Vivek Subbiah, Muhammad Rizwan Khawaja, David S. Hong, Behrang Amini, Jiang Yungfang, Hui Liu, Adrienne Johnson, Alexa B. Schrock, Siraj M. Ali, James X. Sun, David Fabrizio, Sarina Piha-Paul, Siqing Fu, Apostolia M. Tsimberidou, Aung Naing, Filip Janku, Daniel D. Karp, Michael Overman, Cathy Eng, Scott Kopetz, Funda Meric-Bernstam, Gerald S. Falchook
Background. Reports on long-term (≥10 years) effects of cancer vaccines are missing. Therefore, in 2002, we initiated a phase I/II trial in cutaneous melanoma patients to further explore the immunogenicity of our DC vaccine and to establish its long-term toxicity and clinical benefit after a planned 10-year followup.
Methods. Monocyte-derived DCs matured by TNFα, IL-1β, IL-6, and PGE2 and then loaded with 4 HLA class I and 6 class II–restricted tumor peptides were injected intradermally in high doses over 2 years. We performed serial immunomonitoring in all 53 evaluable patients.
Results. Vaccine-specific immune responses including high-affinity, IFNγ-producing CD4+ and lytic polyfunctional CD8+ T cells were de novo induced or boosted in most patients. Exposure of mature DCs to trimeric soluble CD40 ligand, unexpectedly, did not further enhance such immune responses, while keyhole limpet hemocyanin (KLH) pulsing to provide unspecific CD4+ help promoted CD8+ T cell responses — notably, their longevity. An unexpected 19% of nonresectable metastatic melanoma patients are still alive after 11 years, a survival rate similar to that observed in ipilimumab-treated patients and achieved without any major (>grade 2) toxicity. Survival correlated significantly with the development of intense vaccine injection site reactions, and with blood eosinophilia after the first series of vaccinations, suggesting that prolonged survival was a consequence of DC vaccination.
Conclusions. Long-term survival in advanced melanoma patients undergoing DC vaccination is similar to ipilimumab-treated patients and occurs upon induction of tumor-specific T cells, blood eosinophilia, and strong vaccine injection site reactions occurring after the initial vaccinations.
TRIAL REGISTRATION. ClinicalTrials.gov NCT00053391.
FUNDING. European Community, Sixth Framework Programme (Cancerimmunotherapy LSHC-CT-2006-518234; DC-THERA LSHB-CT-2004-512074), and German Research Foundation (CRC 643, C1, Z2).
Stefanie Gross, Michael Erdmann, Ina Haendle, Steve Voland, Thomas Berger, Erwin Schultz, Erwin Strasser, Peter Dankerl, Rolf Janka, Stefan Schliep, Lucie Heinzerling, Karl Sotlar, Pierre Coulie, Gerold Schuler, Beatrice Schuler-Thurner
Wiebke Arlt, Katharina Lang, Alice J. Sitch, Anna S. Dietz, Yara Rhayem, Irina Bancos, Annette Feuchtinger, Vasileios Chortis, Lorna C. Gilligan, Philippe Ludwig, Anna Riester, Evelyn Asbach, Beverly A. Hughes, Donna M. O’Neil, Martin Bidlingmaier, Jeremy W. Tomlinson, Zaki K. Hassan-Smith, D. Aled Rees, Christian Adolf, Stefanie Hahner, Marcus Quinkler, Tanja Dekkers, Jaap Deinum, Michael Biehl, Brian G. Keevil, Cedric H.L. Shackleton, Jonathan J. Deeks, Axel K. Walch, Felix Beuschlein, Martin Reincke
Shadab A. Rahman, Melissa A. St. Hilaire, Anne-Marie Chang, Nayantara Santhi, Jeanne F. Duffy, Richard E. Kronauer, Charles A. Czeisler, Steven W. Lockley, Elizabeth B. Klerman
Martin Niethammer, Chris C. Tang, Peter A. LeWitt, Ali R. Rezai, Maureen A. Leehey, Steven G. Ojemann, Alice W. Flaherty, Emad N. Eskandar, Sandra K. Kostyk, Atom Sarkar, Mustafa S. Siddiqui, Stephen B. Tatter, Jason M. Schwalb, Kathleen L. Poston, Jaimie M. Henderson, Roger M. Kurlan, Irene H. Richard, Christine V. Sapan, David Eidelberg, Matthew J. During, Michael G. Kaplitt, Andrew Feigin
Melanie A. Gasper, Anneke C. Hesseling, Isaac Mohar, Landon Myer, Tali Azenkot, Jo-Ann S. Passmore, Willem Hanekom, Mark F. Cotton, I. Nicholas Crispe, Donald L. Sodora, Heather B. Jaspan
Marie-Astrid Vernet, Stéphanie Reynard, Alexandra Fizet, Justine Schaeffer, Delphine Pannetier, Jeremie Guedj, Max Rives, Nadia Georges, Nathalie Garcia-Bonnet, Aboubacar I. Sylla, Péma Grovogui, Jean-Yves Kerherve, Christophe Savio, Sylvie Savio-Coste, Marie-Laure de Séverac, Philippe Zloczewski, Sandrine Linares, Souley Harouna, Bing M’Lebing Abdoul, Frederic Petitjean, Nenefing Samake, Susan Shepherd, Moumouni Kinda, Fara Roger Koundouno, Ludovic Joxe, Mathieu Mateo, Patrick Lecine, Audrey Page, Tang Maleki Tchamdja, Matthieu Schoenhals, Solenne Barbe, Bernard Simon, Tuan Tran-Minh, Christophe Longuet, François L’Hériteau, Sylvain Baize
Julie E. Bauman, Umamaheswar Duvvuri, William E. Gooding, Tanya J. Rath, Neil D. Gross, John Song, Antonio Jimeno, Wendell G. Yarbrough, Faye M. Johnson, Lin Wang, Simion Chiosea, Malabika Sen, Jason Kass, Jonas T. Johnson, Robert L. Ferris, Seungwon Kim, Fred R. Hirsch, Kimberly Ellison, John T. Flaherty, Gordon B. Mills, Jennifer R. Grandis
Ta-Chiang Liu, Takeo Naito, Zhenqiu Liu, Kelli L. VanDussen, Talin Haritunians, Dalin Li, Katsuya Endo, Yosuke Kawai, Masao Nagasaki, Yoshitaka Kinouchi, Dermot P.B. McGovern, Tooru Shimosegawa, Yoichi Kakuta, Thaddeus S. Stappenbeck
Matthew J. Hartwell, Umut Özbek, Ernst Holler, Anne S. Renteria, Hannah Major-Monfried, Pavan Reddy, Mina Aziz, William J. Hogan, Francis Ayuk, Yvonne A. Efebera, Elizabeth O. Hexner, Udomsak Bunworasate, Muna Qayed, Rainer Ordemann, Matthias Wölfl, Stephan Mielke, Attaphol Pawarode, Yi-Bin Chen, Steven Devine, Andrew C. Harris, Madan Jagasia, Carrie L. Kitko, Mark R. Litzow, Nicolaus Kröger, Franco Locatelli, George Morales, Ryotaro Nakamura, Ran Reshef, Wolf Rösler, Daniela Weber, Kitsada Wudhikarn, Gregory A. Yanik, John E. Levine, James L.M. Ferrara
BACKGROUND. In dilated cardiomyopathies (DCMs) changes in expression of protein-coding genes are associated with reverse remodeling, and these changes can be regulated by microRNAs (miRs). We tested the general hypothesis that dynamic changes in myocardial miR expression are predictive of β-blocker–associated reverse remodeling.
METHODS. Forty-three idiopathic DCM patients (mean left ventricular ejection fraction 0.24 ± 0.09) were treated with β-blockers. Serial ventriculography and endomyocardial biopsies were performed at baseline, and after 3 and 12 months of treatment. Changes in RT-PCR (candidate miRs) or array-measured miRs were compared based on the presence (R) or absence (NR) of a reverse-remodeling response, and a miR-mRNA-function pathway analysis (PA) was performed.
RESULTS. At 3 months, 2 candidate miRs were selectively changed in Rs, decreases in miR-208a-3p and miR-591. PA revealed changes in miR-mRNA interactions predictive of decreased apoptosis and myocardial cell death. At 12 months, 5 miRs exhibited selective changes in Rs (decreases in miR-208a-3p, -208b-3p, 21-5p, and 199a-5p; increase in miR-1-3p). PA predicted decreases in apoptosis, cardiac myocyte cell death, hypertrophy, and heart failure, with increases in contractile and overall cardiac functions.
CONCLUSIONS. In DCMs, myocardial miRs predict the time-dependent reverse-remodeling response to β-blocker treatment, and likely regulate the expression of remodeling-associated miRs.
TRIAL REGISTRATION. ClinicalTrials.gov NCT01798992.
FUNDING. NIH 2R01 HL48013, 1R01 HL71118 (Bristow, PI); sponsored research agreements from Glaxo-SmithKline and AstraZeneca (Bristow, PI); NIH P20 HL101435 (Lowes, Port multi-PD/PI); sponsored research agreement from Miragen Therapeutics (Port, PI).
Carmen C. Sucharov, David P. Kao, J. David Port, Anis Karimpour-Fard, Robert A. Quaife, Wayne Minobe, Karin Nunley, Brian D. Lowes, Edward M. Gilbert, Michael R. Bristow
Jan A. Burger, Kelvin W. Li, Michael J. Keating, Mariela Sivina, Ahmed M. Amer, Naveen Garg, Alessandra Ferrajoli, Xuelin Huang, Hagop Kantarjian, William G. Wierda, Susan O’Brien, Marc K. Hellerstein, Scott M. Turner, Claire L. Emson, Shih-Shih Chen, Xiao-Jie Yan, Dominik Wodarz, Nicholas Chiorazzi
Zachary Richards, Ken Batai, Rachael Farhat, Ebony Shah, Andrew Makowski, Peter H. Gann, Rick Kittles, Larisa Nonn
Judith E. Epstein, Kristopher M. Paolino, Thomas L. Richie, Martha Sedegah, Alexandra Singer, Adam J. Ruben, Sumana Chakravarty, April Stafford, Richard C. Ruck, Abraham G. Eappen, Tao Li, Peter F. Billingsley, Anita Manoj, Joana C. Silva, Kara Moser, Robin Nielsen, Donna Tosh, Susan Cicatelli, Harini Ganeshan, Jessica Case, Debbie Padilla, Silas Davidson, Lindsey Garver, Elizabeth Saverino, Tooba Murshedkar, Anusha Gunasekera, Patrick S. Twomey, Sharina Reyes, James E. Moon, Eric R. James, Natasha KC, Minglin Li, Esteban Abot, Arnel Belmonte, Kevin Hauns, Maria Belmonte, Jun Huang, Carlos Vasquez, Shon Remich, Mary Carrington, Yonas Abebe, Amy Tillman, Bradley Hickey, Jason Regules, Eileen Villasante, B. Kim Lee Sim, Stephen L. Hoffman
Jack D. Stopa, Donna Neuberg, Maneka Puligandla, Bruce Furie, Robert Flaumenhaft, Jeffrey I. Zwicker
Craig Balmforth, Job J.M.H. van Bragt, Titia Ruijs, James R. Cameron, Robert Kimmitt, Rebecca Moorhouse, Alicja Czopek, May Khei Hu, Peter J. Gallacher, James W. Dear, Shyamanga Borooah, Iain M. MacIntyre, Tom M.C. Pearson, Laura Willox, Dinesh Talwar, Muriel Tafflet, Christophe Roubeix, Florian Sennlaub, Siddharthan Chandran, Baljean Dhillon, David J. Webb, Neeraj Dhaun
Rebecca A. Sosa, Ali Zarrinpar, Maura Rossetti, Charles R. Lassman, Bita V. Naini, Nakul Datta, Ping Rao, Nicholas Harre, Ying Zheng, Roberto Spreafico, Alexander Hoffmann, Ronald W. Busuttil, David W. Gjertson, Yuan Zhai, Jerzy W. Kupiec-Weglinski, Elaine F. Reed
Lynette M. Sholl, Khanh Do, Priyanka Shivdasani, Ethan Cerami, Adrian M. Dubuc, Frank C. Kuo, Elizabeth P. Garcia, Yonghui Jia, Phani Davineni, Ryan P. Abo, Trevor J. Pugh, Paul van Hummelen, Aaron R. Thorner, Matthew Ducar, Alice H. Berger, Mizuki Nishino, Katherine A. Janeway, Alanna Church, Marian Harris, Lauren L. Ritterhouse, Joshua D. Campbell, Vanesa Rojas-Rudilla, Azra H. Ligon, Shakti Ramkissoon, James M. Cleary, Ursula Matulonis, Geoffrey R. Oxnard, Richard Chao, Vanessa Tassell, James Christensen, William C. Hahn, Philip W. Kantoff, David J. Kwiatkowski, Bruce E. Johnson, Matthew Meyerson, Levi A. Garraway, Geoffrey I. Shapiro, Barrett J. Rollins, Neal I. Lindeman, Laura E. MacConaill
Monique A.J. van Eijndhoven, Josée M. Zijlstra, Nils J. Groenewegen, Esther E.E. Drees, Stuart van Niele, S. Rubina Baglio, Danijela Koppers-Lalic, Hans van der Voorn, Sten F.W.M. Libregts, Marca H.M. Wauben, Renee X. de Menezes, Jan R.T. van Weering, Rienk Nieuwland, Lydia Visser, Anke van den Berg, Daphne de Jong, D. Michiel Pegtel
Marc A. Simon, Rebecca R. Vanderpool, Mehdi Nouraie, Timothy N. Bachman, Pamela M. White, Masataka Sugahara, John Gorcsan III, Ed L. Parsley, Mark T. Gladwin
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