  • Kim Bullock459,
  • Mark E. Smolkin459,
  • Kelly Smith459,
  • Nadejda Galeassi459,
  • Donna H. Deacon460,
  • Elizabeth Gaughan459,
  • Craig L. SlingluffJr461,
  • Maurizio Ghisoli462,
  • Minal Barve462,
  • Robert Mennel463,
  • Gladice Wallraven464,
  • Luisa Manning465,
  • Neil Senzer466,
  • John Nemunaitis466Email author,
  • Masahiro Ogasawara467Email author,
  • Shuichi Ota467,
  • Kaitlin M. Peace468Email author,
  • Diane F. Hale468,
  • Timothy J. Vreeland469,
  • Doreen O. Jackson468,
  • John S. Berry470,
  • Alfred F. Trappey468,
  • Garth S. Herbert468,
  • Guy T. Clifton468,
  • Mark O. Hardin471,
  • Anne Toms472,
  • Na Qiao472,
  • Jennifer Litton472,
  • George E. Peoples473,
  • Elizabeth A. Mittendorf472,
  • Lila Ghamsari474,
  • Emilio Flano474,
  • Judy Jacques474,
  • Biao Liu474,
  • Jonathan Havel475,
  • Vladimir Makarov475,
  • Taha Merghoub476,
  • Jedd D. Wolchok477,
  • Matthew D. Hellmann477,
  • Timothy A. Chan475,
  • Jessica B. Flechtner474Email author,
  • Pierini Stefano478Email author,
  • Andrea Facciabene478,
  • John Facciponte478,
  • Stefano Ugel478,
  • Francesco De Sanctis478,
  • George Coukos478,
  • Sébastien Paris479,
  • Agnes Pottier479Email author,
  • Laurent Levy479,
  • Bo Lu480,
  • Federica Cappuccini481,
  • Emily Pollock481,
  • Richard Bryant482,
  • Freddie Hamdy482,
  • Adrian Hill481,
  • Irina Redchenko481Email author,
  • Hussein Sultan483Email author,
  • Takumi Kumai483,
  • Valentyna Fesenkova483,
  • Esteban Celis483,
  • Kwong Tsang484Email author,
  • Massimo Fantini484,
  • Ingrid Fernando484,
  • Claudia Palena484,
  • Justin M. David484,
  • James Hodge484,
  • Elizabeth Gabitzsch485,
  • Frank Jones485,
  • James L. Gulley486,
  • Jeffrey Schlom487,
  • Mireia Uribe Herranz488Email author,
  • Stavros Rafail488,
  • Stefano Ugel488,
  • John Facciponte488,
  • Pierini Stefano488,
  • Andrea Facciabene488,
  • Hiroshi Wada489Email author,
  • Atsushi Shimizu489,
  • Toshihiro Osada489,
  • Satoshi Fukaya489,
  • Eiji Sasaki489,
  • Milad Abolhalaj490Email author,
  • David Askmyr491,
  • Kristina Lundberg490,
  • Ann-Sofie Albrekt490,
  • Lennart Greiff491,
  • Malin Lindstedt490,
  • Dallas B. Flies492,
  • Tomoe Higuchi493,
  • Wojciech Ornatowski494,
  • Jaryse Harris495,
  • Sarah F. Adams494Email author,
  • Todd Aguilera496Email author,
  • Marjan Rafat496,
  • Laura Castellini496,
  • Hussein Shehade496,
  • Mihalis Kariolis496,
  • Dadi Jang496,
  • Rie vonEbyen496,
  • Edward Graves496,
  • Lesley Ellies497,
  • Erinn Rankin496,
  • Albert Koong496,
  • Amato Giaccia496,
  • Reham Ajina498Email author,
  • Shangzi Wang498,
  • Jill Smith498,
  • Mariaelena Pierobon498,
  • Sandra Jablonski498,
  • Emanuel PetricoinIII499,
  • Louis M. Weiner498,
  • Lorcan Sherry500Email author,
  • John Waller500,
  • Mark Anderson500,
  • Alison Bigley500,
  • Chantale Bernatchez501,
  • Cara Haymaker501,
  • Nizar M. Tannir501,
  • Harriet Kluger502,
  • Michael Tetzlaff501,
  • Natalie Jackson501,
  • Ivan Gergel503,
  • Mary Tagliaferri503,
  • Jonathan Zalevsky503,
  • Ute Hoch503Email author,
  • Patrick Hwu501,
  • Mario Snzol502,
  • Michael Hurwitz502,
  • Adi Diab501,
  • Theresa Barberi504Email author,
  • Allison Martin504,
  • Rahul Suresh504,
  • David Barakat504,
  • Sarah Harris-Bookman504,
  • Charles Drake504,
  • Alan Friedman504,
  • Sara Berkey505Email author,
  • Stephanie Downs-Canner505,
  • Greg M. Delgoffe506,
  • Robert P. Edwards506,
  • Tyler Curiel507,
  • Kunle Odunsi508,
  • David Bartlett505,
  • Nataša Obermajer505,
  • Tullia C. Bruno509Email author,
  • Brandon Moore510,
  • Olivia Squalls510,
  • Peggy Ebner510,
  • Katherine Waugh510,
  • John Mitchell511,
  • Wilbur Franklin512,
  • Daniel Merrick512,
  • Martin McCarter513,
  • Brent Palmer514,
  • Jeffrey Kern515,
  • Dario Vignali516,
  • Jill Slansky510,
  • Anissa S. H. Chan517Email author,
  • Xiaohong Qiu517,
  • Kathryn Fraser517,
  • Adria Jonas517,
  • Nadine Ottoson517,
  • Keith Gordon517,
  • Takashi O. Kangas517,
  • Steven Leonardo517,
  • Kathleen Ertelt517,
  • Richard Walsh517,
  • Mark Uhlik517,
  • Jeremy Graff517,
  • Nandita Bose517,
  • Ravi Gupta518,
  • Nitin Mandloi518,
  • Kiran Paul518,
  • Ashwini Patil518,
  • Rekha Sathian518,
  • Aparna Mohan518,
  • Malini Manoharan518,
  • Amitabha Chaudhuri518Email author,
  • Yu Chen519Email author,
  • Jing Lin519,
  • Yun-bin Ye519,
  • Chun-wei Xu519,
  • Gang Chen519,
  • Zeng-qing Guo519,
  • Andrey Komarov520Email author,
  • Alex Chenchik520,
  • Michael Makhanov520,
  • Costa Frangou520,
  • Yi Zheng521Email author,
  • Carla Coltharp521,
  • Darryn Unfricht521,
  • Ryan Dilworth521,
  • Leticia Fridman521,
  • Linying Liu521,
  • Milind Rajopadhye521,
  • Peter Miller521,
  • Fernando Concha-Benavente522Email author,
  • Julie Bauman522,
  • Sumita Trivedi522,
  • Raghvendra Srivastava522,
  • James Ohr522,
  • Dwight Heron522,
  • Uma Duvvuri522,
  • Seungwon Kim522,
  • William Gooding522,
  • Robert L. Ferris522,
  • Heather Torrey523,
  • Toshi Mera523,
  • Yoshiaki Okubo523,
  • Eva Vanamee523,
  • Rosemary Foster523,
  • Denise Faustman523Email author,
  • Robyn Gartrell524Email author,
  • Edward Stack525,
  • Yan Lu524,
  • Daisuke Izaki526,
  • Kristen Beck527,
  • Dan Tong Jia527,
  • Paul Armenta527,
  • Ashley White-Stern527,
  • Yichun Fu527,
  • Zoe Blake524,
  • Douglas Marks524,
  • Howard L. Kaufman528,
  • Bret Taback524,
  • Basil Horst524,
  • Yvonne M. Saenger529,
  • Laura Hix Glickman530Email author,
  • David B. Kanne530,
  • Kelsey S. Gauthier530,
  • Anthony L. Desbien530,
  • Brian Francica531,
  • George Katibah530,
  • Leticia P. Corrales532,
  • Justin L. Leong530,
  • Leonard Sung530,
  • Ken Metchette530,
  • Shailaja Kasibhatla533,
  • Anne Marie Pferdekamper533,
  • Lianxing Zheng534,
  • Charles Cho533,
  • Yan Feng534,
  • Jeffery M. McKenna534,
  • John Tallarico534,
  • Steven Bender533,
  • Chudi Ndubaku530,
  • Sarah M. McWhirter530,
  • Charles G. Drake535,
  • Thomas F. Gajewski536,
  • Thomas W. Dubensky530,
  • Elena Gonzalez Gugel537Email author,
  • Charles J. M. Bell538,
  • Adiel Munk537,
  • Luciana Muniz537,
  • Nina Bhardwaj537,
  • Fei Zhao539,
  • Kathy Evans539,
  • Christine Xiao539,
  • Alisha Holtzhausen540,
  • Brent A. Hanks539Email author,
  • Nathalie Scholler541Email author,
  • Catherine Yin541,
  • Pien Van der Meijs542,
  • Andrew M. Prantner543,
  • Cecile M. Krejsa544,
  • Leia Smith544,
  • Brian Johnson545,
  • Daniel Branstetter546,
  • Paul L. Stein541,
  • Juan C. Jaen547Email author,
  • Joanne BL Tan547,
  • Ada Chen547,
  • Yu Chen547,
  • Timothy Park547,
  • Jay P. Powers547,
  • Holly Sexton547,
  • Guifen Xu547,
  • Steve W. Young547,
  • Ulrike Schindler547,
  • Wentao Deng548,
  • David John Klinke548Email author,
  • Hannah M. Komar549Email author,
  • Thomas Mace549,
  • Gregory Serpa549,
  • Omar Elnaggar549,
  • Darwin Conwell549,
  • Philip Hart550,
  • Carl Schmidt550,
  • Mary Dillhoff550,
  • Ming Jin550,
  • Michael C. Ostrowski549,
  • Gregory B. Lesinski549,
  • Madhuri Koti551Email author,
  • Katrina Au551,
  • Nichole Peterson551,
  • Peter Truesdell551,
  • Gillian Reid-Schachter551,
  • Charles Graham551,
  • Andrew Craig551,
  • Julie-Ann Francis551,
  • Beatrix Kotlan552Email author,
  • Timea Balatoni552,
  • Emil Farkas552,
  • Laszlo Toth552,
  • Mihaly Ujhelyi552,
  • Akos Savolt552,
  • Zoltan Doleschall552,
  • Szabolcs Horvath552,
  • Klara Eles552,
  • Judit Olasz552,
  • Orsolya Csuka552,
  • Miklos Kasler552,
  • Gabriella Liszkay552,
  • Eytan Barnea553,
  • Sushil Kumar554,
  • Takahiro Tsujikawa554,
  • Collin Blakely555,
  • Patrick Flynn554,
  • Reid Goodman554,
  • Raphael Bueno556,
  • David Sugarbaker557,
  • David Jablons558,
  • V. Courtney Broaddus555,
  • Brian West559,
  • Lisa M. Coussens554Email author,
  • Paul R. Kunk560Email author,
  • Joseph M. Obeid560,
  • Kevin Winters560,
  • Patcharin Pramoonjago560,
  • Mark E. Smolkin561,
  • Edward B. Stelow560,
  • Todd W. Bauer560,
  • Craig L. SlingluffJr562,
  • Osama E. Rahma563,
  • Adam Lamble564,
  • Yoko Kosaka564,
  • Fei Huang565,
  • Kate A. Saser565,
  • Homer Adams565,
  • Christina E. Tognon564,
  • Ted Laderas564,
  • Shannon McWeeney564,
  • Marc Loriaux564,
  • Jeffery W. Tyner564,
  • Brian J. Druker566,
  • Evan F. Lind564Email author,
  • Zhuqing Liu567Email author,
  • Shanhong Lu567,
  • Lawrence P. Kane568,
  • Robert L. Ferris569,
  • Zhuqing Liu570Email author,
  • Gulidanna Shayan570,
  • Shanhong Lu570,
  • Robert L. Ferris571,
  • Julia Femel572,
  • Takahiro Tsujikawa572,
  • Ryan Lane572,
  • Jamie Booth572,
  • Amanda W. Lund572Email author,
  • Marit Melssen573Email author,
  • Anthony Rodriguez573,
  • Craig L. SlingluffJr574,
  • Victor H. Engelhard573,
  • Alessandra Metelli575Email author,
  • Bill X. Wu575,
  • Caroline W. Fugle575,
  • Rachidi Saleh575,
  • Shaoli Sun575,
  • Jennifer Wu575,
  • Bei Liu575,
  • Zihai Li575,
  • Zachary S. Morris576Email author,
  • Emily I. Guy576,
  • Clinton Heinze576,
  • Jasdeep Kler576,
  • Monica M. Gressett576,
  • Lauryn R. Werner576,
  • Stephen D. Gillies577,
  • Alan J. Korman578,
  • Hans Loibner579,
  • Jacquelyn A. Hank576,
  • Alexander L. Rakhmilevich576,
  • Paul M. Harari576,
  • Paul M. Sondel576,
  • Jenna Newman580Email author,
  • Andrew Zloza581,
  • Erica Huelsmann582,
  • Joseph Broucek582,
  • Howard L. Kaufman581,
  • Dorothee Brech583,
  • Tobias Straub584,
  • Martin Irmler585,
  • Johannes Beckers585,
  • Florian Buettner586,
  • Elke Schaeffeler586,
  • Matthias Schwab587, 588,
  • Elfriede Noessner589Email author,
  • Snjezana Anand590,
  • Amanda McDaniel590,
  • John Cha590,
  • Darrin Uecker590,
  • Richard Nuccitelli590Email author,
  • Peter Ordentlich591Email author,
  • Alison Wolfreys592,
  • Andre Da Costa593,
  • John Silva592,
  • Andrea Crosby592,
  • Ludovicus Staelens593,
  • Graham Craggs592,
  • Annick Cauvin593,
  • Sean Mason592,
  • Alison M. Paterson594,
  • Andrew C. Lake594,
  • Caroline M. Armet594,
  • Rachel W. O’Connor594,
  • Jonathan A. Hill594,
  • Emmanuel Normant594,
  • Ammar Adam594,
  • Detlev M. Biniszkiewicz594,
  • Scott C. Chappel594,
  • Vito J. Palombella594,
  • Pamela M. Holland594,
  • Jay P. Powers595Email author,
  • Annette Becker595,
  • Ada Chen595,
  • Manmohan R. Leleti595,
  • Eric Newcomb595,
  • Holly Sexton595,
  • Ulrike Schindler595,
  • Joanne B. L. Tan595,
  • Steve W. Young595,
  • Juan C. Jaen595,
  • Suthee Rapisuwon596Email author,
  • Arash Radfar597,
  • Kellie Gardner598,
  • Geoffrey Gibney598,
  • Michael Atkins598,
  • Keith R. Rennier599,
  • Robert Crowder599,
  • Ping Wang599,
  • Russell K. Pachynski599,
  • Rosa M. Santana Carrero600Email author,
  • Sarai Rivas601,
  • Figen Beceren-Braun601,
  • Scott Anthony602,
  • Kimberly S. Schluns601,
  • Deepali Sawant603Email author,
  • Maria Chikina603,
  • Hiroshi Yano603,
  • Creg Workman603,
  • Dario Vignali603,
  • Elise Salerno604,
  • Davide Bedognetti605,
  • Ileana Mauldin606,
  • Donna Deacon606,
  • Sofia Shea607,
  • Joel Pinczewski608,
  • Joseph M. Obeid609,
  • George Coukos610,
  • Ena Wang605,
  • Thomas Gajewski611,
  • Franco M. Marincola605,
  • Craig L. SlingluffJr606Email author,
  • Stefani Spranger612Email author,
  • Brendan Horton612,
  • Thomas F. Gajewski613,
  • Akiko Suzuki614Email author,
  • Pamela Leland614,
  • Bharat H. Joshi614,
  • Raj K. Puri614,
  • Randy F. Sweis615Email author,
  • Riyue Bao615,
  • Jason Luke615,
  • Thomas F. Gajewski613,
  • Marie-Nicole Theodoraki616Email author,
  • Frances-Mary Mogundo617,
  • Robert P. Edwards617,
  • Pawel Kalinski618, 619,
  • Haejung Won620Email author,
  • Dayson Moreira620,
  • Chan Gao620,
  • Xingli Zhao620,
  • Priyanka Duttagupta620,
  • Jeremy Jones620,
  • Massimo D’Apuzzo620,
  • Sumanta Pal620 and
  • Marcin Kortylewski620
Journal for ImmunoTherapy of Cancer20164(Suppl 1):73

https://doi.org/10.1186/s40425-016-0173-6

Published: 16 November 2016

Combinations: Immunotherapy/Immunotherapy

P189 Rational combinations of intratumoral T cell and myeloid agonists mobilize abscopal responses in prostate cancer

Casey Ager1, Matthew Reilley2, Courtney Nicholas1, Todd Bartkowiak1, Ashvin Jaiswal1, Michael Curran1

1Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX, USA; 2Department of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
Correspondence: Casey Ager (crager@mdanderson.org)

Background

Despite the success of checkpoint blockade immunotherapy in characteristically immunogenic cancers such as melanoma, these antibodies remain ineffective against poorly T cell-infiltrated malignancies including prostate cancer. Sensitizing these “cold” tumors to immunotherapy will require interventions which enhance tumor antigen presentation and T cell priming, while suppressing microenvironmental signals which constrain T cell expansion, survival, and effector function independent of coinhibitory signaling. We investigated whether intratumoral administration of either the STING agonist c-di-GMP (CDG) or dendritic cell (DC) growth factor Flt3-ligand can potentiate the therapeutic effects of T cell checkpoint modulation with αCTLA-4, αPD-1, and α4-1BB in a bilateral subcutaneous model of prostate adenocarcinoma. Additionally, we tested whether intratumoral delivery of low-dose checkpoint modulators with CDG at a single lesion can achieve abscopal control of distal lesions.

Methods

Male C57BL/6 mice were challenged subcutaneously on both flanks with TRAMP-C2 prostate adenocarcinoma, and treatment was administered intraperitoneally and/or intratumorally for 3 doses every 4 days, beginning on day 14 post-implantation for survival experiments or day 31 for flow analysis experiments.

Results

Intratumoral delivery of STING agonist CDG alone potently rejects all injected TRAMP-C2 tumors, but fails to generate systemic control of uninjected lesions. Systemic administration of αCTLA-4, αPD-1, and α4-1BB cures 40 % of mice with bilateral TRAMP-C2, and concurrent administration of CDG at one or both flanks enhances survival to 75 %. Similar effects are observed with intratumoral Flt3L, although administration at both flanks is required for full effect. Intratumoral low-dose αCTLA-4, αPD-1, and α4-1BB at a single flank induces abscopal effects in 20 % of mice, and concurrent administration of CDG enhances systemic immunity to cure up to 50 % of mice. We observe that the level of STING activation required to mediate rejection without inducing ulcerative toxicity is proportional to initial tumor size. Functionally, local STING activation complements intratumoral checkpoint modulation to reduce local MDSC infiltration, enhance CD8:Treg ratios, and downregulate the M2 macrophage marker CD206. In contrast, local Flt3L robustly enhances immune infiltration of injected and distal tumors, but therapeutic benefit is attenuated due to concomitant induction of FoxP3+ Treg.

Conclusions

Intratumoral STING activation via CDG or DC expansion with Flt3L potentiates the therapeutic effects of systemically-delivered αCTLA-4, αPD-1, and α4-1BB against multi-focal TRAMP-C2 prostate cancer. The abscopal potential of CDG alone is weak, in contrast to prior observations, but combining CDG with low-dose checkpoint blockade intratumorally can induce systemic immunity, suggesting an alternative approach for clinical implementation of combination immunotherapies at reduced doses.

P190 Multi-genome reassortant dendritic cell-tropic vector platform (ZVex®-Multi) allows flexible co-expression of multiple antigens and immune modulators for optimal induction of anti-tumor CD8+ T cell responses

Tina C Albershardt, Anshika Bajaj, Jacob F Archer, Rebecca S Reeves, Lisa Y Ngo, Peter Berglund, Jan ter Meulen

Immune Design, Seattle, WA, USA
Correspondence: Tina C Albershardt (tina.albershardt@immunedesign.com)

Background

Induction of immune responses against multiple antigens expressed from conventional vector platforms is often ineffective for reasons not well understood. Common methods of expressing multiple antigens within a single vector construct include the use of fusion proteins, endoprotease cleavage sites, or internal ribosome entry sites. These methods often lead to decreased expression of antigens-of-interest and/or reduced induction of T cell responses against the encoded antigens. Circumventing these limitations, we have developed a novel production process for our integration-deficient, dendritic cell-targeting lentiviral vector platform, ZVex, enabling highly flexible and effective multigene delivery in vivo, making it possibly the most versatile vector platform in the industry.

Methods

Up to five vector genome plasmids, each encoding one full-length antigen or immuno-modulator, were mixed with four constant plasmids, each encoding vector particle proteins, prior to transfection of production cells. Due to the propensity of lentiviruses forming genomic reassortants, the resulting vector preparations hypothetically contain a mix of homozygous and heterozygous vector particles. qRT-PCR was used to determine total and antigen-specific titers of ZVex-Multi vectors, defined as vector genome counts. Mice were immunized with ZVex-Multi vectors or monozygous vectors expressing multiple antigens from the same backbone to compare immunogenicity via intracellular cytokine staining. Two tumor models were used to evaluate therapeutic efficacy: 1) a B16 melanoma model, where tumor cells were inoculated in the flank and measured 2–3 times per week; and 2) a metastatic CT26 colon carcinoma model, where tumor cells were inoculated intravenously, and lung nodules were enumerated 17–19 days post-tumor inoculation.

Results

Titrations by qRT-PCR of multiple ZVex-Multi vector lots demonstrated that production yields of ZVex-Multi expressing up to four different tumor-associated antigens (e.g., NY-ESO-1, MAGE-A3) and two immuno-modulators (e.g., IL-12, anti-CTLA-4 or anti-PD-L1) were highly reproducible. Compared to mice immunized with vectors expressing multiple antigens from the same backbone, mice immunized with ZVex-Multi vectors consistently developed T cells against all targeted TAAs and exhibited improved tumor growth control and survival.

Conclusions

ZVex-Multi is a next generation DC-tropic vector platform designed to overcome limitations of single-genome vector platforms with respect to efficient co-expression of any combination of desired genes. Unlike other vector platforms, ZVex-Multi eliminates multiple cloning steps modifying the vector backbone, which can often result in unpredictable expression patterns of coded gene products. Its versatility and agility makes ZVex-Multi potentially the best-in-class vector platform for co-expression of multiple tumor antigens and immuno-modulators for enhanced cancer immunotherapy against a broad range of tumors.

P191 NK, T cells and IFN-gamma are required for the anti-tumor efficacy of combination-treatment with NKG2A and PD-1/PD-L1 checkpoint inhibitors in preclinical models

Caroline Denis1, Hormas Ghadially2, Thomas Arnoux1, Fabien Chanuc1, Nicolas Fuseri1, Robert W Wilkinson2, Nicolai Wagtmann1, Yannis Morel1, Pascale Andre1

1Innate Pharma, Marseille, Provence-Alpes-Cote d'Azur, France; 2MedImmune, Cambridge, England, UK
Correspondence: Pascale Andre (pascale.andre@innate-pharma.fr)

Background

Monalizumab (IPH2201) is a first-in-class humanized IgG4 targeting NKG2A, which is expressed as heterodimer with CD94 on the surface of NK, γδT and tumor infiltrating CD8+ T cells. This inhibitory receptor binds to HLA-E in humans and to Qa-1b in mice. HLA-E is frequently up-regulated on cancer cells, protecting from killing by NKG2A+ cells. Monalizumab blocks binding of CD94-NKG2A to HLA-E, reducing inhibitory signaling thereby enhancing NK and T cell responses. PD-1/PD-L1 inhibitors are successfully being used to treat patients with a wide variety of cancers. Combined blockade of NKG2A/HLA-E and PD-1/PD-L1 may be a promising strategy to better fight cancer by activating both the adaptive and innate immune systems.

Methods

To assess the effect of combined blockade of NKG2A/HLA-E and PD-1/PD-L1 in vivo, anti-mouse NKG2A and PD-1 antibodies were used in mice engrafted with A20 mouse B lymphoma cell line. For in vitro assays, anti-PD-L1 antibody durvalumab, and monalizumab were tested in human PBMC staphylococcal enterotoxin b assays.

Results

When cultured in vitro, the A20 cells express ligands for PD-1 but not for NKG2A. Exposure to IFN-γ in vitro, or subcutaneous injection into mice, induced expression of Qa-1b, resulting in a tumor model co-expressing PD-L1 and Qa-1b. Monotherapy with PD-1 or NKG2A blockers resulted in moderate anti-tumor efficacy while treatment with combination of NKG2A and PD-1 blockers resulted in a significantly higher anti-tumor immunity, and an increased rate of complete tumor regression. Depletion of either NK, or CD8+ T cells, or IFN-γ was enough to abrogate the efficacy of PD-1 and NKG2A blockade, indicating that both of these effector populations contribute to the efficacy of the combination treatment. To further explore this possibility and to assess the potential therapeutic relevance in humans, well-validated PBMC-based assays were used which showed that blocking both axes with a combination of durvalumab and monalizumab led to increased production of cytokines by both T and NK cells. Furthermore, the magnitude of the increase in cytokine secretion was dependent on the production of high levels of IFN-γ. Since IFN-γ is known to induce HLA-E this suggests that blockade of NKG2A could have a beneficial role in activation of immune cells through the combined blockade of PD-1/PD-L1.

Conclusions

Together, these data indicate that blocking NKG2A in conjunction with PD-1/PD-L1 checkpoint inhibitors provides increased anti-tumor efficacy mediated by IFN-γ and support the rationale for assessing this combination in clinical trials.

P192 Pharmacokinetics and immunogenicity of pembrolizumab when given in combination with ipilimumab: data from KEYNOTE-029

Michael B Atkins1, Matteo S Carlino2, Antoni Ribas3, John A Thompson4, Toni K Choueiri5, F Stephen Hodi5, Wen-Jen Hwu6, David F McDermott7, Victoria Atkinson8, Jonathan S Cebon9, Bernie Fitzharris10, Michael B Jameson11, Catriona McNeil12, Andrew G Hill13, Eric Mangin14, Malidi Ahamadi14, Marianne van Vugt15, Mariëlle van Zutphen15, Nageatte Ibrahim14, Georgina V Long16

1Georgetown-Lombardi Comprehensive Cancer Center, Washington, DC, USA; 2Westmead and Blacktown Hospitals, Melanoma Institute Australia, and the University of Sydney, Westmead, New South Wales, Australia; 3University of California, Los Angeles, CA, USA; 4University of Washington, Seattle, WA, USA; 5Dana-Farber Cancer Institute/Brigham and Women’s Hospital, Harvard University, Boston, MA, USA; 6University of Texas MD Anderson Cancer Center, Houston, TX, USA; 7Beth Israel Deaconess Medical Center, Boston, MA, USA; 8Gallipoli Medical Research Foundation, Greenslopes Private Hospital, and the University of Queensland, Greenslopes, Queensland, Australia; 9Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia; 10Canterbury District Health Board, Christchurch Hospital, Christchurch, New Zealand; 11Waikato Hospital Regional Cancer Centre, Hamilton, New Zealand; 12Royal Prince Alfred Hospital, Melanoma Institute Australia, the University of Sydney, and Chris O’Brien Lifehouse, Camperdown, New South Wales, Australia; 13Tasman Oncology Research, Southport Gold Coast, Queensland, Australia; 14Merck & Co., Inc., Kenilworth, NJ, USA; 15Quantitative Solutions, a Certara company, Oss, Netherlands; 16Melanoma Institute Australia, the University of Sydney, Mater Hospital, and Royal North Shore Hospital, Wollstonecraft, New South Wales, Australia
Correspondence: Michael B Atkins (mba41@georgetown.edu)

Background

The pharmacokinetics of pembrolizumab given as monotherapy are well characterized. Consistent with other monoclonal antibodies, pembrolizumab has low clearance (0.202 L/day), limited central (3.53 L) and peripheral (3.85 L) volume of distribution, and low variability in the central volume of distribution (19 % coefficient of variation). Pembrolizumab monotherapy has low immunogenicity potential, with an observed incidence of treatment-emergent anti-drug antibodies (ADA) of < 1 %. We present data on the pharmacokinetics and immunogenicity of pembrolizumab when given in combination with ipilimumab in the phase I KEYNOTE-029 study.

Methods

KEYNOTE-029 included 2 cohorts that assessed the safety and antitumor activity of pembrolizumab plus ipilimumab: a safety run-in that included patients with advanced melanoma or renal cell carcinoma (RCC) (N = 22) and a melanoma expansion cohort (N = 153). In both cohorts, patients received 4 doses of pembrolizumab 2 mg/kg plus ipilimumab 1 mg/kg Q3W followed by pembrolizumab 2 mg/kg Q3W for up to 2 years. Pembrolizumab serum concentration was quantified with an electrochemiluminescence-based immunoassay (lower limit of quantitation, 10 ng/mL). A validated bridging electrochemiluminescence immunoassay using a standard 3-tiered approach (drug tolerance level, 124 μg/mL) was used to detect ADA in serum.

Results

Across cohorts, 175 patients received pembrolizumab plus ipilimumab: 165 with melanoma and 10 with RCC. At least 1 evaluable sample for pharmacokinetic assessment was available for all 10 patients with RCC and 162 patients with melanoma. The predose serum concentration versus time profiles for pembrolizumab were similar in patients with RCC and melanoma (Fig. 1). Observed serum concentrations were within the range predicted for pembrolizumab 2 mg/kg Q3W given as monotherapy (Fig. 2). Of the 160 patients with melanoma who provided postdose ADA samples, 156 (97.5 %) were negative, 2 (1.3 %) were inconclusive, and 2 (1.3 %) were positive for treatment-emergent ADA. Best overall response in the ADA-positive patients was stable disease in one and progressive disease in the other. No patient with RCC had treatment-emergent ADA.

Conclusions

The addition of ipilimumab does not appear to impact pembrolizumab serum concentration or increase the risk of developing ADA in patients with advanced melanoma or RCC.

Trial Registration

ClinicalTrials.gov identifier NCT02089685.
Fig. 1 (abstract P192).

Arithmetic mean (SE) predose serum concentration-time profile of pembrolizumab following multiple doses of pembrolizumab plus ipilimumab (linear-linear scale)

Fig. 2 (abstract P192).

Observed pembrolizumab serum concentrations from patients with melanoma treated with pembrolizumab plus ipilimumab in relation to the predicted concentration interval (gray) for pembrolizumab 2 mg/kg Q3W monotherapy (log scale)

P193 Establishing a model for successful immunotherapy with T-Vec combined with BRAF inhibition and anti-PD-1 in genetically engineered murine melanoma

Robyn Gartrell1, Zoe Blake1, Ines Simoes2, Yichun Fu1, Takuro Saito3, Yingzhi Qian1, Yan Lu1, Yvonne M Saenger4

1Columbia University Medical Center, New York, NY, USA; 2Institut d'Investigacions Biomediques August Pi i Sunyer, Barcelona, Catalonia, Spain; 3Icahn School of Medicine at Mount Sinai, New York, NY, USA; 4New York Presbyterian/Columbia University Medical Center, New York, NY, USA
Correspondence: Zoe Blake (zb2161@cumc.columbia.edu)

Background

Talimogene laherparepvec (T-Vec) is the first oncolytic virus to be U.S. Food and Drug Administration (FDA) approved for the treatment of cancer. T-Vec, a modified herpes simplex type I (HSV I) virus, has two proposed mechanisms of action: direct cell lysis and immune activation. Combination immunotherapy using T-Vec and checkpoint blockade has shown promise in clinical trials. In preliminary work, our laboratory has shown that T-Vec causes up-regulation of programmed cell death protein 1 (PD-1) on infiltrating T cells in mice, suggesting potential synergy of T-Vec and anti-PD-1 (αPD-1).

Methods

In a temporally and spatially regulated murine model of BRAFCA PTEN−/− spontaneous melanoma [1], tumors are induced on right flank. When tumors reach >5 mm in diameter, mice are randomized into 6 treatment groups comparing combinations of BRAF inhibition (BRAFi), αPD-1, and T–Vec (Table 1). Tumor growth is measured twice a week until end of study. Flow cytometry is performed on tumor, lymph node, and spleen to assess immune microenvironment.

Results

Mean tumor volume and survival was plotted to compare groups (Figs. 3 and 4). Mice treated with triple combination have decreased tumor growth. Mice treated with combination T-Vec + BRAFi with or without αPD-1 have longer survival compared to mice treated with control or single drug arms. Flow cytometry shows increase in percent CD3+/CD45+ cells in tumors of mice treated with combination αPD-1 + T-Vec compared to the control and single drug arms. Percent CD8+/CD3+ cells in tumors treated with immunotherapy appears to be increased compared to the control and BRAFi only group (Fig. 5). Additionally, percent of FOXP3+/CD4+ cells in tumors appears to be decreased in groups receiving T-Vec (Fig. 6) while no change in FOXP3+/CD4+ populations was observed in tumors from groups receiving αPD-1 without T-Vec or in draining lymph node or spleen.

Conclusions

Initial findings show that combination therapy of BRAFi + αPD-1 + T-Vec is more effective than any single treatment. Combination immunotherapy increases infiltration of T cells into tumor. Furthermore, oncolytic virus appears to decrease regulatory T cells infiltrating tumor. This study is ongoing and further analysis will continue as we further evaluate the immune microenvironment using flow cytometry and immunohistochemistry.

Acknowledgements

The study was funded by the Melanoma Research Alliance and Amgen (Amgen-CUMC-MRA Established Investigator Academic-Industry Partnership Award). Reference

1. Dankort, Curley, Cartlidge, et al.: Braf(V600E) cooperates with Pten loss to induce metastatic melanoma. Nature Genetics 2009, 41:544–552.
Table 1 (abstract P193).

Treatment groups

Group

Treatment

Group 1 (Red)

Control Chow + IP 2A3 + IT PBS

Group 2 (Orange)

BRAFi Chow + IP 2A3 + IT PBS

Group 3 (Yellow)

BRAFi Chow + Ip α-PD1 + IT PBS

Group 4 (Green)

BRAFi Chow + IP 2A3 + IT T-Vec

Group 5 (Blue)

BRAFi Chow + IP α-PD1 + IT T-Vec

Group 6 (Purple)

Control Chow + IP α=PD1 + IT T-Vec

IP intraperitoneal, IT intratumoral, BRAFi brief inhibiotor, α-PD1 anti programmed cell death 1, T-Vec talimogene Leherparepvec

Fig. 3 (abstract P193).

Tumor volume comparison of all mice

Fig. 4 (abstract P193).

Survival comparison of treatment groups

Fig. 5 (abstract P193).

Flow cytometry data of CD8+ cells per CD3+ cell populations

Fig. 6 (abstract P193).

Flow cytometry data of CD4+/FOXP3+ cells per CD4+ cell populations

P194 Phosphatidylserine targeting antibody in combination with checkpoint blockade and tumor radiation therapy promotes anti-cancer activity in mouse melanoma

Sadna Budhu1, Olivier De Henau1, Roberta Zappasodi1, Kyle Schlunegger2, Bruce Freimark2, Jeff Hutchins2, Christopher A Barker1, Jedd D Wolchok1, Taha Merghoub1

1Memorial Sloan Kettering Cancer Center, New York, NY, USA; 2Peregrine Pharmaceuticals, Inc., Tustin, CA, USA
Correspondence: Sadna Budhu (budhus@mskcc.org)

Background

Phosphatidylserine (PS) is a phospholipid that is exposed on the surface of apoptotic cells, some tumor cells and tumor endothelium. PS has been shown to promote anti-inflammatory and immunosuppressive signals in the tumor microenvironment. Antibodies that target PS have been shown to reactivate anti-tumor immunity by repolarizing tumor associated macrophages to a M1-like phenotype, reducing the number of MDSCs in tumors and promote the maturation of dendritic cells into functional APCs. In a B16 melanoma model, targeting PS in combination with immune checkpoint blockade has been shown to have a significantly greater anti-cancer effect than either agent alone. This combination was shown to enhance CD4+ and CD8+ T cell infiltration and activation in the tumors of treated animals. Radiation therapy is an effective focal treatment of primary solid tumors, but is less effective in treating metastatic solid tumors as a monotherapy. There is evidence that radiation induces immunogenic tumor cell death and enhances tumor-specific T cell infiltration in irradiated tumors. In addition, the abscopal effect, a phenomenon in which tumor regression occurs outside the site of radiation therapy, has been observed in both preclinical and clinical trials with the combination of radiation therapy and immunotherapy.

Methods

We examined the effects of combining tumor radiation therapy with an antibody that targets PS (1 N11) and an immune checkpoint blockade (anti-PD-1) using the mouse B16 melanoma model. Tumor surface area and overall survival of mice were used to determine efficacy of the combinations.

Results

We examined the expression of PS on immune cells infiltrating B16 melanomas. CD11b + myeloid cells expressed the highest levels of PS on their surface whereas T cells and B16 tumor cells express little to no PS. These data suggest that targeting PS in B16 melanoma would induce a pro-inflammatory myeloid tumor microenvironment. We hypothesize that therapies that induce apoptotic cell death on tumor cells would enhance the activity of PS-targeting antibodies. We therefore examined the effects of combining a PS-targeting antibody with local tumor radiation. We found that the PS-targeting antibody synergizes with both anti-PD-1 and radiation therapy to improve anti-cancer activity and overall survival. In addition, the triple combination of the PS-targeting antibody, tumor radiation and anti-PD-1 treatment displayed even greater anti-cancer and survival benefit.

Conclusions

This finding highlights the potential of combining these three agents to improve outcome in patients with advanced-stage melanoma and may inform the design of future clinical trials with PS targeting in melanoma and other cancers.

P195 A novel anti-human LAG-3 antibody in combination with anti-human PD-1 (REGN2810) shows enhanced anti-tumor activity in PD-1 x LAG-3 dual-humanized mice and favorable pharmacokinetic and safety profiles in cynomolgus monkeys

Elena Burova, Omaira Allbritton, Peter Hong, Jie Dai, Jerry Pei, Matt Liu, Joel Kantrowitz, Venus Lai, William Poueymirou, Douglas MacDonald, Ella Ioffe, Markus Mohrs, William Olson, Gavin Thurston

Regeneron, Tarrytown, NY, USA
Correspondence: Elena Burova (elena.burova@regeneron.com)

Background

In the tumor microenvironment, T cell inhibitory checkpoint receptors trigger signals that suppress T cell effector function, resulting in tumor immune evasion. Clinical antibodies blocking one of these receptors, PD-1, yield positive responses in multiple cancers; however, their efficacy is limited. Simultaneously targeting more than one inhibitory checkpoint receptor has emerged as a promising therapeutic strategy. In support of this concept, mice deficient in PD-1 and LAG-3, an inhibitory checkpoint receptor often co-expressed with PD-1 in the tumor microenvironment, exhibit enhanced anti-tumor activity. Here, we demonstrate increased anti-tumor efficacy of a combined anti–human PD-1 (hPD-1) and anti–human LAG-3 (hLAG-3) therapy using fully human monoclonal antibodies in dual humanized PD-1 x LAG-3 mice. The pharmacokinetics and toxicology of the novel anti-hLAG-3 antibody were assessed in non-human primates to support clinical development.

Methods

REGN2810, a high affinity anti-hPD-1 monoclonal antibody that blocks PD-1 interaction with PD-L1 and PD-L2, and a novel high affinity monoclonal anti–hLAG-3 antibody, which blocks the LAG-3/MHC II interaction were generated. Dual humanized PD-1 x LAG-3 mice were engineered by replacing the extracellular domains of mouse Pdcd1 and Lag3 with the corresponding regions of hPD-1 and hLAG-3 and were used for testing antibody efficacy in a MC38.ova syngeneic tumor model. Expression of humanized PD-1 and LAG-3 were analyzed by flow cytometry. Binding of hLAG-3 to mouse MHC II was confirmed with a cell adhesion assay, and binding of hPD-1 to mouse PD-L1 was confirmed using surface plasmon resonance. The pharmacokinetics of anti-hLAG-3 antibody following a single i.v. dose, and the safety profile in a 4-week weekly i.v. dose regimen of up to 50 mg/kg/dose, were determined in cynomolgus monkeys.

Results

Treatment of MC38.ova tumor-bearing humanized mice with a combination of anti-hPD-1 and anti-hLAG-3 antibodies triggered activation of intratumoral and peripheral T cells. Importantly, the combination treatment exhibited an additive, dose dependent anti-tumor effect compared to the respective monotherapies. Anti-hLAG-3 antibody pharmacokinetics in cynomolgus monkeys followed a standard mean concentration-time profile characterized by an initial brief distribution phase and a linear beta elimination phase. Exposure to anti-hLAG-3 increased in a dose-proportional manner, with elimination half-lives ranging from 10.8 to 11.5 days. Anti-hLAG-3 antibody was well tolerated, and no-observed-adverse-effect level (NOAEL) could be established up to 50 mg/kg.

Conclusions

Preclinical anti-tumor efficacy of combined REGN2810 and anti-hLAG-3 antibody treatment, together with favorable pharmacokinetic and safety data for anti-hLAG-3 antibody in cynomolgus monkeys, support clinical development of this cancer combination immunotherapy.

P196 Combination of PD-L1 blockade with oncolytic vaccines re-shapes the functional state of tumor infiltrating lymphocytes

Cristian Capasso1, Federica Frascaro2, Sara Carpi3, Siri Tähtinen1, Sara Feola4, Manlio Fusciello1, Karita Peltonen1, Beatriz Martins1, Madeleine Sjöberg1, Sari Pesonen5, Tuuli Ranki5, Lukasz Kyruk1, Erkko Ylösmäki1, Vincenzo Cerullo1

1University of Helsinki, Helsinki, Uusimaa, Finland; 2University of Siena, Supersano (LE), Puglia, Italy; 3University of Pisa, Pisa, Toscana, Italy; 4University of Napoli Federico II, Helsinki, Uusimaa, Finland; 5PeptiCRAd Oy, Helsinki, Uusimaa, Finland
Correspondence: Cristian Capasso (cristian.capasso@helsinki.fi)

Background

The immunological escape of tumors represents one of the main obstacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd.

Methods

We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background.

Results

First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy significantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells suggested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM-3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen specific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ratio between activated and exhausted pentamer positive cells (p = 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We observed that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was increased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4+ T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor microenvironment (p < 0.0001).

Conclusions

In conclusion, we demonstrated that the efficacy of immune checkpoint inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaustion, resulting in long-lasting immunological memory and increased median survival.
Fig. 7 (abstract P196).

Survival of C57 mice bearing B16OVA tumors and treated on day 6 post-implantation with either PBS, PDL1 blockade, OVA-targeting PeptiCRAd or the combination of PDL1-blockade and OVA-PeptiCRAd.

P197 In vitro evaluation of immunotherapy protocols through a label-free impedance-based technology allows dynamic monitoring of immune response and reagent efficacy

Fabio Cerignoli, Biao Xi, Garret Guenther, Naichen Yu, Lincoln Muir, Leyna Zhao, Yama Abassi

ACEA Biosciences Inc., San Diego, CA, USA
Correspondence: Fabio Cerignoli (fcerignoli@aceabio.com)

Background

In vitro characterization of reagent efficacy in the context of cancer immunotherapy is a necessary step before moving to more expensive animal models and clinical studies. However, current in vitro assays like Chromium-51, ATP-based luminescence or flow cytometry are either difficult to implement in high throughput environments or are mainly based on endpoint methodologies that are unable to capture the full dynamic of the immune response. Here, we present the adaptation of an impedance-based platform to monitor cytotoxic activity of immune cells activated trough different means.

Methods

Impedance technology detects cell death and proliferation of adherent cells by measuring changes in conductance of microelectrodes embedded in 96 and 384-wells cell culture plates. We utilized adherent and B cell leukemia/lymphoma cell lines as well as primary tumor cells as in vitro models for immunotherapy reagent evaluation. We seeded the cells on electrodes coated 96-well plates and monitored cell adhesion and proliferation for 24 hours. The following day effector cells were added at multiple effector:target ratios in presence of BiTEs antibodies and/or anti PD-1/PD-L1 antibodies. Impedance signal was monitored for up to seven days. Control wells were set up with effector cells only or with target plus effector cells but without antibodies. We adapted such adhesion-based technology to monitor non-adherent B-leukemia/lymphoma cells, by developing a strategy where the wells are coated with an anti-CD40 antibody. The coating allows specific adhesion and retention of B cells and measurement of changes in impedance that are proportional to cell number.

Results

Using increasing concentrations of EpCAM/CD3 BiTE, we demonstrated the suitability of an impedance-based approach to quantitatively monitor the efficacy of immune cells-mediated cancer cell killing both under different effector:target ratios and antibody concentrations. Combination treatments with checkpoint reduced timing and increased amount of killed cancer cells. Similar results were also obtained with engineered CAR-T cells against CD19 or NK cell lines, demonstrating specific killing of tumor B cells at very low effector:target ratios. The results were also confirmed by flow cytometry.

Conclusions

Overall, our results demonstrate the value of an impedance-based approach in measuring the cytotoxic response across the temporal scale, an aspect that is otherwise very difficult to assess with more canonical end point assays. Furthermore, the availability of 384-well format and minimal sample handling place the technology in an ideal spot for applications in large reagent validation screening or personalized medicine, like therapeutic protocol validation directly on patient samples.

P198 Tumor necrosis factor alpha and interleukin-2 expressing adenovirus plus PD-1 blockade as a boost for T cell therapy in the context of solid tumor therapies

Víctor Cervera-Carrascón1, Mikko Siurala1, João Santos1, Riikka Havunen2, Suvi Parviainen1, Akseli Hemminki1

1TILT Biotherapeutics, Helsinki, Uusimaa, Finland; 2University of Helsinki, Helsinki, Uusimaa, Finland
Correspondence: Víctor Cervera-Carrascón (victor@tiltbio.com)

Background

Because of the immunosuppressive tumor microenvironment, the immune system is unable to develop effective responses against tumor cells. This phenomenon also acts against the effectiveness of adoptive T cell therapy. In order to overcome this situation in the tumor, an attractive therapeutic combination is the combination of oncolytic viruses and immune checkpoint inhibitors. In this case, besides the last two therapies mentioned above, combinations with T cell therapy were also included. The virus used was engineered to express tumor necrosis factor α (TNFα) and interleukin (IL)-2, two cytokines that will boost the immunogenicity of the virus and thus its antitumor properties. On the other hand, the use of anti-PD-1 will avoid exhaustion on tumor infiltrating T cells and hence remove the barriers that could dampen the desired immune response against the tumor.

Methods

In the study of the antitumor effect of this three armed treatment we used an in vivo model of subcutaneous B16-OVA melanoma-bearing mice. Two experiments were carried out; the first one (n = 47) to establish the differences between the triple, double, and single armed combination therapies and the second experiment (n = 84) was focused on study the differences between the groups that showed the best outcomes in the first one and also optimize viral and anti-PD-1 administration regimes.

Results

Preliminary results show a statistically significant positive effect coming out from the combination of virus therapy and immune checkpoint blockade with regard to both tumor progression and overall survival, with up to 43 % complete tumor regression achieved in some of the groups after 96 days post treatment. On the other hand, the effect of adoptive cell therapy in this combination is not completely clear. More results will be presented after analyzing biological samples collected during both experiments.

Conclusions

Preclinical studies are a key step to detect which combinations are more suitable for success in human trials. In this study we developed a rationale for the combination relying on two concepts: to make silent tumors more visible to the immune system and to counter immunosuppressive mechanisms to unleash the full potential of T cells against the tumor, rendering in a modification of the tumor microenvironment that makes it more susceptible for T cell mediated killing. According to the results displayed from these experiments, the combination of this genetically modified adenovirus and PD-1 blockade is an efficient combination to be considered for future application in humans.

P199 IMM-101 primes for increased complete responses following checkpoint inhibitors in metastatic melanoma; 3 case reports

Angus Dalgleish1, Satvinder Mudan2

1St George's University of London, London, UK; 2The Royal Marsden Hospital and Imperial College London, London, UK
Correspondence: Angus Dalgleish (dalgleis@sgul.ac.uk)

Background

IMM-101, a heat-killed borate-buffered whole cell product of Mycobacterium obuense has been shown to enhance cell mediated cytokine responses and innate immune responses involving NK and gamma delta cells [1]. Complete responses (CR) in patients with melanoma lung metastases demonstrated. Follow up of original publication [2] h