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 one

National Harbor, MD, USA. 9-13 November 2016
  • Andreas Lundqvist1Email author,
  • Vincent van Hoef1,
  • Xiaonan Zhang1,
  • Erik Wennerberg2,
  • Julie Lorent1,
  • Kristina Witt1,
  • Laia Masvidal Sanz1,
  • Shuo Liang1,
  • Shannon Murray3,
  • Ola Larsson1,
  • Rolf Kiessling1,
  • Yumeng Mao1,
  • John-William Sidhom4Email author,
  • Catherine A. Bessell5,
  • Jonathan Havel6,
  • Jonathan Schneck7,
  • Timothy A. Chan6,
  • Eliot Sachsenmeier8,
  • David Woods9Email author,
  • Anders Berglund10,
  • Rupal Ramakrishnan10,
  • Andressa Sodre9,
  • Jeffrey Weber9,
  • Roberta Zappasodi11Email author,
  • Yanyun Li11,
  • Jingjing Qi12,
  • Philip Wong12,
  • Cynthia Sirard13,
  • Michael Postow14,
  • Walter Newman13,
  • Henry Koon15,
  • Vamsidhar Velcheti16,
  • Margaret K. Callahan17,
  • Jedd D. Wolchok14,
  • Taha Merghoub11,
  • Lawrence G. Lum18Email author,
  • Minsig Choi19,
  • Archana Thakur18,
  • Abhinav Deol20,
  • Gregory Dyson20,
  • Anthony Shields20,
  • Cara Haymaker21Email author,
  • Marc Uemura21,
  • Ravi Murthy21,
  • Marihella James21,
  • Daqing Wang22,
  • Julie Brevard22,
  • Catherine Monaghan22,
  • Suzanne Swann22,
  • James Geib22,
  • Mark Cornfeld22,
  • Srinivas Chunduru22,
  • Sudhir Agrawal22,
  • Cassian Yee21,
  • Jennifer Wargo21,
  • Sapna P. Patel21,
  • Rodabe Amaria21,
  • Hussein Tawbi21,
  • Isabella Glitza21,
  • Scott Woodman21,
  • Wen-Jen Hwu21,
  • Michael A. Davies21,
  • Patrick Hwu21,
  • Willem W. Overwijk21,
  • Chantale Bernatchez21,
  • Adi Diab21,
  • Erminia Massarelli23Email author,
  • Neil H. Segal24,
  • Vincent Ribrag25,
  • Ignacio Melero26,
  • Tara C. Gangadhar27,
  • Walter Urba28,
  • Dirk Schadendorf29,
  • Robert L. Ferris30,
  • Roch Houot31,
  • Franck Morschhauser32,
  • Theodore Logan33,
  • Jason J. Luke34,
  • William Sharfman35,
  • Fabrice Barlesi36,
  • Patrick A. Ott37,
  • Laura Mansi38,
  • Shivaani Kummar39,
  • Gilles Salles40,
  • Cecilia Carpio41,
  • Roland Meier42,
  • Suba Krishnan42,
  • Dan McDonald42,
  • Matthew Maurer42,
  • Xuemin Gu42,
  • Jaclyn Neely42,
  • Satyendra Suryawanshi42,
  • Ronald Levy39,
  • Nikhil Khushalani43,
  • Jennifer Wu44Email author,
  • Jinyu Zhang44,
  • Fahmin Basher44,
  • Mark Rubinstein44,
  • Mark Bucsek45Email author,
  • Guanxi Qiao45,
  • Cameron MacDonald45,
  • Bonnie Hylander45,
  • Elizabeth Repasky45,
  • Shilpak Chatterjee46Email author,
  • Anusara Daenthanasanmak46,
  • Paramita Chakraborty46,
  • Kyle Toth46,
  • Megan Meek46,
  • Elizabeth Garrett-Mayer46,
  • Michael Nishimura47,
  • Chrystal Paulos46,
  • Craig Beeson46,
  • Xuezhong Yu46,
  • Shikhar Mehrotra46,
  • Fei Zhao48,
  • Kathy Evans48,
  • Christine Xiao48,
  • Alisha Holtzhausen49,
  • Brent A. Hanks1Email author,
  • Nicole Scharping50Email author,
  • Ashley V. Menk51,
  • Rebecca Moreci51,
  • Ryan Whetstone50,
  • Rebekah Dadey50,
  • Simon Watkins50,
  • Robert Ferris50,
  • Greg M. Delgoffe50,
  • Jonathan Peled52Email author,
  • Sean Devlin52,
  • Anna Staffas52,
  • Melissa Lumish52,
  • Kori Porosnicu Rodriguez52,
  • Katya Ahr52,
  • Miguel Perales52,
  • Sergio Giralt52,
  • Ying Taur52,
  • Eric Pamer52,
  • Marcel R. M. van den Brink52,
  • Robert Jenq52,
  • Nicola Annels53Email author,
  • Hardev Pandha53,
  • Guy Simpson53,
  • Hugh Mostafid54,
  • Kevin Harrington55,
  • Alan Melcher56,
  • Mark Grose57,
  • Bronwyn Davies57,
  • Gough Au57,
  • Roberta Karpathy57,
  • Darren Shafren57,
  • Jacob Ricca58Email author,
  • Taha Merghoub59,
  • Jedd D. Wolchok60,
  • Dmitriy Zamarin58,
  • Luciana Batista61,
  • Florence Marliot62,
  • Angela Vasaturo63,
  • Sabrina Carpentier64,
  • Cécile Poggionovo61,
  • Véronique Frayssinet61,
  • Jacques Fieschi61,
  • Marc Van den Eynde65,
  • Franck Pagès66,
  • Jérôme Galon63,
  • Fabienne Hermitte61Email author,
  • Sean G. Smith67Email author,
  • Khue Nguyen68,
  • Sruthi Ravindranathan69,
  • Bhanu Koppolu67,
  • David Zaharoff67,
  • Gustavo Schvartsman70Email author,
  • Roland Bassett70,
  • Jennifer L. McQuade70,
  • Lauren E. Haydu70,
  • Michael A. Davies70,
  • Hussein Tawbi70,
  • Isabella Glitza70,
  • Douglas Kline71,
  • Xiufen Chen72,
  • Dominick Fosco72,
  • Justin Kline73Email author,
  • Abigail Overacre74Email author,
  • Maria Chikina74,
  • Erin Brunazzi74,
  • Gulidanna Shayan75,
  • William Horne74,
  • Jay Kolls74,
  • Robert L. Ferris74,
  • Greg M. Delgoffe74,
  • Tullia C. Bruno76,
  • Creg Workman74,
  • Dario Vignali74,
  • Prasad S. Adusumilli77Email author,
  • Ephraim A Ansa-Addo78Email author,
  • Zihai Li78,
  • Andrew Gerry79Email author,
  • Joseph P. Sanderson79,
  • Karen Howe79,
  • Roslin Docta79,
  • Qian Gao79,
  • Eleanor A. L. Bagg79,
  • Nicholas Tribble79,
  • Miguel Maroto79,
  • Gareth Betts80,
  • Natalie Bath80,
  • Luca Melchiori80,
  • Daniel E. Lowther80,
  • Indu Ramachandran80,
  • Gabor Kari80,
  • Samik Basu80Email author,
  • Gwendolyn Binder-Scholl80,
  • Karen Chagin80,
  • Lini Pandite80,
  • Tom Holdich80,
  • Rafael Amado80,
  • Hua Zhang81,
  • John Glod81,
  • Donna Bernstein81,
  • Bent Jakobsen82,
  • Crystal Mackall83,
  • Ryan Wong84,
  • Jonathan D. Silk84,
  • Katherine Adams84,
  • Garth Hamilton84,
  • Alan D. Bennett84,
  • Sara Brett85,
  • Junping Jing85,
  • Adriano Quattrini84,
  • Manoj Saini84,
  • Guy Wiedermann84,
  • Andrew Gerry84Email author,
  • Bent Jakobsen84,
  • Gwendolyn Binder-Scholl86,
  • Joanna Brewer84,
  • MyLinh Duong87,
  • An Lu87,
  • Peter Chang87,
  • Aruna Mahendravada87,
  • Nicholas Shinners87,
  • Kevin Slawin87,
  • David M. Spencer88,
  • Aaron E. Foster87,
  • J. Henri Bayle87Email author,
  • Cristina Bergamaschi89Email author,
  • Sinnie Sin Man Ng89,
  • Bethany Nagy89,
  • Shawn Jensen90,
  • Xintao Hu89,
  • Candido Alicea89,
  • Bernard Fox90,
  • Barbara Felber89,
  • George Pavlakis89,
  • Jessica Chacon91Email author,
  • Tori Yamamoto91,
  • Thomas Garrabrant91,
  • Luis Cortina91,
  • Daniel J. Powell92,
  • Marco Donia93Email author,
  • Julie Westerlin Kjeldsen94,
  • Rikke Andersen93,
  • Marie Christine Wulff Westergaard93,
  • Valentina Bianchi95,
  • Mateusz Legut95,
  • Meriem Attaf95,
  • Garry Dolton95,
  • Barbara Szomolay96,
  • Sascha Ott97,
  • Rikke Lyngaa98,
  • Sine Reker Hadrup98,
  • Andrew Kelvin Sewell95,
  • Inge Marie Svane93,
  • Aaron Fan99Email author,
  • Takumi Kumai100,
  • Esteban Celis100,
  • Ian Frank101Email author,
  • Amanda Stramer101,
  • Michelle A. Blaskovich101,
  • Seth Wardell101,
  • Maria Fardis101,
  • James Bender101,
  • Michael T. Lotze101,
  • Stephanie L. Goff102Email author,
  • Nikolaos Zacharakis102,
  • Yasmine Assadipour102,
  • Todd D. Prickett102,
  • Jared J. Gartner102,
  • Robert Somerville103,
  • Mary Black102,
  • Hui Xu102,
  • Harshini Chinnasamy102,
  • Isaac Kriley102,
  • Lily Lu102,
  • John Wunderlich102,
  • Paul F. Robbins102,
  • Steven Rosenberg102,
  • Steven A. Feldman102,
  • Kasia Trebska-McGowan104,
  • Isaac Kriley104,
  • Parisa Malekzadeh104,
  • Eden Payabyab104,
  • Richard Sherry105,
  • Steven Rosenberg104,
  • Stephanie L. Goff104Email author,
  • Aishwarya Gokuldass106Email author,
  • Michelle A. Blaskovich106,
  • Charlene Kopits106,
  • Brian Rabinovich106,
  • Michael T. Lotze106,
  • Daniel S. Green107Email author,
  • Olena Kamenyeva108,
  • Kathryn C. Zoon109,
  • Christina M. Annunziata107,
  • Joanne Hammill110Email author,
  • Christopher Helsen110,
  • Craig Aarts110,
  • Jonathan Bramson110,
  • Yui Harada111Email author,
  • Yoshikazu Yonemitsu111,
  • Christopher Helsen112Email author,
  • Joanne Hammill112,
  • Kenneth Mwawasi112,
  • Galina Denisova112,
  • Jonathan Bramson112,
  • Rajanish Giri113,
  • Benjamin Jin114,
  • Tracy Campbell114,
  • Lindsey M. Draper115,
  • Sanja Stevanovic114,
  • Zhiya Yu116,
  • Bianca Weissbrich117,
  • Nicholas P. Restifo116,
  • Cornelia L. Trimble118,
  • Steven Rosenberg116,
  • Christian S. Hinrichs116Email author,
  • Kwong Tsang119,
  • Massimo Fantini119,
  • James W. Hodge120Email author,
  • Rika Fujii120,
  • Ingrid Fernando119,
  • Caroline Jochems119,
  • Christopher Heery119,
  • James Gulley119,
  • Patrick Soon-Shiong121,
  • Jeffrey Schlom122,
  • Weiqing Jing123,
  • Jill Gershan123,
  • Grace Blitzer123,
  • James Weber123,
  • Laura McOlash123,
  • Bryon D. Johnson123Email author,
  • Simin Kiany124Email author,
  • Huang Gangxiong124,
  • Eugenie S. Kleinerman124,
  • Michael Klichinsky125Email author,
  • Marco Ruella125,
  • Olga Shestova125,
  • Saad Kenderian125,
  • Miriam Kim125,
  • John Scholler125,
  • Carl H. June125,
  • Saar Gill125,
  • Duane Moogk126,
  • Shi Zhong127,
  • Zhiya Yu128,
  • Ivan Liadi129,
  • William Rittase130,
  • Victoria Fang131,
  • Janna Dougherty126,
  • Arianne Perez-Garcia132,
  • Iman Osman133,
  • Cheng Zhu130,
  • Navin Varadarajan129,
  • Nicholas P. Restifo128,
  • Alan Frey134,
  • Michelle Krogsgaard135Email author,
  • Daniel Landi136Email author,
  • Kristen Fousek136,
  • Malini Mukherjee136,
  • Ankita Shree136,
  • Sujith Joseph136,
  • Kevin Bielamowicz136,
  • Tiara Byrd136,
  • Nabil Ahmed136,
  • Meenakshi Hegde136,
  • Sylvia Lee137Email author,
  • David Byrd138,
  • John Thompson139,
  • Shailender Bhatia140,
  • Scott Tykodi140,
  • Judy Delismon141,
  • Liz Chu141,
  • Siddiq Abdul-Alim141,
  • Arpy Ohanian141,
  • Anna Marie DeVito142,
  • Stanley Riddell141,
  • Kim Margolin143,
  • Isabelle Magalhaes144Email author,
  • Jonas Mattsson144,
  • Michael Uhlin144,
  • Satoshi Nemoto145,
  • Patricio Pérez Villarroel145,
  • Ryosuke Nakagawa145,
  • James J. Mule146,
  • Adam W. Mailloux145Email author,
  • Melinda Mata147Email author,
  • Phuong Nguyen147,
  • Claudia Gerken147,
  • Christopher DeRenzo147,
  • David M. Spencer148,
  • Stephen Gottschalk147,
  • Mélissa Mathieu149Email author,
  • Sandy Pelletier149,
  • John Stagg149,
  • Simon Turcotte149,
  • Nicholas Minutolo150Email author,
  • Prannda Sharma150,
  • Andrew Tsourkas151,
  • Daniel J. Powell150,
  • Nadine Mockel-Tenbrinck152Email author,
  • Daniela Mauer152,
  • Katharina Drechsel152,
  • Carola Barth152,
  • Katharina Freese152,
  • Ulrike Kolrep152,
  • Silke Schult152,
  • Mario Assenmacher152,
  • Andrew Kaiser152,
  • John Mullinax153Email author,
  • MacLean Hall153,
  • Julie Le153,
  • Krithika Kodumudi153,
  • Erica Royster153,
  • Allison Richards153,
  • Ricardo Gonzalez153,
  • Amod Sarnaik153,
  • Shari Pilon-Thomas153,
  • Morten Nielsen154Email author,
  • Anders Krarup-Hansen155,
  • Dorrit Hovgaard156,
  • Michael Mørk Petersen156,
  • Anand Chainsukh Loya157,
  • Niels Junker158,
  • Inge Marie Svane158,
  • Charlotte Rivas159,
  • Robin Parihar159,
  • Stephen Gottschalk160,
  • Cliona M. Rooney159,
  • Haiying Qin161Email author,
  • Sang Nguyen161,
  • Paul Su161,
  • Chad Burk161,
  • Brynn Duncan161,
  • Bong-Hyun Kim162,
  • M. Eric Kohler161,
  • Terry Fry161,
  • Arjun A. Rao163Email author,
  • Noam Teyssier163,
  • Jacob Pfeil163,
  • Nikolaos Sgourakis163,
  • Sofie Salama163,
  • David Haussler164,
  • Sarah A. Richman165Email author,
  • Selene Nunez-Cruz166,
  • Zack Gershenson166,
  • Zissimos Mourelatos167,
  • David Barrett165,
  • Stephan Grupp165,
  • Michael Milone167,
  • Alba Rodriguez-Garcia168Email author,
  • Matthew K. Robinson169,
  • Gregory P. Adams169,
  • Daniel J. Powell170,
  • João Santos171Email author,
  • Riikka Havunen172,
  • Mikko Siurala172,
  • Víctor Cervera-Carrascón171,
  • Suvi Parviainen171,
  • Marjukka Antilla173,
  • Akseli Hemminki172,
  • Jyothi Sethuraman174Email author,
  • Laurelis Santiago174,
  • Jie Qing Chen174,
  • Zhimin Dai174,
  • Seth Wardell174,
  • James Bender174,
  • Michael T. Lotze174,
  • Huizi Sha175Email author,
  • Shu Su175,
  • Naiqing Ding175,
  • Baorui Liu175,
  • Sanja Stevanovic176Email author,
  • Anna Pasetto177,
  • Sarah R. Helman176,
  • Jared J. Gartner177,
  • Todd D. Prickett177,
  • Paul F. Robbins177,
  • Steven A. Rosenberg177,
  • Christian S. Hinrichs176,
  • Shailender Bhatia178Email author,
  • Melissa Burgess179,
  • Hui Zhang180,
  • Tien Lee181,
  • Hans Klingemann181,
  • Patrick Soon-Shiong181,
  • Paul Nghiem178,
  • John M. Kirkwood182,
  • John M. Rossi183,
  • Marika Sherman183,
  • Allen Xue183,
  • Yueh-wei Shen183,
  • Lynn Navale183,
  • Steven A. Rosenberg184,
  • James N. Kochenderfer185,
  • Adrian Bot183Email author,
  • Anandaraman Veerapathran186Email author,
  • Aishwarya Gokuldass186,
  • Amanda Stramer186,
  • Jyothi Sethuraman186,
  • Michelle A. Blaskovich186,
  • Doris Wiener186,
  • Ian Frank186,
  • Laurelis Santiago186,
  • Brian Rabinovich186,
  • Maria Fardis186,
  • James Bender186,
  • Michael T. Lotze186,
  • Edmund K. Waller187Email author,
  • Jian-Ming Li187,
  • Christopher Petersen187,
  • Bruce R. Blazar188,
  • Jingxia Li187,
  • Cynthia R. Giver187,
  • Ziming Wang189Email author,
  • Steven K. Grossenbacher189,
  • Ian Sturgill190,
  • Robert J. Canter189,
  • William J. Murphy189,
  • Congcong Zhang191,
  • Michael C. Burger192,
  • Lukas Jennewein193,
  • Anja Waldmann191,
  • Michel Mittelbronn193,
  • Torsten Tonn194,
  • Joachim P. Steinbach192,
  • Winfried S. Wels191Email author,
  • Jason B. Williams195Email author,
  • Yuanyuan Zha195,
  • Thomas F. Gajewski196,
  • LaTerrica C. Williams197Email author,
  • Giedre Krenciute197,
  • Mamta Kalra197,
  • Chrystal Louis197,
  • Stephen Gottschalk198,
  • Gang Xin199Email author,
  • David Schauder199,
  • Aimin Jiang200,
  • Nikhil Joshi201,
  • Weiguo Cui199,
  • Xue Zeng202Email author,
  • Ashley V. Menk202,
  • Nicole Scharping203,
  • Greg M. Delgoffe203,
  • Zeguo Zhao204Email author,
  • Mohamad Hamieh204,
  • Justin Eyquem204,
  • Gertrude Gunset204,
  • Neil Bander205,
  • Michel Sadelain204,
  • David Askmyr206,
  • Milad Abolhalaj207Email author,
  • Kristina Lundberg207,
  • Lennart Greiff208,
  • Malin Lindstedt207,
  • Helen K. Angell209Email author,
  • Kyoung-Mee Kim210,
  • Seung-Tae Kim210,
  • Sung Kim211,
  • Alan D. Sharpe209,
  • Julia Ogden212,
  • Anna Davenport213,
  • Darren R. Hodgson212,
  • Carl Barrett214,
  • Jeeyun Lee211,
  • Elaine Kilgour212,
  • Jodi Hanson215Email author,
  • Richard Caspell215,
  • Alexey Karulin215,
  • Paul Lehmann215,
  • Tameem Ansari216Email author,
  • Annemarie Schiller216,
  • Srividya Sundararaman216,
  • Paul Lehmann216,
  • Jodi Hanson217Email author,
  • Diana Roen217,
  • Alexey Karulin217,
  • Paul Lehmann217,
  • Mark Ayers218Email author,
  • Diane Levitan219,
  • Gladys Arreaza219,
  • Fang Liu219,
  • Robin Mogg219,
  • Yung-Jue Bang220,
  • Bert O’Neil221,
  • Razvan Cristescu219,
  • Philip Friedlander222,
  • Karl Wassman223,
  • Chrisann Kyi222,
  • William Oh222,
  • Nina Bhardwaj224Email author,
  • Svetlana Bornschlegl225Email author,
  • Michael P. Gustafson225,
  • Dennis A. Gastineau225,
  • Ian F. Parney225,
  • Allan B. Dietz225,
  • Daniel Carvajal-Hausdorf226Email author,
  • Nikita Mani226,
  • Vamsidhar Velcheti227,
  • Kurt Schalper226,
  • David Rimm226,
  • Serena Chang228Email author,
  • Ronald Levy228,
  • John Kurland229,
  • Suba Krishnan229,
  • Christoph Matthias Ahlers229,
  • Maria Jure-Kunkel229,
  • Lewis Cohen229,
  • Holden Maecker228,
  • Holbrook Kohrt228,
  • Shuming Chen230Email author,
  • George Crabill230,
  • Theresa Pritchard230,
  • Tracee McMiller230,
  • Drew Pardoll231,
  • Fan Pan231,
  • Suzanne Topalian230,
  • Patrick Danaher232Email author,
  • Sarah Warren232,
  • Lucas Dennis232,
  • Andrew M. White232,
  • Leonard D’Amico233,
  • Melissa Geller234,
  • Mary L. Disis233,
  • Joseph Beechem232,
  • Kunle Odunsi235,
  • Steven Fling233,
  • Roshanak Derakhshandeh236Email author,
  • Tonya J. Webb236,
  • Sigrid Dubois237Email author,
  • Kevin Conlon237,
  • Bonita Bryant237,
  • Jennifer Hsu237,
  • Nancy Beltran237,
  • Jürgen Müller237,
  • Thomas Waldmann237,
  • Rebekka Duhen238Email author,
  • Thomas Duhen239,
  • Lucas Thompson240,
  • Ryan Montler239,
  • Andrew Weinberg238,
  • Max Kates241,
  • Brandon Early242Email author,
  • Erik Yusko243,
  • Taylor H. Schreiber242,
  • Trinity J. Bivalacqua241,
  • Mark Ayers244Email author,
  • Jared Lunceford244,
  • Michael Nebozhyn244,
  • Erin Murphy244,
  • Andrey Loboda244,
  • David R. Kaufman244,
  • Andrew Albright244,
  • Jonathan Cheng244,
  • S. Peter Kang244,
  • Veena Shankaran245,
  • Sarina A. Piha-Paul246,
  • Jennifer Yearley244,
  • Tanguy Seiwert247,
  • Antoni Ribas248,
  • Terrill K. McClanahan244,
  • Razvan Cristescu249,
  • Robin Mogg249,
  • Mark Ayers249Email author,
  • Andrew Albright249,
  • Erin Murphy249,
  • Jennifer Yearley249,
  • Xinwei Sher249,
  • Xiao Qiao Liu250,
  • Michael Nebozhyn249,
  • Jared Lunceford249,
  • Andrew Joe249,
  • Jonathan Cheng249,
  • Elizabeth Plimack251,
  • Patrick A. Ott252,
  • Terrill K. McClanahan249,
  • Andrey Loboda249,
  • David R. Kaufman249,
  • Alex Forrest-Hay253Email author,
  • Cheryl A. Guyre254Email author,
  • Kohei Narumiya255,
  • Marc Delcommenne255,
  • Heather A. Hirsch256Email author,
  • Amit Deshpande256,
  • Jason Reeves256,
  • Jenny Shu256,
  • Tong Zi256,
  • Jennifer Michaelson256,
  • Debbie Law256,
  • Elizabeth Trehu256,
  • Sriram Sathyanaryanan256,
  • Brendan P. Hodkinson257Email author,
  • Natalie A. Hutnick257,
  • Michael E. Schaffer257,
  • Michael Gormley257,
  • Tyler Hulett258Email author,
  • Shawn Jensen258,
  • Carmen Ballesteros-Merino259,
  • Christopher Dubay258,
  • Michael Afentoulis258,
  • Ashok Reddy260,
  • Larry David260,
  • Bernard Fox258,
  • Kumar Jayant261Email author,
  • Swati Agrawal261,
  • Rajendra Agrawal261,
  • Ghayathri Jeyakumar262Email author,
  • Seongho Kim262,
  • Heejin Kim262,
  • Cynthia Silski262,
  • Stacey Suisham262,
  • Elisabeth Heath262,
  • Ulka Vaishampayan263,
  • Natalie Vandeven264,
  • Natasja Nielsen Viller265,
  • Alison O’Connor265,
  • Hui Chen265,
  • Bolette Bossen265,
  • Eric Sievers265,
  • Robert Uger265,
  • Paul Nghiem264,
  • Lisa Johnson265Email author,
  • Hsiang-Fong Kao266Email author,
  • Chin-Fu Hsiao267,
  • Shu-Chuan Lai267,
  • Chun-Wei Wang266,
  • Jenq-Yuh Ko268,
  • Pei-Jen Lou268,
  • Tsai-Jan Lee266,
  • Tsang-Wu Liu269,
  • Ruey-Long Hong266,
  • Staci J. Kearney270Email author,
  • Joshua C. Black270,
  • Benjamin J. Landis270,
  • Sally Koegler270,
  • Brooke Hirsch270,
  • Roberto Gianani270,
  • Jeffrey Kim271Email author,
  • Ming-Xiao He271,
  • Bingqing Zhang271,
  • Nan Su271,
  • Yuling Luo271,
  • Xiao-Jun Ma271,
  • Emily Park271,
  • Dae Won Kim272Email author,
  • Domenico Copploa272,
  • Nishi Kothari272,
  • Young doo Chang272,
  • Richard Kim272,
  • Namyong Kim273,
  • Melvin Lye273Email author,
  • Ee Wan273,
  • Namyong Kim274,
  • Melvin Lye274Email author,
  • Ee Wan274,
  • Namyong Kim275,
  • Melvin Lye275Email author,
  • Ee Wan275,
  • Hanna A. Knaus276Email author,
  • Sofia Berglund276,
  • Hubert Hackl277,
  • Judith E. Karp278,
  • Ivana Gojo276,
  • Leo Luznik276,
  • Henoch S. Hong279,
  • Sven D. Koch279Email author,
  • Birgit Scheel279,
  • Ulrike Gnad-Vogt280,
  • Karl-Josef Kallen279,
  • Volker Wiegand280,
  • Linus Backert281,
  • Oliver Kohlbacher281,
  • Ingmar Hoerr279,
  • Mariola Fotin-Mleczek279,
  • James M. Billingsley282,
  • Yoshinobu Koguchi283Email author,
  • Valerie Conrad283,
  • William Miller283,
  • Iliana Gonzalez283,
  • Tomasz Poplonski283,
  • Tanisha Meeuwsen283,
  • Ana Howells-Ferreira283,
  • Rogan Rattray283,
  • Mary Campbell283,
  • Carlo Bifulco284,
  • Christopher Dubay285,
  • Keith Bahjat283,
  • Brendan Curti283,
  • Walter Urba283,
  • E-K Vetsika286,
  • G. Kallergi286,
  • Despoina Aggouraki286,
  • Z. Lyristi286,
  • P. Katsarlinos286,
  • Filippos Koinis286,
  • V. Georgoulias286,
  • Athanasios Kotsakis286Email author,
  • Nathan T. Martin287Email author,
  • Famke Aeffner287,
  • Staci J. Kearney287,
  • Joshua C. Black287,
  • Logan Cerkovnik287,
  • Luke Pratte287,
  • Rebecca Kim287,
  • Brooke Hirsch287,
  • Joseph Krueger287,
  • Roberto Gianani287,
  • Amaia Martínez-Usatorre288Email author,
  • Camilla Jandus288,
  • Alena Donda288,
  • Laura Carretero-Iglesia289,
  • Daniel E. Speiser288,
  • Dietmar Zehn290,
  • Nathalie Rufer291,
  • Pedro Romero288,
  • Anshuman Panda292,
  • Janice Mehnert293Email author,
  • Kim M. Hirshfield293,
  • Greg Riedlinger293,
  • Sherri Damare293,
  • Tracie Saunders293,
  • Levi Sokol294,
  • Mark Stein293,
  • Elizabeth Poplin293,
  • Lorna Rodriguez-Rodriguez293,
  • Ann Silk293,
  • Nancy Chan293,
  • Melissa Frankel293,
  • Michael Kane293,
  • Jyoti Malhotra293,
  • Joseph Aisner293,
  • Howard L. Kaufman293,
  • Siraj Ali295,
  • Jeffrey Ross295,
  • Eileen White293,
  • Gyan Bhanot293,
  • Shridar Ganesan293,
  • Anne Monette296Email author,
  • Derek Bergeron296,
  • Amira Ben Amor297,
  • Liliane Meunier298,
  • Christine Caron298,
  • Antigoni Morou296,
  • Daniel Kaufmann296,
  • Moishe Liberman299,
  • Igor Jurisica300,
  • Anne-Marie Mes-Masson296,
  • Kamel Hamzaoui297,
  • Rejean Lapointe297,
  • Ann Mongan301Email author,
  • Yuan-Chieh Ku301,
  • Warren Tom301,
  • Yongming Sun301,
  • Alex Pankov301,
  • Tim Looney301,
  • Janice Au-Young301,
  • Fiona Hyland301,
  • Jeff Conroy302Email author,
  • Carl Morrison302,
  • Sean Glenn303,
  • Blake Burgher303,
  • He Ji303,
  • Mark Gardner303,
  • Ann Mongan304,
  • Angela R. Omilian302,
  • Jeff Conroy305,
  • Wiam Bshara305,
  • Omilian Angela305,
  • Blake Burgher306,
  • He Ji306,
  • Sean Glenn306,
  • Carl Morrison305Email author,
  • Ann Mongan307,
  • Joseph M. Obeid308Email author,
  • Gulsun Erdag309,
  • Mark E. Smolkin310,
  • Donna H. Deacon308,
  • James W. Patterson311,
  • Lieping Chen312,
  • Timothy N. Bullock311,
  • Craig L. Slingluff313,
  • Joseph M. Obeid314Email author,
  • Gulsun Erdag315,
  • Donna H. Deacon314,
  • Craig L. Slingluff316,
  • Timothy N. Bullock317,
  • John T. Loffredo318Email author,
  • Raja Vuyyuru318,
  • Sophie Beyer318,
  • Vanessa M. Spires318,
  • Maxine Fox318,
  • Jon M. Ehrmann318,
  • Katrina A. Taylor318,
  • Alan J. Korman318,
  • Robert F. Graziano318,
  • David Page319Email author,
  • Katherine Sanchez320,
  • Carmen Ballesteros-Merino319,
  • Maritza Martel320,
  • Carlo Bifulco321,
  • Walter Urba322,
  • Bernard Fox321,
  • Sapna P. Patel323Email author,
  • Mariana Petaccia De Macedo323,
  • Yong Qin323,
  • Alex Reuben323,
  • Christine Spencer323,
  • Michele Guindani323,
  • Roland Bassett323,
  • Jennifer Wargo323,
  • Adriana Racolta324Email author,
  • Brian Kelly324,
  • Tobin Jones324,
  • Nathan Polaske324,
  • Noah Theiss324,
  • Mark Robida324,
  • Jeffrey Meridew324,
  • Iva Habensus324,
  • Liping Zhang324,
  • Lidija Pestic-Dragovich324,
  • Lei Tang324,
  • Ryan J. Sullivan325,
  • Theodore Logan326,
  • Nikhil Khushalani327,
  • Kim Margolin328,
  • Henry Koon329,
  • Thomas Olencki330,
  • Thomas Hutson331,
  • Brendan Curti332,
  • Joanna Roder333Email author,
  • Shauna Blackmon334,
  • Heinrich Roder333,
  • John Stewart335,
  • Asim Amin336,
  • Marc S. Ernstoff337,
  • Joseph I. Clark338,
  • Michael B. Atkins339,
  • Howard L. Kaufman340,
  • Jeffrey Sosman341,
  • Jeffrey Weber342,
  • David F. McDermott343,
  • Jeffrey Weber344,
  • Harriet Kluger345,
  • Ruth Halaban346,
  • Mario Snzol345,
  • Heinrich Roder347,
  • Joanna Roder347Email author,
  • Senait Asmellash347,
  • Arni Steingrimsson347,
  • Shauna Blackmon348,
  • Ryan J. Sullivan349,
  • Chichung Wang350,
  • Kristin Roman350Email author,
  • Amanda Clement350,
  • Sean Downing350,
  • Clifford Hoyt350,
  • Nathalie Harder351,
  • Guenter Schmidt351Email author,
  • Ralf Schoenmeyer351,
  • Nicolas Brieu351,
  • Mehmet Yigitsoy351,
  • Gabriele Madonna352,
  • Gerardo Botti352,
  • Antonio Grimaldi353,
  • Paolo A. Ascierto353,
  • Ralf Huss351,
  • Maria Athelogou354,
  • Harald Hessel355,
  • Nathalie Harder354,
  • Alexander Buchner356,
  • Guenter Schmidt354Email author,
  • Christian Stief356,
  • Ralf Huss354,
  • Gerd Binnig354,
  • Thomas Kirchner355,
  • Shankar Sellappan357Email author,
  • Sheeno Thyparambil357,
  • Sarit Schwartz357,
  • Fabiola Cecchi357,
  • Andrew Nguyen358,
  • Charles Vaske358,
  • Todd Hembrough357,
  • Jan Spacek359Email author,
  • Michal Vocka359,
  • Eva Zavadova359,
  • Helena Skalova359,
  • Pavel Dundr359,
  • Lubos Petruzelka359,
  • Nicole Francis359,
  • Rau T. Tilman360,
  • Arndt Hartmann361,
  • Irena Netikova359,
  • Carmen Ballesteros-Merino362,
  • Julia Stump363, 364Email author,
  • Amanda Tufman363, 364,
  • Frank Berger365,
  • Michael Neuberger366,
  • Rudolf Hatz367, 368, 369,
  • Michael Lindner370, 371,
  • Rachel E. Sanborn372,
  • John Handy372,
  • Bernard Fox372,
  • Carlo Bifulco372,
  • Rudolf M. Huber363, 364,
  • Hauke Winter366,
  • Simone Reu373,
  • Cheng Sun374Email author,
  • Weihua Xiao374,
  • Zhigang Tian374,
  • Kshitij Arora375,
  • Niyati Desai375,
  • Anupriya Kulkarni375,
  • Mihir Rajurkar375,
  • Miguel Rivera375,
  • Vikram Deshpande376,
  • David Ting375Email author,
  • Katy Tsai377Email author,
  • Adi Nosrati377,
  • Simone Goldinger378,
  • Omid Hamid379,
  • Alain Algazi377,
  • Paul Tumeh380,
  • Jimmy Hwang377,
  • Jacqueline Liu377,
  • Lawrence Chen377,
  • Reinhard Dummer378,
  • Michael Rosenblum377,
  • Adil Daud377,
  • Tsu-Shuen Tsao381Email author,
  • Julia Ashworth-Sharpe381,
  • Donald Johnson381,
  • Srabani Bhaumik381,
  • Christopher Bieniarz381,
  • Joseph Couto382,
  • Michael Farrell381,
  • Mahsa Ghaffari381,
  • Iva Habensus381,
  • Antony Hubbard381,
  • Tobin Jones381,
  • Brian Kelly381,
  • Jerome Kosmeder381,
  • Cleo Lee382,
  • Erin Marner381,
  • Jeffrey Meridew381,
  • Nathan Polaske381,
  • Adriana Racolta381,
  • Diana Uribe381,
  • Hongjun Zhang381,
  • Jian Zhang381,
  • Wenjun Zhang381,
  • Yifei Zhu382,
  • Larry Morrison381,
  • Lidija Pestic-Dragovich381,
  • Lei Tang381,
  • Takahiro Tsujikawa383,
  • Rohan N. Borkar384,
  • Vahid Azimi384,
  • Sushil Kumar383,
  • Guillaume Thibault383,
  • Motomi Mori383,
  • Edward El Rassi383,
  • Daniel R. Clayburgh383,
  • Molly F. Kulesz-Martin383,
  • Paul W. Flint383,
  • Lisa M. Coussens383Email author,
  • Lisa Villabona385Email author,
  • Giuseppe V. Masucci385,
  • Gary Geiss386,
  • Brian Birditt386,
  • Qian Mei386,
  • Alan Huang386,
  • Andrew M. White386,
  • Maribeth A. Eagan386,
  • Eduardo Ignacio386,
  • Nathan Elliott386,
  • Dwayne Dunaway386,
  • Lucas Dennis386,
  • Sarah Warren386Email author,
  • Joseph Beechem386Email author,
  • Dwayne Dunaway387,
  • Jaemyeong Jung387,
  • Chris Merritt387,
  • Isaac Sprague387,
  • Philippa Webster387,
  • Yan Liang387,
  • Sarah Warren387Email author,
  • Joseph Beechem387,
  • Jessica Wenthe388Email author,
  • Gunilla Enblad388,
  • Hannah Karlsson388,
  • Magnus Essand388,
  • Barbara Savoldo389,
  • Gianpietro Dotti389,
  • Martin Höglund388,
  • Malcolm K. Brenner389,
  • Hans Hagberg388,
  • Angelica Loskog388,
  • Matthew J. Bernett390,
  • Gregory L. Moore390,
  • Michael Hedvat390,
  • Christine Bonzon390,
  • Seung Chu390,
  • Rumana Rashid390,
  • Kendra N. Avery390,
  • Umesh Muchhal390,
  • John Desjarlais390Email author,
  • Michael Hedvat391Email author,
  • Matthew J. Bernett391,
  • Gregory L. Moore391,
  • Christine Bonzon391,
  • Rumana Rashid391,
  • Seung Chu391,
  • Kendra N. Avery391,
  • Umesh Muchhal391,
  • John Desjarlais391,
  • Matthew Kraman392Email author,
  • Katarzyna Kmiecik392,
  • Natalie Allen392,
  • Mustapha Faroudi392,
  • Carlo Zimarino392,
  • Mateusz Wydro392,
  • Jacqueline Doody392,
  • Sreesha P. Srinivasa393Email author,
  • Nagaraja Govindappa393,
  • Praveen Reddy393,
  • Aparajita Dubey393,
  • Sankar Periyasamy393,
  • Madhukara Adekandi393,
  • Chaitali Dey393,
  • Mary Joy393,
  • Pieter Fokko van Loo394Email author,
  • Henrike Veninga394,
  • Setareh Shamsili394,
  • Mark Throsby394,
  • Harry Dolstra395,
  • Lex Bakker394,
  • Ajjai Alva396Email author,
  • Juergen Gschwendt397,
  • Yohann Loriot398,
  • Joaquim Bellmunt399,
  • Dai Feng400,
  • Christian Poehlein400,
  • Thomas Powles401,
  • Emmanuel S. Antonarakis402Email author,
  • Charles G. Drake403,
  • Haiyan Wu403,
  • Christian Poehlein404,
  • Johann De Bono405,
  • Rajat Bannerji406Email author,
  • John Byrd407,
  • Gareth Gregory408,
  • Stephen Opat409,
  • Jake Shortt409,
  • Andrew J. Yee410,
  • Noopur Raje410,
  • Seth Thompson411,
  • Arun Balakumaran411,
  • Shaji Kumar412,
  • Brian I. Rini413Email author,
  • Toni K. Choueiri414,
  • Mariangela Mariani415,
  • Laurence Albiges416,
  • John B. Haanen417,
  • Michael B. Atkins418,
  • James Larkin419,
  • Manuela Schmidinger420,
  • Domenico Magazzù415,
  • Alessandra di Pietro415,
  • Robert J. Motzer421,
  • Troels Holz Borch422Email author,
  • Rikke Andersen422,
  • Per Kongsted422,
  • Magnus Pedersen422,
  • Morten Nielsen422,
  • Özcan Met422,
  • Marco Donia422,
  • Inge Marie Svane422,
  • Karim Boudadi423Email author,
  • Hao Wang423,
  • James Vasselli424,
  • Jan E. Baughman425,
  • Jon Wigginton424,
  • Rehab Abdallah423,
  • Ashley Ross423,
  • Charles G. Drake426,
  • Emmanuel S. Antonarakis427,
  • Robert J. Canter428Email author,
  • Jiwon Park428,
  • Ziming Wang428,
  • Steven Grossenbacher428,
  • Jesus I. Luna428,
  • Sita Withers429,
  • William Culp429,
  • Mingyi Chen428,
  • Arta Monjazeb428,
  • Michael S. Kent429,
  • William J. Murphy428,
  • Smita Chandran430Email author,
  • Robert Somerville430,
  • John Wunderlich430,
  • David Danforth430,
  • James Yang430,
  • Richard Sherry430,
  • Christopher Klebanoff430,
  • Stephanie Goff430,
  • Biman Paria430,
  • Arvind Sabesan430,
  • Abhishek Srivastava430,
  • Steven A. Rosenberg431,
  • Udai Kammula430,
  • Brendan Curti432Email author,
  • Jon Richards433,
  • Mark Faries434,
  • Robert H. I. Andtbacka435,
  • Mark Grose436,
  • Darren Shafren437,
  • Luis A. DiazJr.438Email author,
  • Dung T. Le438,
  • Takayuki Yoshino439,
  • Thierry André440,
  • Johanna Bendell441,
  • Minori Koshiji442,
  • Yayan Zhang442,
  • S Peter Kang442,
  • Bao Lam442,
  • Dirk Jäger443,
  • Todd M. Bauer444Email author,
  • Judy S. Wang445,
  • Jean K. Lee446,
  • Gulam A. Manji447,
  • Ragini Kudchadkar448,
  • John S. Kauh449,
  • Shande Tang449,
  • Naomi Laing450,
  • Gerald Falchook451,
  • Edward B. Garon452Email author,
  • Balazs Halmos453,
  • Hui Rina454,
  • Natasha Leighl455,
  • Sung Sook Lee456,
  • William Walsh457,
  • Konstanin Dragnev458,
  • Bilal Piperdi459,
  • Luis Paz-Ares Rodriguez460,
  • Nabeegha Shinwari459,
  • Ziewn Wei459,
  • Michael P. Gustafson461Email author,
  • Mary L Maas461,
  • Michael Deeds461,
  • Adam Armstrong461,
  • Svetlana Bornschlegl461,
  • Tim Peterson461,
  • Sue Steinmetz461,
  • Dennis A. Gastineau461,
  • Ian F. Parney461,
  • Allan B. Dietz461,
  • Thomas Herzog462Email author,
  • Floor J. Backes463,
  • Larry Copeland464,
  • Maria Del Pilar Estevez Diz465,
  • Thomas W. Hare466,
  • Warner Huh467,
  • Byoung-Gie Kim468,
  • Kathleen M. Moore469,
  • Ana Oaknin470,
  • William Small471,
  • Krishnansu S. Tewari472,
  • Bradley J. Monk473,
  • Ashish M. Kamat474Email author,
  • Joaquim Bellmunt475,
  • Toni K. Choueiri476,
  • Kijoeng Nam477,
  • Maria De Santis478,
  • Robert Dreicer479,
  • Noah M. Hahn480,
  • Rodolfo Perini477,
  • Arlene Siefker-Radtke474,
  • Guru Sonpavde481,
  • Ronald de Wit482,
  • J. Alfred Witjes483,
  • Stephen Keefe477,
  • Dean Bajorin484,
  • Justin Kline485Email author,
  • Philippe Armand486,
  • John Kuruvilla487,
  • Craig Moskowitz488,
  • Mehdi Hamadani489,
  • Vincent Ribrag490,
  • Pier Luigi Zinzani491,
  • Sabine Chlosta492,
  • Seth Thompson492,
  • Arun Balakumaran492,
  • Nancy Bartlett493,
  • Chrisann Kyi494Email author,
  • Rachel Sabado494,
  • Yvonne Saenger495,
  • Loging William496,
  • Michael Joseph Donovan496,
  • Erlinda Sacris494,
  • John Mandeli496,
  • Andres M. Salazar497,
  • Philip Friedlander494,
  • Nina Bhardwaj494,
  • John Powderly498,
  • Joshua Brody499,
  • John Nemunaitis500,
  • Leisha Emens501,
  • Jason J. Luke502,
  • Amita Patnaik503,
  • Ian McCaffery504,
  • Richard Miller504,
  • Ginna Laport504Email author,
  • Andrew L. Coveler505,
  • David C. Smith506,
  • Juneko E. Grilley-Olson507,
  • Thomas F. Gajewski508,
  • Sanjay Goel509,
  • Shyra J. Gardai510,
  • Che-Leung Law510,
  • Gary Means510,
  • Thomas Manley510Email author,
  • Brendan Curti511,
  • Kristen A. Marrone512Email author,
  • Gary Rosner513,
  • Valsamo Anagnostou512,
  • Joanne Riemer512,
  • Jessica Wakefield512,
  • Cynthia Zanhow512,
  • Stephen Baylin512,
  • Barbara Gitlitz514,
  • Julie Brahmer512,
  • David F. McDermott515Email author,
  • Sabina Signoretti515,
  • Wenting Li516,
  • Charles Schloss516,
  • Jean-Marie Michot517Email author,
  • Philippe Armand518,
  • Wei Ding519,
  • Vincent Ribrag517,
  • Beth Christian520,
  • Arun Balakumaran521,
  • Patricia Marinello521,
  • Sabine Chlosta521,
  • Yayan Zhang521,
  • Margaret Shipp518,
  • Pier Luigi Zinzani522,
  • Yana G. Najjar523Email author,
  • Lin523,
  • Lisa H. Butterfield523,
  • Ahmad A. Tarhini523,
  • Diwakar Davar523,
  • Hassane Zarour523,
  • Elizabeth Rush523,
  • Cindy Sander523,
  • John M. Kirkwood524,
  • Siqing Fu525,
  • Todd Bauer526,
  • Chris Molineaux527,
  • Mark K. Bennett527,
  • Keith W. Orford527Email author,
  • Kyriakos P. Papadopoulos528,
  • Sukhmani K. Padda529Email author,
  • Sumit A. Shah529,
  • A Dimitrios Colevas529,
  • Sujata Narayanan529,
  • George A. Fisher529,
  • Dana Supan529,
  • Heather A. Wakelee529,
  • Rhonda Aoki529,
  • Mark D. Pegram529,
  • Victor M. Villalobos530,
  • Jie Liu531,
  • Chris H. Takimoto532,
  • Mark Chao532,
  • Jens-Peter Volkmer533,
  • Ravindra Majeti534,
  • Irving L. Weissman531,
  • Branimir I. Sikic529,
  • David Page535Email author,
  • Wendy Yu536,
  • Alison Conlin537,
  • Janet Ruzich538,
  • Stacy Lewis539,
  • Anupama Acheson540,
  • Kathleen Kemmer541,
  • Kelly Perlewitz542,
  • Nicole M. Moxon537,
  • Staci Mellinger537,
  • Carlo Bifulco543,
  • Maritza Martel537,
  • Yoshinobu Koguchi544,
  • Bernard Fox543,
  • Walter Urba544,
  • Heather McArthur545,
  • Magnus Pedersen546Email author,
  • Marie Christine Wulff Westergaard546,
  • Troels Holz Borch546,
  • Morten Nielsen546,
  • Per Kongsted546,
  • Trine Juhler-Nøttrup547,
  • Marco Donia546,
  • Inge Marie Svane546,
  • Jayesh Desai548,
  • Ben Markman549,
  • Shahneen Sandhu550,
  • Hui Gan551,
  • Michael L. Friedlander552,
  • Ben Tran553,
  • Tarek Meniawy554,
  • Joanne Lundy550,
  • Duncan Colyer551,
  • Malaka Ameratunga555,
  • Christie Norris556,
  • Jason Yang557,
  • Kang Li557,
  • Lai Wang557,
  • Lusong Luo557,
  • Zhen Qin557Email author,
  • Song Mu558,
  • Xuemei Tan557,
  • James Song558,
  • Michael Millward554,
  • Matthew H. G. Katz559,
  • Todd W. Bauer560,
  • Gauri R. Varadhachary561,
  • Nicolas Acquavella562,
  • Nipun Merchant562,
  • Gina Petroni563,
  • Craig L. SlingluffJr.564,
  • Osama E. Rahma565Email author,
  • Brian I. Rini566Email author,
  • Thomas Powles567,
  • Mei Chen568,
  • Yang Song568,
  • Markus Puhlmann568,
  • Michael B. Atkins569,
  • Sriram Sathyanaryanan570Email author,
  • Heather A. Hirsch570,
  • Jenny Shu570,
  • Amit Deshpande570,
  • Arun Khattri571,
  • Jason Reeves570,
  • Tong Zi570,
  • Ryan Brisson571,
  • Christopher Harvey570,
  • Jennifer Michaelson570,
  • Debbie Law570,
  • Tanguy Seiwert572,
  • Jatin Shah573Email author,
  • Maria Victoria Mateos574,
  • Morio Matsumoto575,
  • Hilary Blacklock576,
  • Albert Oriol Rocafiguera577,
  • Hartmut Goldschmidt578,
  • Shinsuke Iida579,
  • Dina Ben Yehuda580,
  • Enrique Ocio574,
  • Paula Rodríguez-Otero581,
  • Sundar Jagannath582,
  • Sagar Lonial583,
  • Uma Kher584,
  • Patricia Marinello584,
  • Jesus San-Miguel581,
  • Jatin Shah585Email author,
  • Sagar Lonial586,
  • Moacyr Ribeiro de Oliveira587,
  • Habte Yimer588,
  • Maria Victoria Mateos589,
  • Robert Rifkin590,
  • Fredrik Schjesvold591,
  • Enrique Ocio589,
  • Paula Rodríguez-Otero592,
  • Jesus San-Miguel592,
  • Razi Ghori593,
  • Patricia Marinello593,
  • Sundar Jagannath594,
  • Anna Spreafico595Email author,
  • Victor Lee596,
  • Roger K. C. Ngan597,
  • Ka Fai To598,
  • Myung Ju Ahn599,
  • Quan Sing Ng600,
  • Ruey-Long Hong601,
  • Jin-Ching Lin602,
  • Ramona F. Swaby603,
  • Christine Gause603,
  • Sanatan Saraf603,
  • Anthony T. C. Chan598,
  • Elaine Lam604,
  • Nizar M. Tannir605,
  • Funda Meric-Bernstam605,
  • Ulka Vaishampayan606,
  • Keith W. Orford607,
  • Chris Molineaux607,
  • Matt Gross607,
  • Andy MacKinnon607,
  • Sam Whiting607Email author,
  • Martin Voss608,
  • Evan Y. Yu609,
  • Haiyan Wu610,
  • Charles Schloss610,
  • Mark R. Albertini611Email author,
  • Erik A. Ranheim612,
  • Jacquelyn A. Hank612,
  • Cindy Zuleger611,
  • Thomas McFarland611,
  • Jennifer Collins613,
  • Erin Clements614,
  • Sharon Weber611,
  • Tracey Weigel614,
  • Heather Neuman611,
  • Greg Hartig611,
  • David Mahvi615,
  • MaryBeth Henry611,
  • Jacek Gan611,
  • Richard Yang611,
  • Lakeesha Carmichael611,
  • KyungMann Kim611,
  • Stephen D. Gillies616,
  • Paul M. Sondel612,
  • Vivek Subbiah617,
  • Ravi Murthy617,
  • Lori Noffsinger618,
  • Kyle Hendricks618,
  • Marnix Bosch619Email author,
  • Jay M. Lee620,
  • Mi-Heon Lee620,
  • Edward B. Garon620,
  • Jonathan W. Goldman620,
  • Felicita E. Baratelli620,
  • Dorthe Schaue620,
  • Gerald Wang620,
  • Frances Rosen620,
  • Jane Yanagawa620,
  • Tonya C. Walser620,
  • Ying Q. Lin620,
  • Sharon Adams621,
  • Franco M. Marincola622,
  • Paul C. Tumeh620,
  • Fereidoun Abtin620,
  • Robert Suh620,
  • Karen Reckamp623,
  • William D. Wallace620,
  • Gang Zeng620,
  • David A. Elashoff620,
  • Sherven Sharma624,
  • Steven M. Dubinett620Email author,
  • Nina Bhardwaj625,
  • Philip Friedlander626,
  • Anna C. Pavlick627,
  • Marc S. Ernstoff628,
  • Brian Gastman629,
  • Brent Hanks630,
  • Mark R. Albertini631,
  • Jason J. Luke632,
  • Tibor Keler633,
  • Tom Davis633,
  • Laura A. Vitale633,
  • Elad Sharon634,
  • Patrick Danaher635,
  • Chihiro Morishima636,
  • Martin Cheever637,
  • Steven Fling637Email author,
  • Christopher R. Heery638Email author,
  • Joseph W. Kim639,
  • Elizabeth Lamping640,
  • Jennifer Marte640,
  • Sheri McMahon640,
  • Lisa Cordes640,
  • Farhad Fakhrejahani640,
  • Ravi Madan640,
  • Kwong Tsang641,
  • Caroline Jochems638,
  • Rachel Salazar642,
  • Maggie Zhang642,
  • Christoph Helwig643,
  • Jeffrey Schlom644,
  • James L Gulley645,
  • Roger Li646Email author,
  • John Amrhein647,
  • Zvi Cohen648,
  • Monique Champagne648,
  • Ashish Kamat646,
  • M. Angela Aznar649Email author,
  • Sara Labiano649,
  • Angel Diaz-Lagares650,
  • Manel Esteller651,
  • Juan Sandoval652,
  • Ignacio Melero649,
  • Susannah D. Barbee653Email author,
  • David I. Bellovin653,
  • John C. Timmer654,
  • Nebiyu Wondyfraw653,
  • Susan Johnson653,
  • Johanna Park653,
  • Amanda Chen653,
  • Mikayel Mkrtichyan653,
  • Amir S. Razai654,
  • Kyle S. Jones654,
  • Chelsie Y. Hata654,
  • Denise Gonzalez653,
  • Quinn Deveraux653,
  • Brendan P. Eckelman654,
  • Luis Borges653,
  • Rukmini Bhardwaj655Email author,
  • Raj K. Puri655,
  • Akiko Suzuki655,
  • Pamela Leland655,
  • Bharat H. Joshi655,
  • Todd Bartkowiak656,
  • Ashvin Jaiswal656,
  • Casey Ager656,
  • Midan Ai657,
  • Pratha Budhani657,
  • Renee Chin657,
  • David Hong657,
  • Michael Curran656Email author,
  • William D. Hastings658,
  • Maria Pinzon-Ortiz658,
  • Masato Murakami659,
  • Jason R. Dobson658Email author,
  • David Quinn658,
  • Joel P. Wagner658,
  • Xianhui Rong658,
  • Pamela Shaw660,
  • Ernesta Dammassa659,
  • Wei Guan658,
  • Glenn Dranoff658,
  • Alexander Cao661,
  • Ross B. Fulton662Email author,
  • Steven Leonardo662,
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  • Nadine Ottoson662,
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  • Richard D. Huhn662,
  • Jeremy Graff662,
  • Jamie Lowe662,
  • Keith Gorden662,
  • Mark Uhlik662,
  • Laura A. Vitale663,
  • Thomas O’Neill663,
  • Jenifer Widger663,
  • Andrea Crocker663,
  • Li-Zhen He663,
  • Jeffrey Weidlick663,
  • Karuna Sundarapandiyan663,
  • Venky Ramakrishna663,
  • James Storey664,
  • Lawrence J. Thomas664,
  • Joel Goldstein663Email author,
  • Henry C. Marsh664,
  • Tibor Keler663,
  • Jamison Grailer665Email author,
  • Julia Gilden665,
  • Pete Stecha665,
  • Denise Garvin665,
  • Jim Hartnett665,
  • Frank Fan665,
  • Mei Cong665,
  • Zhi-jie Jey Cheng665,
  • Marlon J. Hinner666Email author,
  • Rachida-Siham Bel Aiba666,
  • Corinna Schlosser666,
  • Thomas Jaquin666,
  • Andrea Allersdorfer666,
  • Sven Berger666,
  • Alexander Wiedenmann666,
  • Gabriele Matschiner666,
  • Julia Schüler667,
  • Ulrich Moebius666,
  • Christine Rothe666,
  • Olwill A. Shane666,
  • Brendan Horton668Email author,
  • Stefani Spranger669,
  • Thomas F. Gajewski670,
  • Dayson Moreira671,
  • Tomasz Adamus671,
  • Xingli Zhao671,
  • Piotr Swiderski671,
  • Sumanta Pal671,
  • Marcin Kortylewski671Email author,
  • Alyssa Kosmides672Email author,
  • Kevin Necochea673,
  • Jonathan Schneck674,
  • Kathleen M. Mahoney675Email author,
  • Sachet A. Shukla676,
  • Nikolaos Patsoukis677,
  • Apoorvi Chaudhri676,
  • Hung Pham676,
  • Ping Hua676,
  • Xia Bu676,
  • Baogong Zhu676,
  • Nir Hacohen678,
  • Catherine J. Wu676,
  • Edward Fritsch679,
  • Vassiliki A. Boussiotis677,
  • Gordon J. Freeman676,
  • Amy E. Moran680Email author,
  • Fanny Polesso680,
  • Lisa Lukaesko681,
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  • Emelie Rådestad682Email author,
  • Lars Egevad682,
  • Jonas Mattsson682,
  • Berit Sundberg682,
  • Lars Henningsohn682,
  • Victor Levitsky683,
  • Michael Uhlin682,
  • William Rafelson684Email author,
  • John L. Reagan685,
  • Loren Fast685,
  • Pottayil Sasikumar686,
  • Naremaddepalli Sudarshan686,
  • Raghuveer Ramachandra686,
  • Nagesh Gowda686,
  • Dodheri Samiulla686,
  • Talapaneni Chandrasekhar686,
  • Sreenivas Adurthi686,
  • Jiju Mani686,
  • Rashmi Nair686,
  • Amit Dhudashia686,
  • Nagaraj Gowda686,
  • Murali Ramachandra686Email author,
  • Alexander Sankin687Email author,
  • Benjamin Gartrell687,
  • Kerwin Cumberbatch687,
  • Hongying Huang687,
  • Joshua Stern687,
  • Mark Schoenberg687,
  • Xingxing Zang687,
  • Ryan Swanson688Email author,
  • Michael Kornacker688,
  • Lawrence Evans688,
  • Erika Rickel688,
  • Martin Wolfson688,
  • Sandrine Valsesia-Wittmann689Email author,
  • Tala Shekarian689,
  • François Simard690,
  • Rodrigo Nailo690,
  • Aurélie Dutour690,
  • Anne-Catherine Jallas689,
  • Christophe Caux691 and
  • Aurélien Marabelle692
Journal for ImmunoTherapy of Cancer20164(Suppl 1):82

https://doi.org/10.1186/s40425-016-0172-7

Published: 16 November 2016

Adoptive Cellular Therapy

O1 IL-15 primes an mTOR-regulated gene-expression program to prolong anti-tumor capacity of human natural killer cells

Andreas Lundqvist1, Vincent van Hoef1, Xiaonan Zhang1, Erik Wennerberg2, Julie Lorent1, Kristina Witt1, Laia Masvidal Sanz1, Shuo Liang1, Shannon Murray3, Ola Larsson1, Rolf Kiessling1, Yumeng Mao1

1Karolinska Institutet, Stockholm, Stockholms Lan, Sweden; 2Weill Cornell Medical College, New York, NY, USA; 3Nova Southeastern University, Cell Therapy Institute, Fort Lauderdale, FL, USA
Correspondence: Andreas Lundqvist (andreas.lundqvist@ki.se)

Background

NK cell-based immunotherapy is a potential therapeutic modality in patients with advanced cancers as transfer of haploidentical NK cells induces beneficial responses in patients with hematological malignancies; and leukemia clearance correlates with persistence and in vivo expansion of NK cells after infusion. Thus, sustained NK cell activity in vivo likely represents a therapy performance-limiting factor.

Methods

We performed genome-wide analysis of cytosolic and polysome-associated mRNA from interleukin (IL)-2 and IL-15 activated NK cells. Furthermore, the ability of IL-2 and IL-15 to sustain human NK cell activity following cytokine withdrawal as well as their effect on NK cells to resist tumor-induced immunosuppression was compared.

Results

After cytokine withdrawal, IL-15-treated NK cells maintained a higher level of cytotoxicity (p < 0.05) and showed lower levels of apoptosis (p < 0.05) compared with cells treated with IL-2. IL-15 augmented mTOR signaling, which correlated with increased expression of genes related to cell metabolism and respiration. Consistently, mTOR inhibition abrogated IL-15-induced cell function advantages. Moreover, mTOR-independent STAT-5 signaling contributed to improved NK cell function during cytokine activation but not following cytokine withdrawal. Upon co-culture with tumor cells or exposure to tumor cell supernatant, IL-15 activated NK cell maintained a significantly higher level of proliferation and cytotoxic activity (p < 0.05). Mechanistically, tumor-derived prostaglandin-E2 suppressed IL-2 cultured NK cells while IL-15 cultured NK cells remained activated. The superior performance of IL-15 stimulated NK cells was also observed using a clinically applicable protocol for NK cell expansion in vitro and in vivo.

Conclusions

This study adds to our understanding about establishment and maintenance of tumor-reactive NK cells and supports clinical implementation of IL-15 for adoptive NK cell therapy. More broadly, our studies suggest that a large aspect of cytokine-mediated gene expression programs and downstream cellular functions, including anti-tumor capacity, are overlooked if post-activation conditions are omitted. This is likely not limited to NK cells and should hence be considered in similar studies of other immune cells.

Biomarkers and Immune Monitoring

O2 ImmunoMap: a novel bioinformatics tool for analysis of T cell receptor repertoire data in model systems and clinical settings

John-William Sidhom1, Catherine A Bessell2, Jonathan Havel3, Jonathan Schneck4, Timothy A Chan3, Eliot Sachsenmeier5

1Johns Hopkins University School of Medicine, Baltimore, MD, USA; 2Immunology Program, Johns Hopkins University, School of Medicine, Columbia, MD, USA; 3Memorial Sloan Kettering Cancer Center, New York, NY, USA; 4Johns Hopkins Medical Institute, Baltimore, MD, USA; 5University of Rochester, Monrovia, MD, USA
Correspondence: John-William Sidhom (jsidhom1@jhmi.edu)

Background

There has been a dramatic increase in T cell receptor (TCR) sequencing spurred, in part, by the widespread adoption of this technology across academic medical centers and by the rapid commercialization of TCR sequencing. While the raw TCR sequencing data has increased, there has been little in the way of approaches to parse the data in a biologically meaningful fashion. The ability to parse this new type of ‘big data’ quickly and efficiently to understand the T cell repertoire in a structurally relevant manner has the potential to open the way to new discoveries about how the immune system is able to respond to insults such as cancer and infectious diseases.

Methods

Here we describe a novel method utilizing phylogenetic and sequencing analysis to visualize and quantify TCR repertoire diversity. To demonstrate the utility of the approach, we have applied it to understanding the shaping of the CD8 T Cell response to self (Kb-TRP2) and foreign (Kb-SIY) antigens in naïve and tumor bearing B6 mice. Additionally, this method was applied to tumor infiltrating lymphocytes (TIL’s) from patients undergoing Nivolumab (anti-PD-1) therapy in a clinical trial for metastatic melanoma to understand TCR repertoire characteristics between responders and non-responders.

Results

Analysis of the naïve CD8 response to SIY showed a lower clonality yet more closely structurally related response whereas CD8 responses to TRP2 were highly clonal yet less structurally related. Presence of tumor exhibited interesting differential effects on SIY vs. TRP2. We believe that differences in TCR repertoire suggest effects from central and peripheral tolerance on self vs. foreign antigens. In clinical trial data, the phylogenetic analysis revealed unique TCR repertoire signatures that differentiated responders from non-responders to anti-PD-1 therapy, including some that could be detected prior to initiation of therapy. Additionally, this analysis revealed that patients whose CD8 response had a larger contribution from novel and unique structural clones responded better to therapy.

Conclusions

In summary, we have developed and demonstrated a novel method to meaningfully parse and interpret TCR repertoire data and have applied it to yield a novel understanding of CD8 T Cell responses to different types of antigens as well as key characteristics in those who respond to anti-PD-1 therapy.
Fig. 1

(Abstract O2). a Weighted Phylogenetic Trees Comparing Kb-SIY vs Kb-TRP2 TCR Repertoire. Size of circles proportional to frequency of sequence. Color of circle corresponds to V-Beta Usage. b Dominant Motifs gathered from phylogenetic trees determined by homologous sequences and their contribution to the response c V-Beta Usage of Kb-SIY vs Kb-TRP2 Response

Fig. 2

(Abstract O2). a Weighted Phylogenetic Trees comparing Naive to Tumor-Bearing TCR Repertoire from spleen. Size of Circles proportional to frequency of sequence. Blue Circles = Naive Repertoire. Red Circles = Tumor-Bearing Repertoire. b V-Segment Usage of Kb-SIY vs Kb-TRP2 Responses for Naive vs Tumor-Bearing Response

Fig. 3

(Abstract O2). Examples of weighted phylogenetic trees from four cohorts of responders on anti-PD-1 therapy. Size of circles proportional to frequency of sequence. Blue = TCR repertoire prior to therapy. Red = TCR repertoire on therapy

O3 Increased STAT3 signaling and decreased suppressive function of regulatory T cells are biomarkers of positive patient outcome to nivolumab therapy

David Woods1, Anders Berglund2, Rupal Ramakrishnan2, Andressa Sodre1, Jeffrey Weber1

1NYU Langone Medical Center, New York, NY, USA; 2H. Lee Moffitt Cancer Center, Tampa, FL, USA
Correspondence: David Woods (david.woods@nyumc.org)

Background

Antibody-mediated blockade of the inhibitory receptor PD-1 on T cells has shown clinical efficacy in the treatment of various malignancies. However, biomarkers of response and mechanisms of resistance remain largely unidentified. To address this gap, we sought to identify the role(s) of regulatory T cells (Tregs) in metastatic melanoma patients treated with the PD-1 antibody nivolumab.

Methods

Pre and post-treatment Tregs were isolated from the peripheral blood of surgically resected stage III/IV metastatic melanoma patients treated with adjuvant nivolumab. Suppressive capacity was assessed in an allogeneic mixed lymphocyte reaction. Paired (pre vs. post-treatment) Tregs were assessed by flow cytometry for phosphorylated STAT3 (pSTAT3) expression. Finally, paired Treg samples were assessed for gene expression by RNA-sequencing.

Results

Tregs from non-relapsing patients demonstrated a significant decrease in suppressive capacity post-treatment (p < 0.05). However, suppressive capacity in relapsing patients did not decrease and their Tregs were significantly more suppressive post-treatment relative to non-relapsers (p < 0.01). Significantly increased levels of pSTAT3 post treatment were observed in non-relapsers (p < 0.05) but not in relapsers (p < 0.40). Significantly increased pSTAT3 was not seen in conventional T cells after nivolumab therapy. Culturing treatment-naïve T cells with PD-1 blocking antibodies in vitro resulted in increased levels of pSTAT3 in Tregs compared to IgG controls (p < 0.01). In vitro PD-1 blockade also significantly increased the number of Tregs (p < 0.01), and significant increases were seen in paired patient samples (p < 0.05). Paired analysis of Treg RNA-seq data using Panther and GeneGo. Metacore showed several significantly increased pathways associated with proliferation in non-relapsers. Changes in these pathways were absent in relapsers. Gene Set Enrichment Analysis of non-relapser Tregs showed significant (q=8.2e-18) overlap with known STAT3 target genes. Conversely, Enrichr analysis of relapsers showed significant upregulation of STAT1 and STAT2 target genes. No overlap of significantly changed gene expression or pathways in Tregs vs. conventional CD4+ T cells were observed.

Conclusions

These results highlight the potential importance of Tregs in mediating benefit with PD-1 blockade, demonstrating pSTAT3 induction and reduced suppressive capacity as biomarkers of clinical benefit. PD-1 blockade also increased the percentages of Tregs, consistent with the known roles of STAT3 in promoting cell survival and proliferation. RNA-seq data demonstrated increased STAT3 and proliferation associated gene expression. Intriguingly, Tregs from relapsing patients had increased expression of genes associated with STAT1/2 signaling, warranting further investigation of these pathways. In addition to highlighting STAT signaling as a biomarker of relapse, these results demonstrate distinct differences in the impact of PD-1 blockade in Treg vs. conventional T cells.

O4 Analysis of pharmacodynamic biomarkers in the first in-human trial of GITR co-stimulation with the agonist antibody TRX-518 in advanced solid cancer patients

Roberta Zappasodi1, Yanyun Li1, Jingjing Qi2, Philip Wong2, Cynthia Sirard3, Michael Postow4, Walter Newman3, Henry Koon5, Vamsidhar Velcheti6, Margaret K Callahan7, Jedd D Wolchok4, Taha Merghoub1

1Ludwig Collaborative Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY, USA; 2Immune Monitoring Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA; 3Leap Therapeutics, Cambridge, MA, USA; 4Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; 5Case Western Reserve University, Cleveland, OH, USA; 6Cleveland Clinic Main Campus, Cleveland, OH, USA; 7Memorial Sloan Kettering Cancer Center, New York, NY, USA
Correspondence: Roberta Zappasodi (zappasor@mskcc.org)

Background

GITR is a tumor necrosis factor receptor expressed at high levels on regulatory T cells (Tregs) and up-regulated on T cells upon activation. GITR stimulation abrogates Treg suppression and enhances T cell effector function. These observations suggest that GITR could be an attractive target for immunotherapy with agonist antibodies. GITR stimulation in tumor-bearing mice has shown therapeutic activity associated with both Treg reduction and modulation. Here we report results of pharmacodynamic analyses in the first in-human phase I trial with the fully humanized agonist anti-GITR antibody TRX518 as monotherapy in patients with advanced refractory solid tumors.

Methods

Patients were accrued to 9 cohorts (up to 6 patients/cohort) to receive a single dose of TRX518 (dose range: 0.0001-8 mg/kg). Pharmacodynamic analyses included flow cytometric evaluation of frequency and phenotype of circulating T cells and cytokine quantification in serum samples at different time points up to 12 weeks after treatment. Relevant changes observed with these analyses were monitored in pre- and post-treatment tumor biopsies by immunofluorescence staining.

Results

Here we report results obtained in 37 patients treated with ≥0.005 mg/kg TRX518 (cohorts 3-9), including 6 melanoma, 7 non-small cell lung cancer (NSCLC) and 7 colorectal cancer (CRC) patients and 17 patients with 11 other solid tumors. Among the T cell parameters analyzed, we found frequent reduction in circulating Tregs after treatment with TRX518 across all cohorts, with some exceptions. Importantly, this effect could be maintained over the 12-week observation period. When the analysis was performed by disease type, it revealed a pronounced TRX518 dose-dependent down-regulation of peripheral Tregs in both melanoma and CRC patients. Interestingly, in NSCLC cancer patients, Tregs did not always decrease after treatment. In a subset of patients (n=6; 2 melanoma, 2 CRC, 2 lung), for whom we had pre- and post-treatment tumor biopsies in addition to PBMCs, we tested whether intra-tumor Tregs were consistently affected. In melanoma and CRC patients, intra-tumor Foxp3+ Tregs were significantly reduced after treatment, in agreement with the peripheral Treg down-modulation observed in the same patients. In lung cancer patients, lack of circulating Treg reduction was consistently associated with stable or increased intra-tumor Treg infiltration after TRX518.

Conclusions

Circulating Treg reduction is a potential pharmacodynamic biomarker of TRX518 biological activity. This parameter may allow predictive correlation with changes in intratumoral Treg infiltration. We plan to further investigate this effect and its relevance for the association with clinical responses in our recently opened TRX518 multi-dose study.

Trial Registration

ClinicalTrials.gov identifier NCT01239134.

Consent

Written informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.

Bispecific Antibodies

O5 Clinical responses in advanced pancreatic patients treated with bispecific antibody armed T cells (BATS)

Lawrence G. Lum1, Minsig Choi2, Archana Thakur1, Abhinav Deol3, Gregory Dyson3, Anthony Shields3

1University of Virginia Cancer Center, Charlottesville, VA, USA; 2Stony Brook University Medical Center, Stony Brook, NY, USA; 3Karmanos Cancer Institute, Detroit, MI, USA
Correspondence: Lawrence G. Lum (lgl4f@virginia.edu)

Background

Conventional chemotherapy (chemo) for locally advanced pancreatic cancer (LAPC) and metastatic pancreatic cancer (PC) is associated with dismal responses and poor survival rates. Arming activated T cells (ATC) with anti-CD3 x anti-EGFR bispecific antibody (EGFRBi) turns every ATC into a non-MHC restricted EGFR-specific cytotoxic T lymphocyte [1]. Engagement of CD3 on T cells and EGFR on Mia PACA-2 leads to cytokine secretion, proliferation, cytotoxicity by ATC and inhibition of tumor growth [2]. An earlier study using Infusions of anti-CD3 x anti-HER2 (HER2Bi) armed ATC in metastatic breast cancer provided encouraging survival (OS = 36 months) and evidence of anti-breast cancer immunity [3].

Methods

In this study, we used anti-CD3 x anti-EGFR bispecific antibody (EGFRBi)-armed T cells (EGFR BATs) to target EGFR in 5 metastatic PC patients and 6 colorectal cancer patients treated at Karmanos Cancer Institute on Protocol #2014-025 in a phase I dose escalation involving 3 weekly infusions of 10, 20, and 40 x 109 BATs/infusion followed by a booster infusion 3 months later.

Results

In the 5 PC patients, we report 1 patient was stable for 6.5 months and 2 patients in whom infusions of EGFR BATs may have “sensitized” the tumor to subsequent chemotherapy. The patient with stable disease had a near partial response. The median overall survival in 5 patients is 23.5 months with the median time to progression (TTP) of 7.0 months. Patient IT20102 received BATs and was stable (decreased marker lesion by 27%) at 6.5 mos. IT20091 had a remarkable clinical response to chemotherapy after progressing after immunotherapy at 4.6 months. After 3 BATs infusions, patient IT2010 had a “flare” or progression and subsequently had a complete response to Xeloda and remains in remission. This phase I study shows: 1) long-term stabilization in one patient; 2) a persistent complete responder after BATs "progression" followed by chemotherapy; 3) improved chemotherapy responsiveness after EGFRBi-BATs therapy; and 4) two patients with slow progressive disease who survived beyond 400 days. Survival for the 5 patients was 13.6, 14.5, 23.3 (alive in CR), 24.9 (alive, stable), and 31.0 months after enrollment, respectively (as of 7-20-16).

Conclusions

Targeting PC with EGFR BATs resulted in improved survival and remarkable post-immunotherapy chemotherapy responses in a small series of patients. The series provides evidence for anti-tumor activity of EGFR BATs as well as evidence that BATs infusions can sensitize tumors to subsequent chemotherapy.

Acknowledgements

Funding for this study was provided by Helen Kay Trust and Philanthropy and Startup Funds at KCI. We acknowledge the efforts of clinical coordinating staff, the clinical trials office staff, GMP laboratory staff, and clinical nursing support staff to making this study possible. The study was conducted at KCI.

References

1. Reusch U, Sundarum M, Davol PA, Olson SD, Davis JB, Demel K, et al: Anti-CD3 x anti-EGFR Bispecific Antibody Redirects T Cell Cytolytic Activity to EGFR-Positive Cancers In Vitro and in an Animal Model. CCR 2006, 12:183-190.

2. Grabert RC, Cousens LP, Smith JA, Olson S, Gall J, Young WB, et al: Human T Cells Armed with Her2/neu Bispecific Antibodies Divide, Are Cytotoxic, and Secrete Cytokines with Repeated Stimulation. CCR 2006, 12:569-576.

3. Lum LG, Thakur A, Al-Kadhimi Z, Colvin G, Cummings F, Legare R, et al: Targeted T cell Therapy in Stage IV Breast Cancer: A Phase I Clinical Trial. CCR 2015, 21:2305-2314.
Table 1

(Abstract O5). Clinical data

Pt

Age

Disease

Prior Tx

BATS (x 109)

TTP (mo)

OS (mo)

Comments

IT20087

58

Mets to liver

Folfirinox

47

6 mo

Died 13.6 mo

Progressed after Immunotherapy

IT20091

63

T3 N1Mets to liver. S/P Whipple

5FU, Leu/5FU Folfirinox

9 79

4.8 mo

Died 31 mo

Folfirinox induced CR after IT and responded a 2nd time to Folfirinox

IT20092

64

T2b Abd Nodes, S/P Whipple

Gemzar, 5FU, radiation

36

7 mo

Died 14.5 mo

Slowly progress with chronic diarrhea

IT20102

56

T4, Mets to liver, lungs

Folfirinox

74

6.5 mo

Alive 24.9 mo

Progressed after 6.5 mo

IT20104

51

T4, Abd Node

FOLFOX, X eloda

72

2.2 mo

Alive 23.3 mo

Chemo Induced CR after IT; On Xeloda

Combinations: Immunotherapy/Immunotherapy

O6 Reactivating the anti-tumor immune response by targeting innate and adaptive immunity in a phase I/II study of intratumoral IMO-2125 in combination with systemic ipilimumab in patients with anti-PD-1 refractory metastatic melanoma

Cara Haymaker1, Marc Uemura1, Ravi Murthy1, Marihella James1, Daqing Wang2, Julie Brevard2, Catherine Monaghan2, Suzanne Swann2, James Geib2, Mark Cornfeld2, Srinivas Chunduru2, Sudhir Agrawal2, Cassian Yee1, Jennifer Wargo1, Sapna P Patel1, Rodabe Amaria1, Hussein Tawbi1, Isabella Glitza1, Scott Woodman1, Wen-Jen Hwu1, Michael A Davies1, Patrick Hwu1, Willem W Overwijk1, Chantale Bernatchez1, Adi Diab1

1University of Texas MD Anderson Cancer Center, Houston, TX, USA; 2Idera Pharmaceuticals, Inc., Cambridge, MA, USA
Correspondence: Cara Haymaker (chaymaker@mdanderson.org)

Background

While checkpoint inhibitor (CPI) therapy has transformed metastatic melanoma (MM) treatment, many patients remain refractory. We reasoned that combining CPI with an agent that activates antigen presenting cells and improves T cell priming may result in improved response. Our approach is to modulate the tumor microenvironment through intratumoral (i.t.) injection of the TLR9 agonist, IMO-2125, in combination with ipilimumab (ipi). We hypothesize that this will result in dendritic cell (DC) activation and induction of tumor-specific CD8+T cells which will synergize with ipilimumab to overcome immune-escape. Based on this rationale we initiated a phase I/II clinical trial.

Methods

Adults with refractory MM despite up to 2 lines of CPI including PD-1 blockade therapy (with or without a BRAF inhibitor) are eligible. IMO-2125, in doses escalating from 4mg to 32mg, is given i.t. weeks 1, 2, 3, 5, 8, and 11 along with ipilimumab i.v. 3 mg/kg weeks 2, 5, 8, and 11. Dose-limiting toxicity (DLT) is evaluated using a modified Toxicity Probability Interval design. Primary endpoints are safety, tumor response, and PK. Blood and injected and distal tumor biopsies are obtained pre- and on-treatment. Immune analyses include DC subsets and their activation status as well as T cell activation, function and proliferation. T cell repertoire diversity will be evaluated by high throughput CDR3 sequencing.

Results

As of August 2, 2016, 11 pts have been enrolled. DLT has not been observed. Grade 3 hypophysitis (2 subjects) is the only immune-related AE observed to date. No other drug-related grade 3-5 AEs were documented and only 1 subject experienced a grade 2 fever. Five patients are evaluable for response - 2 PR, 2SD, 1PD per investigator assessment. Fresh tumor biopsies show maturation (upregulation of HLA-DR) of the myeloid DC1 subset (CD1c+CD303-) in the IMO-2125 injected tumor lesion 24 hrs post-treatment compared to pre-treatment biopsy. On-treatment biopsy results are consistent with a higher rate of proliferative (Ki67) effector CD4+ and CD8+ T cells in responders. Cytokine analysis shows a 2-3 fold increase in circulating IFNγ levels compared to pretreatment in responders.

Conclusions

Though preliminary, these results demonstrate that the combination of ipi and IMO-2125 is well tolerated with encouraging preliminary activity in a PD-1 refractory population. Dose escalation is ongoing and a phase II expansion will include IMO-2125 in combination with both ipi and anti-PD-1. Updated safety, antitumor activity, and biomarker data will be presented.

Trial Registration

ClinicalTrials.gov identifier NCT02644967.

O7 Clinical safety and efficacy assessment of the CD137 agonist urelumab alone and in combination with nivolumab in patients with hematologic and solid tumor malignancies

Erminia Massarelli1, Neil H Segal2, Vincent Ribrag3, Ignacio Melero4, Tara C Gangadhar5, Walter Urba6, Dirk Schadendorf7, Robert L Ferris8, Roch Houot9, Franck Morschhauser10, Theodore Logan11, Jason J Luke12, William Sharfman13, Fabrice Barlesi14, Patrick A Ott15, Laura Mansi16, Shivaani Kummar17, Gilles Salles18, Cecilia Carpio19, Roland Meier20, Suba Krishnan20, Dan McDonald20, Matthew Maurer20, Xuemin Gu20, Jaclyn Neely20, Satyendra Suryawanshi20, Ronald Levy17, Nikhil Khushalani21

1University of Texas MD Anderson Cancer Center, Houston, TX, USA; 2Memorial Sloan Kettering Cancer Center, New York, NY, USA; 3Institut Gustave Roussy, Villejuif, Ile-de-France, France; 4Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Navarra, Spain; 5University of Pennsylvania, Philadelphia, PA, USA; 6Earle A. Chiles Research Institute, Providence Cancer Center, Portland, OR, USA; 7Universitätsklinikum Essen, Essen, Nordrhein-Westfalen, Germany; 8University of Pittsburgh, Pittsburgh, PA, USA; 9CHU Rennes, Service Hématologie Clinique and INSERM 0203, Unité d'Investigation Clinique, Rennes, Bretagne, France; 10Centre Hospitalier Régional Universitaire de Lille, Lille, Nord-Pas-de-Calais, France; 11Simon Cancer Center, Indiana University, Indianapolis, IN, USA; 12University of Chicago School of Medicine, Chicago, IL, USA; 13Johns Hopkins University School of Medicine, Lutherville, MD, USA; 14Multidisciplinary Oncology and Therapeutic Innovations, Hôpital Nord, Marseille, Provence-Alpes-Cote d'Azur, France; 15Dana-Farber Cancer Institute, Boston, MA, USA; 16Centre Hospitalier Régional Universitaire Hôpital Jean Minjoz, Besançon, Franche-Comte, France; 17Stanford University School of Medicine, Stanford, CA, USA; 18Hospices Civils de Lyon-Université de Lyon, Pierre Benite, Auvergne, France; 19Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Catalonia, Spain; 20Bristol-Myers Squibb, Princeton, NJ, USA; 21H. Lee Moffitt Cancer Center, Tampa, FL, USA
Correspondence: Erminia Massarelli (emassarelli@coh.org)

Background

Urelumab is a fully human CD137 agonistic monoclonal antibody (mAb) that enhances T cell and natural killer (NK) cell antitumor activity in preclinical models. Nivolumab, a fully human programmed death-1 (PD-1) mAb that blocks the inhibitory function of the PD-1 receptor on T cells, has shown single-agent activity in many advanced malignancies. We hypothesized that the distinct, non-redundant mechanisms of these two mAbs could enhance antitumor activity without compromising safety. Here we report safety/tolerability, pharmacodynamics, and preliminary efficacy of urelumab and urelumab plus nivolumab combination therapy in patients with advanced malignancies.

Methods

The monotherapy study evaluated urelumab in patients with advanced malignancies (0.1 or 0.3 mg/kg Q3W) or advanced non-Hodgkin lymphoma (8 mg Q3W or Q6W). The combination study evaluated urelumab (3 or 8 mg Q4W) plus nivolumab (3 mg/kg or 240 mg Q2W) in patients with advanced solid tumors or B cell lymphoma (dose escalation) or patients with diffuse large B cell lymphoma (DLBCL), melanoma, non-small cell lung cancer (NSCLC), or squamous cell carcinoma of the head and neck (SCCHN; cohort expansion). Based on preliminary safety/tolerability/pharmacokinetic assessments of urelumab, cohort expansion focused on flat doses of 8 mg.

Results

Overall, patients who received urelumab monotherapy (N=123) experienced infrequent treatment-related serious AEs (7%) and treatment-related AEs (TRAEs) leading to discontinuation (5%; Table 2). In 104 patients treated with urelumab plus nivolumab (melanoma, n=40; NSCLC, n=20; SCCHN, n=22; DLBCL, n=22), the most frequent TRAE was fatigue (26%); grade 3/4 ALT/AST elevations (3%/3%) and TRAEs leading to discontinuation (7%) were infrequent. No treatment-related deaths were reported. Urelumab stimulated peripheral IFN-γ–induced cytokine production; induction was greater with urelumab plus nivolumab. In most melanoma tumors evaluated, a trend toward increased T and NK cell number and expression of IFN-γ and CXCL9 was observed upon treatment with the combination. Six patients with lymphoma treated with urelumab monotherapy had a partial (n=3) or complete (n=3) remission. Nine of 86 evaluable patients treated with the combination had partial responses (melanoma, n=8; SCCHN, n=1); no patients with NSCLC or DLBCL had confirmed responses at the interim analysis. Of 71 patients treated with urelumab plus nivolumab with RECIST/IWG assessments, 33 had reductions in tumor burden (Fig. 4).
Table 2

(Abstract O7). Treatment-related safety events

Patients, n (%)

Urelumab monotherapy N=23

Urelumab + nivolumab N=104

Treatment-related AEs

65 (53)

65 (53)

Most frequent treatment-related AEsa

  

Fatigue

18 (15)

27 (26)

AST increased

16 (13)

9 (9)

ALT increased

12 (10)

13 (13)

Treatment-related grade ¾ AST elevation

4 (3)

3 (3)

Treatment-related ¾ ALT elevation

3 (2)

3 (3)

Treatment-related serious AEs

9 (7)

10 (10)

Treatment-related AEs leading to discontinuation

6 (5)

7 (7)

Treatment-related deaths

0

0

AE, adverse event; AKT, alanine aminotransferase; AST, aspartate aminotransferase.

aTreatment-related AEs occurring in ≥10% of all patients

Fig. 4

(Abstract O7). Best percent reduction in target lesion tumor burden with urelumab plus nivolumab

Conclusions

Urelumab with or without nivolumab is safe/tolerable at flat and weight-based doses of 8 mg and 0.1 mg/kg. Although urelumab has demonstrated single-agent pharmacodynamic and antitumor activity in lymphoma, combination with nivolumab did not appear to provide significant additive/synergistic clinical benefit at the doses evaluated.

Trial Registration

ClinicalTrials.gov identifier NCT01471210 and NCT02253992.

O8 Beyond immune checkpoint: first-in-class antibody targeting soluble NKG2D ligand sMIC for cancer immunotherapy

Jennifer Wu, Jinyu Zhang, Fahmin Basher, Mark Rubinstein

Medical University of South Carolina, Charleston, SC, USA
Correspondence: Jennifer Wu (wujjd@musc.edu)

Background

In response to oncogenic insult, human cells were induced to express a family of MHC I-chain related molecules A and B (MICA and MICB, generally termed MIC) on the surface which serve as the ligands for the activating immune receptor NKG2D expressed by all human NK, CD8 T, NKT, and subsets of gamma-delta T cells. Theoretically, engagement of NKG2D by tumor cell surface MIC is thought to signal and provoke the immune system to eliminate transformed cells. Clinically, almost all advanced tumors in cancer patients produce soluble MIC through proteolytic shedding mediated by metalloproteases, or by release in exosomes derived from the cell membrane. Tumor-derived sMIC is known to be highly immune suppressive and profoundly insults the immune system by downregulating receptor NKG2D expression on effector NK and T cells, driving the expansion of tumor-favoring myeloid suppressor cells, skewing macrophages into alternatively activated phenotypes, and perturbing NK cell peripheral maintenance. High levels of serum sMIC significantly correlate with advanced diseases of many types of cancer. These observations clearly endorse sMIC to be a cancer immune therapeutic target. However, due to mice lacking homologues to human MIC, this concept was not proven until our recent studies.

Methods

Using a “humanized” MIC-transgenic spontaneous mouse model which recapitulates the NKG2D-mediated onco-immune dynamics of human cancer patients, we addressed whether sMIC is a cancer immunotherapeutic target and whether antibody targeting sMIC synergizes with immune checkpoint blockade or adoptive T or NK cell therapy.

Results

We show that therapy with a first-in-field non-blocking antibody B10 that does not block the interaction of MIC with NKG2D revamps endogenous innate and antigen-specific CD8+ T cell responses and remodels immune reactive tumor microenvironment, by restoring NK cell hemostatic maintenance and function, enhancing CD8+ T cell infiltration to tumors and TCR clonality/diversity, modulating CD8+ T cells metabolic preferences, eliminating MDSCs and TAMS. Anti-sMIC stand-alone therapy resulted in effective debulking of primary tumors and eliminated metastasis. Using multiple pre-clinical animal models, we further demonstrate that antibody B10 neutralizing sMIC synergizes with CTLA-4 and PD-1/PD-L1 checkpoint blockade therapy and adoptive cell based therapy with no observed toxicity.

Conclusions

Our study has launched a new avenue of cancer immunotherapy which can be readily translated into clinical trials.
Fig. 5

(Abstract O8). These are the examples in human cancer patients, prostate cancer, Oral cancer, and HBV-induced Liver cancer, where high levels of circulating sMIC correlates with advanced disease stages and poor survival.

Fig. 6

(Abstract O8). a. Therapy of the clinically relevant spontaneous prostate tumor TRAMP/MICB model (Liu et al, 2013, JCI 123 (10) 4410 ) with CuraB10 (also called B10G5) or control IgG (placebo) at advanced stage via I.P. injection at the dose of 3.8 mg/KG body weight twice weekly for 8 weeks (b). Mice with CuraB-1o therapy all enjoyed longtime survived whereas mice in placebo group are succumbed to cancer (c). Prostate weight. Comparisons made between Placebo group and CuraB-10 group and between before and after treatment of CuraB-10. (d). Representative images of the prostate. Top showing large tumor burden. Bottom showing normal prostate size. (e). All mice in the control group developed metastasis whereas no metastasis was detected in animals received CuraB-10 therapy. In summary, the data demonstrate that CuraB-10 stand-alone therapy can effectively induce regression of primary tumors and eliminate metastasis

Fig. 7

(Abstract O8). We further addressed the synergistic effect of CuraB-10 therapy with FDA approved checkpoint blockade therapy using the clinically relevant TRAMP/MIC spontaneous prostate tumor mouse model. Two points: 1) a percentage of TRAMP/MIC mice do not respond to checkpoint (CTLA4 or PD-1) blockade therapy, whereas all TRAMP/MIC mice are responsive to CuraB-10 therapy; also, a population of TRAMP/MICB animals died at 3-4 weeks of CTLA4 Rx alone. 2) CuraB-10 synergizes with checkpoint blockade (CTLA4 or PD-1) therapy when used in combination

Fig. 8

(Abstract O8). Because rodents do not express MIC, we engineered mouse melanoma B16 tumor cells to express sMIC (B16-sMIC). We implanted B16-sMIC into syngeneic host. When tumors grew to 50-100mm3 in size, treatment starts. Four treatments were given: Adoptive transfer of melanoma antigen-specific Pmel CD8 T cells once, B10G5 (CuraB-10) twice 2 week Adoptive transfer of melanoma antigen-specific Pmel CD8 T cells once, control IgG (cIgG) twice 2 week B10G5 alone 4) cIgG alone Tumor growth curve demonstrating that treatment with B10G5 (CuraB-10) effectuates the effect of Pmel CD8 T therapy Survival curve. Tumor volume of 1000mm3 was defined as survival end point. In one experiment, 2/7 animals received B10G5 and Pmel therapy had complete tumor regression. Note: currently Adoptive T cell transfer (ACT) requires prior-depletion of patient’s immune cells with chemotherapy to be effective. With B10G5 therapy, not only lymph depletion is not required prior to ACT, but also ACT is more effective

Diet, Exercise and/or Stress and Impact on the Immune System

O9 β-adrenergic signaling induced by cool housing temperatures mediates immune suppression and impairs the efficacy of anti-PD-1 checkpoint blockade immunotherapy in laboratory mice

Mark Bucsek, Guanxi Qiao, Cameron MacDonald, Bonnie Hylander, Elizabeth Repasky

Roswell Park Cancer Institute, Buffalo, NY, USA
Correspondence: Mark Bucsek (mark.bucsek@roswellpark.org)

Background

Recent work from our laboratory has shown that anti-tumor immunity is suppressed in mice housed at standard temperatures (ST; 22°C) which could be reversed by housing mice at warmer, thermoneutral temperatures (TT; 30°C) [1]. However, the mechanisms causing this impairment at ST remain unclear. Cold stress is mediated specifically by activation of the sympathetic nervous system and the release of norepinephrine (NE), which is highly suppressive when signaling through β-adrenergic receptors (β-ARs) on immune cells. We found that NE levels are significantly elevated in tumor-bearing mice housed at ST compared to TT, which led us to hypothesize that chronic stress induced by cool housing temperatures increases β-AR signaling that dampens the anti-tumor immune response and the efficacy of immune modulating therapies.

Methods

We used both physiologic (housing temperature; ST and TT) and pharmacologic blockade (β-blockers) to modulate β-AR signaling levels in immune-competent and SCID mice bearing 4T1 or B16-OVA tumors. Flow cytometry was used for immune cell analysis. Anti-PD-1 checkpoint blockade was given in 6, 200μg doses (Days 0, 2, 4, 6, 9, and 12) starting the day after tumors became detectable.

Results

We found that the addition of β-blockade significantly delayed 4T1 and B16-OVA tumor growth in mice housed at ST, recapitulating the slower tumor growth observed in mice housed at TT. However, β-blockade had no impact on tumor growth in SCID mice at ST or TT indicating dependence on the adaptive immune system. Analysis of 4T1 and B16-OVA tumors from immune-competent mice showed increased IFN-γ expression in both CD4+ and CD8+ T cells in mice treated with β-blockade indicating a more robust anti-tumor immune response. Lastly, we investigated the impact of β-AR signaling on anti-PD-1 checkpoint blockade efficacy and found that reducing β-AR signaling by both physiologic (TT) and pharmacologic (β-blockade) strategies improved responses in both tumor models. Further analysis of 4T1 tumors from mice treated with β-blockade and anti-PD-1 showed an increase in IFN-γ, producing CD8+ T cells compared to either β-blockade or anti-PD-1 alone.

Conclusions

Taken together, these data indicate that elevated β-AR stress signaling caused by cool housing temperatures impairs anti-tumor immunity and the response of tumors to anti-PD-1 checkpoint blockade.

Acknowledgements

Supported by: The Peter T. Rowley Breast Cancer Research Grant, The Harry J. Lloyd Charitable Trust, the Roswell Park Alliance Foundation, and 5T32CA085183-12.

Reference

1. Kokolus K, et al: Baseline tumor growth and immune control in laboratory mice are significantly influenced by subthermoneutral housing temperature. PNAS 2013, 110:20176-20181.

Immune Metabolism

O10 NAD-Sirt1 axis is central to the unique immuno-metabolic phenotype of Th1/17 hybrid cells in regulating its enhanced anti-tumor potential

Shilpak Chatterjee1, Anusara Daenthanasanmak1, Paramita Chakraborty1, Kyle Toth1, Megan Meek1, Elizabeth Garrett-Mayer1, Michael Nishimura2, Chrystal Paulos1, Craig Beeson1, Xuezhong Yu1, Shikhar Mehrotra1

1MUSC, Charleston, SC, USA; 2Loyola Cancer Center, Maywood, IL, USA
Correspondence: Shilpak Chatterjee (chatherj@musc.edu)

Background

Th17 cells hold promise for immunotherapy of cancer [1]. While the anti-tumor potential of Th17 cells primarily depends upon IFN-γ secretion and persistence [1], a long-term tumor control has still remained elusive. Given that both the “effector” and “stemness like” features are prerequisites for T cells to mount durable anti-tumor responses, we hypothesized that combining the culture conditions of Th1 (effector) and Th17 (stemness like) cells could generate hybrid Th1/17 cells with improved anti-tumor properties.

Methods

Melanoma epitope tyrosinase reactive CD4+ T cells obtained from h3T TCR transgenic mice were differentiated ex vivo to Th1, Th17, and Th1/17 cells before adoptive transfer (0.25×106 cells/animal i.v.) to C57BL/6 recipient animals with subcutaneously established B16 melanoma. Quantitative PCR (q-PCR), flow cytometry, and metabolomic analyses were used to evaluate the expression of various metabolism and stemness associated genes as well as protein expression in the T cells. To compare the metabolic commitment between different subsets (Th1, Th17 and Th1/17), real time metabolic flux analyzer (Seahorse Biosciences, USA) and radioactive tracer studies were used.

Results

The combined culture conditions of Th1 and Th17 generates hybrid Th1/17 cells with a IFN-γhi, IL17hi, GM-CSFhi, CD107ahi, T-bethi, Granzyme Bhi, IL23Rhi, IL22hi, Bcl6hi, Tcf7hi signature. These hybrid Th1/17 cells exhibit enhanced tumor control in subcutaneous and lung metastasis models of murine melanoma. A hypothesis generating transcriptional, metabolic, and proteomic profiling, followed by confirmatory experiments established that the enhanced anti-tumor properties were attributed to increased NAD+ mediated activity of histone deacetylase Sirt1 in hybrid Th1/17 cells. Inhibition of NAD+ and Sirt1 activity either pharmacologically or by genetic ablation (Sirt1-KO T cells) led to loss of stable anti-tumor control. Importantly, anti-tumor T cells or tumor infiltrating lymphocytes programmed in the presence of exogenous NAD+ also led to the similar metabolic phenotype and improved anti-tumor control.

Conclusions

The present study discloses that metabolic status plays an important role in dictating the anti-tumor response of the T cells. Combining the culture conditions of Th1 and Th17 cells renders hybrid Th1/17 cells with a unique immune-metabolic feature that enables them to orchestrate distinct transcriptional programs leading to highly effector and stem-like T cells.

Reference

1. Muranski P, Boni A, Antony PA, et al: Tumor-specific Th17-polarized cells eradicate large established melanoma. Blood 2008, 112:362-373.

O11 The Wnt5a-beta-catenin pathway triggers a metabolic switch that drives indoleamine 2,3-dioxygenase activity and dendritic cell tolerization in the melanoma microenvironment: optimizing checkpoint inhibitor immunotherapy

Fei Zhao1, Kathy Evans1, Christine Xiao1, Alisha Holtzhausen2, Brent A. Hanks1

1Duke University Medical Center, Durham, NC, USA; 2Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA
Correspondence: Brent A. Hanks (hanks004@mc.duke.edu)

Background

Despite recent advances, many cancers remain refractory to available immunotherapies by developing various strategies to evade the immune system. Emerging evidence indicates that the tolerization of local dendritic cells (DCs) within the tumor microenvironment plays a critical role in immune evasion. The role of metabolic re-programming in DC tolerization remains poorly characterized and the mechanisms by which cancers may utilize these pathways to promote the establishment of an immunotolerant microenvironment have not been described.

Methods

We investigated the role of the Wnt-beta-catenin pathway in the metabolic reprogramming of melanoma-derived DCs using real-time metabolic flux analysis. The impact of DC metabolic re-programming on the enzymatic activity of indoleamine 2,3-dioxygenase (IDO) was analyzed by HPLC while protoporphyrin IX(PpIX) levels were quantified by flow cytometry. The role of DC fatty acid oxidation (FAO) on regulatory T cell (Treg) generation was investigated using pharmacologic and genetic approaches. The impact of FAO inhibition on anti-tumor immune responses to anti-PD-1 antibody therapy were investigated in a transgenic melanoma model.

Results

We show that the Wnt5a-beta-catenin-PPARg pathway shifts DCs from glycolysis to FAO in the melanoma microenvironment in a manner dependent upon induction of the mitochondrial fatty acid transporter, CPT1A (Fig. 9). This metabolic shift promotes DC tolerization by 1) elevating DC levels of the PpIX prosthetic group of IDO, resulting in the enhanced activity of this enzyme (Fig. 10) and 2) potently suppressing DC-expression of IL-6 and IL-12, both culminating in the generation of Tregs both in vitro and in vivo (Fig. 11). Genetic silencing and the pharmacologic inhibition of CPT1A potently enhances the ability of DCs to stimulate effector T cell responses. Indeed, genetic silencing of melanoma-expressed Wnt5a significantly promotes T cell tumor infiltration and augments PD-L1 expression in this melanoma model. Consistent with these findings, we further show FAO inhibition to enhance the efficacy of anti-PD-1 therapy while augmenting melanoma antigen-specific T cell responses (Fig. 12).
Fig. 9

(Abstract O11). Wnt5a Promotes DC FAO in the Melanoma Microenvironment. A. Schematic of tumor-infiltrating DC (TIDC) metabolic analysis. B. Melanoma-derived Wnt5a promotes TIDC OXPHOS. C. Wnt5a promotes DC FAO

Fig. 10

(Abstract O11). Wnt5a-induced FAO Promotes DC Synthesis of PpIX and Enhances IDO Enzyme Activity. A. Wnt5a stimulates DC PpIX synthesis. B,C. Wnt5a promotes DC IDO activity in a FAO-dependent manner both in vitro and in vivo

Fig. 11

(Abstract O11). Wnt5a-induced DC OXPHOS Promotes Treg Generation in the Melanoma Microenvironment. Melanoma-derived Wnt5a conditions DCs to promote Treg generation in vivo

Fig. 12

(Abstract O11). Inhibition Wnt5a-DC FAO Enhances Melanoma PD-L1 Expression and Augments anti-PD-1 antibody Efficacy. A. Schematic of Wnt5a paracrine signaling pathway. B,C. Genetic silencing of Wnt5a in melanoma promotes T cell infiltration and PD-L1 upregulation. D. Inhibition of CPT1A/FAO synergizes with anti-PD-1 antibody therapy in melanoma

Conclusions

Our findings implicate the Wnt5a-beta-catenin-PPARg-CPT1A paracrine signaling axis as a driver of DC FAO and functional DC tolerization in the melanoma microenvironment and connect this pathway with the promotion of a “non-inflamed” phenotype in melanoma. This work describes a novel association between DC metabolism and the regulation of IDO enzymatic activity and suggests that this pathway may be a potent pharmacological target for increasing the responsiveness of “non-inflamed” tumors to anti-PD-1 antibody immunotherapy.

O12 Mitochondrial biogenesis is repressed in tumor-infiltrating CD8+ T cells resulting in metabolic insufficiency and T cell dysfunction

Nicole Scharping1, Ashley V Menk2, Rebecca Moreci2, Ryan Whetstone1, Rebekah Dadey1, Simon Watkins1, Robert Ferris1, Greg M Delgoffe1

1University of Pittsburgh, Pittsburgh, PA, USA; 2University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
Correspondence: Nicole Scharping (nes63@pitt.edu)

Background

CD8+ tumor-infiltrating T lymphocytes (CD8+ TIL) in the tumor microenvironment (TME) are unable to effectively control their tumor targets due to a variety of immunosuppressive mechanisms, including direct tumor cell-T cell inhibition and soluble immunosuppressive factors. This allows cancer to progress unchecked as T cells are rendered functionally inert. Recently, poor metabolite availability in the TME has been identified as an additional suppressive mechanism exploited by bioenergetically-dysregulated tumors. Because T cell activation also has robust metabolic demands, we hypothesized that CD8+ TIL dysfunction was a result of metabolic insufficiency.

Methods

Metabolic capacity was measured at the single cell level by 2NBDG and MitoTracker FM. Metabolic output was measured by Seahorse extracellular flux analysis. T cell reprogramming was performed by retroviral transduction on OVA-specific transgenic T cells in vitro before adoptive transfer into B16OVA bearing mice.

Results

We found CD8+ TIL are characterized by dramatic loss of mitochondrial mass in B16, MC38, and LLC implantable mouse tumors and human CD8+ TIL, which correlates with upregulation of co-inhibitory checkpoint molecules PD-1 and Tim-3. CD8+ TIL mitochondrial mass loss is caused by decreased mitochondrial biogenesis, due in part to repression of the transcriptional co-activator PGC1α resulting from chronic Akt signaling. Surprisingly, anti-PD-1 therapy had no effect on increasing PGC1α or mitochondrial mass in CD8+ TIL. We then asked whether improving CD8+ TIL metabolism genetically might result in enhanced effector function, so we reprogrammed tumor-specific CD8+ T cells to upregulate mitochondrial biogenesis prior to adoptive cell therapy. We found increased mitochondrial mass, restored cytotoxic functionality, and dramatically improved tumor regression in mice with reprogrammed CD8+ TIL. To better understand why mitochondrial loss causes T cell dysfunction, we are exploring the importance of mitochondria for T cell functionality, including ATP and nucleotide production, calcium buffering, and ROS production.

Conclusions

Our data support a model in which chronically-activated CD8+ TIL are unable to metabolically support their effector functions. By understanding these metabolic insufficiencies, we can both better understand T cell dysfunction and design metabolic modulation strategies to improve cancer immunotherapy.

Inflammation, Innate Immunity, and the Microbiome

O13 Intestinal microbiota and relapse after hematopoietic-cell transplantation

Jonathan Peled, Sean Devlin, Anna Staffas, Melissa Lumish, Kori Porosnicu Rodriguez, Katya Ahr, Miguel Perales, Sergio Giralt, Ying Taur, Eric Pamer, Marcel R. M. van den Brink, Robert Jenq

Memorial Sloan Kettering Cancer Center, New York, NY, USA
Correspondence: Jonathan Peled (peledj@mskcc.org)

Background

The major causes of mortality after allogeneic hematopoietic-cell transplantation (allo-HCT) are relapse, graft-versus-host disease (GVHD), and infection. We have previously reported that alterations in the intestinal flora are associated with GVHD, bacteremia, and reduced overall survival after allo-HCT. As intestinal bacteria are potent modulators of systemic immune responses including antitumor effects triggered by checkpoint blockade, we hypothesized that components of the intestinal flora could be associated with relapse after allo-HCT.

Methods

The intestinal microbiota of 541 patients admitted for allo-HCT was profiled by means of 16S ribosomal sequencing of prospectively collected stool samples. We hypothesized that evolutionarily related species exhibit functional similarities, and we therefore defined clusters of related operational taxonomic units (crOTUs) to evaluate for associations with clinical outcomes. To group OTUs by evolutionary distances, a phylogenetic tree was empirically constructed from a sequence alignment of all OTUs identified in the whole cohort (Fig. 13). We examined the relationship between abundance of microbiota species or groups of related species and relapse/progression of disease during two years of follow-up after allo-HCT using cause-specific Cox proportional hazards in a retrospective discovery-validation study (Fig. 14).
Fig. 13

(Abstract O13). Phylogenetic tree of OTUs and clusters of related operational taxonomic units (crOTUs). Each black point is a crOTU. Phylum is color coded along the circumference. Members of the same phyla were largely grouped together, indicating that the tree was broadly concordant with standard taxonomy

Fig. 14

(Abstract O13). Multivariate screening of microbial features for association with relapse. Volcano plot of multivariate p values of crOTUs against the multivariate hazard ratios for relapse/progression of disease in the discovery set. crOTUs are color coded by p value. Multivariate adjustment was performed for Disease Risk Index score, graft source, and conditioning intensity. The most abundant species in each of the labeled crOTUs are 1614: Eubacterium limosum. 2022-3: Streptococcus sinensis. 1638: Eubacterium limosum. 1630-1: Eubacterium limosum. 1790: Parvimonas micra. 0951-3: Leptotrichia hongkongensis 2986: Flavonifractor plautii. 1439: Actinomyces odontolyticus

Results

The intestinal presence of a group comprised mostly of Eubacterium limosum in the validation set was associated with less relapse/progression of disease (HR 0.52, CI 0.31–0.87, p = 0.01, Fig. 15). The two-year cumulative incidence of relapse/progression among patients with and without this group of bacteria was 33.8% and 19.8%, respectively. The relative abundance of this group was also associated with less relapse/progression of disease (HR 0.82, CI 0.71–0.95, p = 0.009). These associations remained significant in multivariate models and were strongest among recipients of T cell-replete allografts.
Fig. 15

(Abstract O13). crOTU 1614, which includes members of family Eubacteriaceae is associated with decreased relapse after allo-HCT.Cumulative incidence of relapse/POD in the discovery (n = 271) and validation (n = 270) sets stratified by presence or absence of crOTU 1614

Conclusions

We found associations between the abundance of a group of bacteria in the intestinal flora and relapse/progression of disease after allo-HCT. These might serve as potential biomarkers or therapeutic targets to prevent relapse and improve survival after allo-HCT.

Oncolytic Viruses

O14 Phase I/II CANON study: oncolytic immunotherapy for the treatment of non-muscle invasive bladder (NMIBC) cancer using intravesical Coxsackievirus A21

Nicola Annels1, Hardev Pandha1, Guy Simpson1, Hugh Mostafid2, Kevin Harrington3, Alan Melcher4, Mark Grose5, Bronwyn Davies5, Gough Au5, Roberta Karpathy5, Darren Shafren5

1University of Surrey, Guildford, England, UK; 2Royal Surrey County Hospital, Guildford, England, UK; 3Institute for Cancer Research, London, England, UK; 4The Institute for Cancer Research, London, England, UK; 5Viralytics, Inc., Sydney, New South Wales, Australia
Correspondence: Nicola Annels (n.annels@surrey.ac.uk)

Background

As a clinical setting in which local live biological therapy is already well established, non-muscle invasive bladder cancer (NMIBC) presents intriguing opportunities for oncolytic virotherapy. Coxsackievirus A21 (CVA21, CAVATAKTM) is a novel intercellular adhesion molecule-1 (ICAM-1)-targeted immunotherapeutic virus which exerts potent oncolytic activity against NMIBC cell lines and ex-vivo human bladder tumour. CVA21 in combination with low doses of Mitomycin C enhances CVA21 viral replication and oncolysis by increasing surface expression levels of ICAM-1.

Methods

A two stage Phase I/II study (CANON) was initiated to study the tolerance of escalating intravesicular (IV) doses of CVA21 administered alone or in combination with MitomycinC (10mg) in 16 first-line NMIBC cancer patients prior to TURBT surgery. Cystoscopy photography was performed before and after treatment. Tissues were analysed for CVA21 replication, apoptosis, changes in immune cell infiltrates (multi-spectral imaging) and immune-checkpoint molecules.

Results

IV administration of CAVATAK was well tolerated with no adverse events. Anti-cancer activity including viral induced tumour inflammation was demonstrated by serial cystoscopy including a complete response observed in one of 3 patients in the highest dose monotherapy cohort. Tumour targeting by CVA21 was shown by detection of secondary viral load peaks in the urine and by immunohistochemical analysis of TURBT tissue displaying tumour-specific viral replication and apoptotic cell death. Nanostring analysis revealed an upregulation of interferon-response and immune checkpoint inhibitory genes in CVA21-treated tissues compared to untreated historical controls. Notable changes in immune cell infiltrates and expression of PD-L1 within the CVA21-treated NMIBC tissue were also observed. Increased urinary levels of the chemokine, HMGB1, was observed in six of eleven patients following exposure to CVA21.

Conclusions

The utility of CVA21 as a potent immunotherapeutic agent has been demonstrated by the observed tumour targeting and viral replication. Upregulation of checkpoint molecules following CVA21 exposure may also allow potential sequential combination therapies with checkpoint targeting.

Trial Registration

ClinicalTrials.gov identifier NCT02316171.

O15 Pre-existing immunity to oncolytic virus potentiates its therapeutic efficacy.

Jacob Ricca1, Taha Merghoub2, Jedd D Wolchok3, Dmitriy Zamarin1

1Memorial Sloan Kettering Cancer Center, New York, NY, USA; 2Ludwig Collaborative Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY, USA; 3Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
Correspondence: Jacob Ricca (riccaj92@gmail.com)

Background

Despite the significant promise of oncolytic viral (OV) therapy in preclinical models, clinical efficacy of systemically-administered viruses has proven to be modest. One major limitation of the systemic OV therapy is neutralization of the virus by pre-existing immunity, or development of neutralizing antibodies shortly after therapy initiation, which limit viral delivery to tumor sites. Recently, we and others have demonstrated that intratumoral therapy with OV can lead to systemic anti-tumor immunity and abscopal effects, and several clinical trials are currently exploring intratumorally administered OVs in patients. The effect of pre-existing anti-viral immunity or the development of new anti-viral immunity on the anti-tumor efficacy, however, is not well defined.

Methods

Using oncolytic Newcastle Disease Virus (NDV) as a model, we explored the effect of pre-existing immunity to the virus on its therapeutic efficacy using syngen