BACKGROUND. Ibrutinib has been shown to have immunomodulatory effects by inhibiting Bruton’s tyrosine kinase (BTK) and IL-2–inducible T cell kinase (ITK). The relative importance of inhibiting these 2 kinases has not been examined despite its relevance to immune-based therapies. METHODS. Peripheral blood mononuclear cells from chronic lymphocytic leukemia (CLL) patients on clinical trials of ibrutinib (BTK/ITK inhibitor; n = 19) or acalabrutinib (selective BTK inhibitor; n = 13) were collected serially. T cell phenotype, immune function, and CLL cell immunosuppressive capacity were evaluated. RESULTS. Ibrutinib markedly increased CD4+ and CD8+ T cell numbers in CLL patients. This effect was more prominent in effector/effector memory subsets and was not observed with acalabrutinib. Ex vivo studies demonstrated that this may be due to diminished activation-induced cell death through ITK inhibition. PD-1 and CTLA-4 expression was significantly markedly reduced in T cells by both agents. While the number of Treg cells remained unchanged, the ratio of these to conventional CD4+ T cells was reduced with ibrutinib, but not acalabrutinib. Both agents reduced expression of the immunosuppressive molecules CD200 and BTLA as well as IL-10 production by CLL cells. CONCLUSIONS. Ibrutinib treatment increased the in vivo persistence of activated T cells, decreased the Treg/CD4+ T cell ratio, and diminished the immune-suppressive properties of CLL cells through BTK-dependent and -independent mechanisms. These features provide a strong rationale for combination immunotherapy approaches with ibrutinib in CLL and other cancers. TRIAL REGISTRATION. ClinicalTrials.gov NCT01589302 and NCT02029443. Samples described here were collected per OSU-0025. FUNDING. The National Cancer Institute.
Meixiao Long, Kyle Beckwith, Priscilla Do, Bethany L. Mundy, Amber Gordon, Amy M. Lehman, Kami J. Maddocks, Carolyn Cheney, Jeffrey A. Jones, Joseph M. Flynn, Leslie A. Andritsos, Farrukh Awan, Joseph A. Fraietta, Carl H. June, Marcela V. Maus, Jennifer A. Woyach, Michael A. Caligiuri, Amy J. Johnson, Natarajan Muthusamy, John C. Byrd
BACKGROUND. The tumor immune response is increasingly associated with better clinical outcomes in breast and other cancers. However, the evaluation of tumor-infiltrating lymphocytes (TILs) relies on histopathological measurements with limited accuracy and reproducibility. Here, we profiled DNA methylation markers to identify a methylation of TIL (MeTIL) signature that recapitulates TIL evaluations and their prognostic value for long-term outcomes in breast cancer (BC). METHODS. MeTIL signature scores were correlated with clinical endpoints reflecting overall or disease-free survival and a pathologic complete response to preoperative anthracycline therapy in 3 BC cohorts from the Jules Bordet Institute in Brussels and in other cancer types from The Cancer Genome Atlas. RESULTS. The MeTIL signature measured TIL distributions in a sensitive manner and predicted survival and response to chemotherapy in BC better than did histopathological assessment of TILs or gene expression–based immune markers, respectively. The MeTIL signature also improved the prediction of survival in other malignancies, including melanoma and lung cancer. Furthermore, the MeTIL signature predicted differences in survival for malignancies in which TILs were not known to have a prognostic value. Finally, we showed that MeTIL markers can be determined by bisulfite pyrosequencing of small amounts of DNA from formalin-fixed, paraffin-embedded tumor tissue, supporting clinical applications for this methodology. CONCLUSIONS. This study highlights the power of DNA methylation to evaluate tumor immune responses and the potential of this approach to improve the diagnosis and treatment of breast and other cancers. FUNDING. This work was funded by the Fonds National de la Recherche Scientifique (FNRS) and Télévie, the INNOVIRIS Brussels Region BRUBREAST Project, the IUAP P7/03 program, the Belgian “Foundation against Cancer,” the Breast Cancer Research Foundation (BCRF), and the Fonds Gaston Ithier.
Jana Jeschke, Martin Bizet, Christine Desmedt, Emilie Calonne, Sarah Dedeurwaerder, Soizic Garaud, Alexander Koch, Denis Larsimont, Roberto Salgado, Gert Van den Eynden, Karen Willard Gallo, Gianluca Bontempi, Matthieu Defrance, Christos Sotiriou, François Fuks
BACKGROUND. The histone deacetylase (HDAC) inhibitor vorinostat (VOR) can increase HIV RNA expression in vivo within resting CD4+ T cells of aviremic HIV+ individuals. However, while studies of VOR or other HDAC inhibitors have reported reversal of latency, none has demonstrated clearance of latent infection. We sought to identify the optimal dosing of VOR for effective serial reversal of HIV latency. METHODS. In a study of 16 HIV-infected, aviremic individuals, we measured resting CD4+ T cell–associated HIV RNA ex vivo and in vivo following a single exposure to VOR, and then in vivo after a pair of doses separated by 48 or 72 hours, and finally following a series of 10 doses given at 72-hour intervals. RESULTS. Serial VOR exposures separated by 72 hours most often resulted in an increase in cell-associated HIV RNA within circulating resting CD4+ T cells. VOR was well tolerated by all participants. However, despite serial reversal of latency over 1 month of VOR dosing, we did not observe a measurable decrease (>0.3 log10) in the frequency of latent infection within resting CD4+ T cells. CONCLUSIONS. These findings outline parameters for the experimental use of VOR to clear latent infection. Latency reversal can be achieved by VOR safely and repeatedly, but effective depletion of persistent HIV infection will require additional advances. In addition to improvements in latency reversal, these advances may include the sustained induction of potent antiviral immune responses capable of recognizing and clearing the rare cells in which HIV latency has been reversed. TRIAL REGISTRATION. Clinicaltrials.gov NCT01319383. FUNDING. NIH grants U01 AI095052, AI50410, and P30 CA016086 and National Center for Advancing Translational Sciences grant KL2 TR001109.
Nancie M. Archin, Jennifer L. Kirchherr, Julia A.M. Sung, Genevieve Clutton, Katherine Sholtis, Yinyan Xu, Brigitte Allard, Erin Stuelke, Angela D. Kashuba, Joann D. Kuruc, Joseph Eron, Cynthia L. Gay, Nilu Goonetilleke, David M. Margolis
BACKGROUND. Recessive dystrophic epidermolysis bullosa (RDEB) is an incurable disease caused by mutations in the gene encoding type VII collagen, the major component of anchoring fibrils (AF). We previously demonstrated that gentamicin produced functional type VII collagen in RDEB cells harboring nonsense mutations. Herein, we determined whether topical or intradermal gentamicin administration induces type VII collagen and AFs in RDEB patients. METHODS. A double-blind, placebo-controlled pilot trial assessed safety and efficacy of topical and intradermal gentamicin in 5 RDEB patients with nonsense mutations. The topical arm tested 0.1% gentamicin ointment or placebo application 3 times daily at 2 open erosion sites for 2 weeks. The intradermal arm tested daily intradermal injection of gentamicin solution (8 mg) or placebo into 2 intact skin sites for 2 days in 4 of 5 patients. Primary outcomes were induction of type VII collagen and AFs at the test sites and safety assessment. A secondary outcome assessed wound closure of topically treated erosions. RESULTS. Both topical and intradermal gentamicin administration induced type VII collagen and AFs at the dermal-epidermal junction of treatment sites. Newly created type VII collagen varied from 20% to 165% of that expressed in normal human skin and persisted for 3 months. Topical gentamicin corrected dermal-epidermal separation, improved wound closure, and reduced blister formation. There were no untoward side effects from gentamicin treatments. Type VII collagen induction did not generate anti–type VII collagen autoantibodies in patients’ blood or skin. CONCLUSION. Topical and intradermal gentamicin suppresses nonsense mutations and induces type VII collagen and AFs in RDEB patients. Gentamicin therapy may provide a readily available treatment for RDEB patients with nonsense mutations. TRIAL REGISTRATION. ClinicalTrials.gov NCT02698735. FUNDING. Epidermolysis Bullosa Research Partnership, Epidermolysis Bullosa Medical Research Foundation, NIH, and VA Merit Award.
David T. Woodley, Jon Cogan, Yingping Hou, Chao Lyu, M. Peter Marinkovich, Douglas Keene, Mei Chen
BACKGROUND. The risk of advanced fibrosis in first-degree relatives of patients with nonalcoholic fatty liver disease and cirrhosis (NAFLD-cirrhosis) is unknown and needs to be systematically quantified. We aimed to prospectively assess the risk of advanced fibrosis in first-degree relatives of probands with NAFLD-cirrhosis. METHODS. This is a cross-sectional analysis of a prospective cohort of 26 probands with NAFLD-cirrhosis and 39 first-degree relatives. The control population included 69 community-dwelling twin, sib-sib, or parent-offspring pairs (n = 138), comprising 69 individuals randomly ascertained to be without evidence of NAFLD and 69 of their first-degree relatives. The primary outcome was presence of advanced fibrosis (stage 3 or 4 fibrosis). NAFLD was assessed clinically and quantified by MRI proton density fat fraction (MRI-PDFF). Advanced fibrosis was diagnosed by liver stiffness greater than 3.63 kPa using magnetic resonance elastography (MRE). RESULTS. The prevalence of advanced fibrosis in first-degree relatives of probands with NAFLD-cirrhosis was significantly higher than that in the control population (17.9% vs. 1.4%, P = 0.0032). Compared with controls, the odds of advanced fibrosis among the first-degree relatives of probands with NAFLD-cirrhosis were odds ratio 14.9 (95% CI, 1.8–126.0, P = 0.0133). Even after multivariable adjustment by age, sex, Hispanic ethnicity, BMI, and diabetes status, the risk of advanced fibrosis remained both statistically and clinically significant (multivariable-adjusted odds ratio 12.5; 95% CI, 1.1–146.1, P = 0.0438). CONCLUSION. Using a well-phenotyped familial cohort, we demonstrated that first-degree relatives of probands with NAFLD-cirrhosis have a 12 times higher risk of advanced fibrosis. Advanced fibrosis screening may be considered in first-degree relatives of NAFLD-cirrhosis patients. TRIAL REGISTRATION. UCSD IRB: 140084. FUNDING. National Institute of Diabetes and Digestive and Kidney Diseases and National Institute of Environmental Health Sciences, NIH.
Cyrielle Caussy, Meera Soni, Jeffrey Cui, Ricki Bettencourt, Nicholas Schork, Chi-Hua Chen, Mahdi Al Ikhwan, Shirin Bassirian, Sandra Cepin, Monica P. Gonzalez, Michel Mendler, Yuko Kono, Irine Vodkin, Kristin Mekeel, Jeffrey Haldorson, Alan Hemming, Barbara Andrews, Joanie Salotti, Lisa Richards, David A. Brenner, Claude B. Sirlin, Rohit Loomba, the Familial NAFLD Cirrhosis Research Consortium
Lothar Seefried, Jasmin Baumann, Sarah Hemsley, Christine Hofmann, Erdmute Kunstmann, Beate Kiese, Yue Huang, Simon Chivers, Marie-Anne Valentin, Babul Borah, Ronenn Roubenoff, Uwe Junker, Franz Jakob
Natalia Rakova, Kento Kitada, Kathrin Lerchl, Anke Dahlmann, Anna Birukov, Steffen Daub, Christoph Kopp, Tetyana Pedchenko, Yahua Zhang, Luis Beck, Bernd Johannes, Adriana Marton, Dominik N. Müller, Manfred Rauh, Friedrich C. Luft, Jens Titze
Philipp S. Wild, Janine F. Felix, Arne Schillert, Alexander Teumer, Ming-Huei Chen, Maarten J.G. Leening, Uwe Völker, Vera Großmann, Jennifer A. Brody, Marguerite R. Irvin, Sanjiv J. Shah, Setia Pramana, Wolfgang Lieb, Reinhold Schmidt, Alice V. Stanton, Dörthe Malzahn, Albert Vernon Smith, Johan Sundström, Cosetta Minelli, Daniela Ruggiero, Leo-Pekka Lyytikäinen, Daniel Tiller, J. Gustav Smith, Claire Monnereau, Marco R. Di Tullio, Solomon K. Musani, Alanna C. Morrison, Tune H. Pers, Michael Morley, Marcus E. Kleber, AortaGen Consortium, Jayashri Aragam, Emelia J. Benjamin, Joshua C. Bis, Egbert Bisping, Ulrich Broeckel, CHARGE-Heart Failure Consortium, Susan Cheng, Jaap W. Deckers, Fabiola Del Greco M, Frank Edelmann, Myriam Fornage, Lude Franke, Nele Friedrich, Tamara B. Harris, Edith Hofer, Albert Hofman, Jie Huang, Alun D. Hughes, Mika Kähönen, KNHI investigators, Jochen Kruppa, Karl J. Lackner, Lars Lannfelt, Rafael Laskowski, Lenore J. Launer, Margrét Leosdottir, Honghuang Lin, Cecilia M. Lindgren, Christina Loley, Calum A. MacRae, Deborah Mascalzoni, Jamil Mayet, Daniel Medenwald, Andrew P. Morris, Christian Müller, Martina Müller-Nurasyid, Stefania Nappo, Peter M. Nilsson, Sebastian Nuding, Teresa Nutile, Annette Peters, Arne Pfeufer, Diana Pietzner, Peter P. Pramstaller, Olli T. Raitakari, Kenneth M. Rice, Fernando Rivadeneira, Jerome I. Rotter, Saku T. Ruohonen, Ralph L. Sacco, Tandaw E. Samdarshi, Helena Schmidt, Andrew S.P. Sharp, Denis C. Shields, Rossella Sorice, Nona Sotoodehnia, Bruno H. Stricker, Praveen Surendran, Simon Thom, Anna M. Töglhofer, André G. Uitterlinden, Rolf Wachter, Henry Völzke, Andreas Ziegler, Thomas Münzel, Winfried März, Thomas P. Cappola, Joel N. Hirschhorn, Gary F. Mitchell, Nicholas L. Smith, Ervin R. Fox, Nicole D. Dueker, Vincent W.V. Jaddoe, Olle Melander, Martin Russ, Terho Lehtimäki, Marina Ciullo, Andrew A. Hicks, Lars Lind, Vilmundur Gudnason, Burkert Pieske, Anthony J. Barron, Robert Zweiker, Heribert Schunkert, Erik Ingelsson, Kiang Liu, Donna K. Arnett, Bruce M. Psaty, Stefan Blankenberg, Martin G. Larson, Stephan B. Felix, Oscar H. Franco, Tanja Zeller, Ramachandran S. Vasan, Marcus Dörr
Kit L. Shaw, Elizabeth Garabedian, Suparna Mishra, Provaboti Barman, Alejandra Davila, Denise Carbonaro, Sally Shupien, Christopher Silvin, Sabine Geiger, Barbara Nowicki, E. Monika Smogorzewska, Berkley Brown, Xiaoyan Wang, Satiro de Oliveira, Yeong Choi, Alan Ikeda, Dayna Terrazas, Pei-Yu Fu, Allen Yu, Beatriz Campo Fernandez, Aaron R. Cooper, Barbara Engel, Greg Podsakoff, Arumugam Balamurugan, Stacie Anderson, Linda Muul, G. Jayashree Jagadeesh, Neena Kapoor, John Tse, Theodore B. Moore, Ken Purdy, Radha Rishi, Kathey Mohan, Suzanne Skoda-Smith, David Buchbinder, Roshini S. Abraham, Andrew Scharenberg, Otto O. Yang, Kenneth Cornetta, David Gjertson, Michael Hershfield, Rob Sokolic, Fabio Candotti, Donald B. Kohn
Sarah R. Langley, Karin Willeit, Athanasios Didangelos, Ljubica Perisic Matic, Philipp Skroblin, Javier Barallobre-Barreiro, Mariette Lengquist, Gregor Rungger, Alexander Kapustin, Ludmilla Kedenko, Chris Molenaar, Ruifang Lu, Temo Barwari, Gonca Suna, Xiaoke Yin, Bernhard Iglseder, Bernhard Paulweber, Peter Willeit, Joseph Shalhoub, Gerard Pasterkamp, Alun H. Davies, Claudia Monaco, Ulf Hedin, Catherine M. Shanahan, Johann Willeit, Stefan Kiechl, Manuel Mayr
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