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Tethered Il-15 to Augment the Therapeutic Potential of T Cells

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The Texas Medical Center Library DigitalCommons@TMC The University of Texas MD Anderson Cancer Center UTHealth Graduate School of The University of Texas MD Anderson Cancer Biomedical Sciences Dissertations and Theses Center UTHealth Graduate School of (Open Access) Biomedical Sciences 5-2014 TETHERED IL-15 TO AUGMENT THE THERAPEUTIC POTENTIAL OF T CELLS EXPRESSING CHIMERIC ANTIGEN RECEPTOR: MAINTAINING MEMORY POTENTIAL, PERSISTENCE, AND ANTITUMOR ACTIVITY Lenka Hurton Follow this and additional works at: https://digitalcommons.library.tmc.edu/utgsbs_dissertations Part of the Medical Biotechnology Commons, Medical Immunology Commons, and the Other Immunology and Infectious Disease Commons Recommended Citation Hurton, Lenka, "TETHERED IL-15 TO AUGMENT THE THERAPEUTIC POTENTIAL OF T CELLS EXPRESSING CHIMERIC ANTIGEN RECEPTOR: MAINTAINING MEMORY POTENTIAL, PERSISTENCE, AND ANTITUMOR ACTIVITY" (2014). The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access). 421. https://digitalcommons.library.tmc.edu/utgsbs_dissertations/421 This Dissertation (PhD) is brought to you for free and open access by the The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences at DigitalCommons@TMC. It has been accepted for inclusion in The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access) by an authorized administrator of DigitalCommons@TMC. For more information, please contact [email protected]. TETHERED IL-15 TO AUGMENT THE THERAPEUTIC POTENTIAL OF T CELLS EXPRESSING CHIMERIC ANTIGEN RECEPTOR: MAINTAINING MEMORY POTENTIAL, PERSISTENCE, AND ANTITUMOR ACTIVITY A DISSERTATION Presented to the Faculty of The University of Texas Health Science Center at Houston And The University of Texas M. D. Anderson Cancer Center Graduate School of Biomedical Sciences In Partial Fulfillment of the Requirements for the Degree of DOCTOR OF PHILOSOPHY by Lenka Victoria Hurton, M.S. Houston, Texas May 2014 Copyright © 2014 Lenka Hurton. All rights reserved. DEDICATION To my husband and best friend, Vin, for believing in me more than I believed in myself, for all of his patience, and for selflessly supporting the pursuit of my career. I couldn’t have done this without you. iii ACKNOWLEDGEMENTS I am eternally grateful to the many people who have helped me along in this journey. It was with their support, encouragement, and advice that made the completion of my Ph.D. studies possible. My deepest appreciation goes to my mentor, Dr. Laurence J.N. Cooper, for his support, enthusiasm, and patience. His passion and dedication to immunotherapy and the development of new cancer treatments is inspiring. And, while a double edged sword, I appreciate his infinite reservoir of project ideas. Thank you for giving me the project that I’ve gotten so very attached to! My appreciation also goes out to my supervisory committee, Drs. Joya Chandra, Gianpietro Dotti, Dean Lee, Brad McIntyre, and Clio Rooney for their support and guidance, and for challenging me to become a better scientist. I would like to thank all of the past and present members of the Cooper Lab. Absolutely everyone has helped me out in some way. A special thanks to Dr. Kirsten Switzer and Tiejuan Mi who were instrumental in the “mouse house”. The hours and hours of imaging and processing samples with me, as well as catching a rogue mouse, or two, or three is much appreciated. To Harjeet Singh, Hillary Caruso, Denise Crossland, Drew Deniger, Marie-Andrée Forget, Colleen O’Connor, Sonny Ang, and Simon Olivares for letting me pick your brains, sharing your protocols, taking care of things for me while I was away, or just giving me a sanity check when I was doubting myself. And finally, a Gold Star for Helen Huls! She is the glue that holds everything together. I am forever grateful for everything that she has done for me and the lab. Appreciation goes to the numerous funding agencies and awards that have gone to supporting the research in this dissertation. The Andrew Sowell – Wade Huggins Scholarship and GSBS Faculty & Alumni Merit Fellowship. Travel awards were received from the UT-Houston GSBS, Immunology Program at UT-Houston GSBS, Society for Immunotherapy of Cancer, and American Society of Hematology. This work was largely supported by the Center for Clinical and Translational Sciences, which is funded by National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number TL1TR000369. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. iv I owe a debt of gratitude to family and friends who stood by me throughout the years, even though it was mind-blowing as to how long I’ve been working at this degree. My parents have always been very supportive of all of my endeavors, and I thank them for their loving support throughout this marathon. I am also fortunate to have loving “in-laws” who support and love me as one of their own. Harjeet, Hillary, and Denise, and I have, at times, spent more time together at work than with our own families. They’re not just my “lab family” but the most supportive and caring friends that one can have. My gratitude goes to them for keeping me sane and having my back. I’m glad to have Hillary as a science buddy in the Caruso family who understood my crazy ways and crazy days, and for being my partner in crime on cupcake runs. And to Vin, thanks for supporting me through the crazy research times and for taking care of things when I was too wrapped up in science to notice anything around me. I am lucky to have all of these people support me the way that they do. Finally, my most humble and sincere appreciation goes to the mice who gave their lives for the pursuit of better cancer treatments. v ABSTRACT Tethered IL-15 to augment the therapeutic potential of T cells expressing chimeric antigen receptor: Maintaining memory potential, persistence, and antitumor activity Adoptive immunotherapy can retarget T cells to CD19, a tumor-associated antigen (TAA) expressed on B-cell malignancies, by the expression of a chimeric antigen receptor (CAR). Infusion of CAR-modified T cells for the treatment B-cell malignancies has demonstrated promise in preclinical and clinical trials. These data highlight the ability of infused CD19- specific T cells to be synchronously activated by large burdens of CD19+ leukemia and lymphoma. This can lead to dramatic antitumor effects, but also exposes the recipient to toxicity associated with tumor-cell lysis and cytokine storm. Clinical trials will now be addressing the targeting of minimal burdens of CD19+ malignancy as patients are enrolled earlier in their disease course and receive concomitant chemotherapy. It is likely that the existing populations of CAR T cells generated ex vivo to address relapsed disease may not be able to address minimal residual disease (MRD). Therefore, we have developed a clinically appealing approach to sustaining the persistence of CAR T cells independent of TAA by providing signaling through the common gamma chain receptor (γc). Administration of exogenous soluble recombinant cytokines that signal through the γc, such as interleukin (IL)-2, have been used clinically to sustain the persistence of adoptively transferred T cells. However, systemic high-dose administration has resulted in dose-limiting toxicities. Unlike IL-2, IL-15 possesses numerous attributes desirable for adoptive therapy and has been ranked among the most valuable immunotherapeutic agent for cancer treatment. It is a pro- survival cytokine that promotes the survival of long-lived T-cell memory subsets and in vivo antitumor activity. Unlike other γc family cytokines, IL-15 is transpresented to responding T cells in the context of IL-15 receptor alpha (IL-15Rα). Therefore, we hypothesized that a membrane-bound IL-15 fusion protein (mIL15) tethered to the cell surface would enhance T-cell costimulation to support persistence independent of CAR activation by preserving T- cell memory potential and maintain antitumor activity in the presence of low TAA. Using clinically compliant methods, the generated mIL15-CAR T cells mimicked the physiologic mechanism of transpresentation to sustain costimulation via phosphorylation of signal transducer and activator of transcription (pSTAT5). In contrast to conventional CD19- specific CAR T cells, mIL15-CAR T cells persisted in mice independent of the presence of TAA and mediated potent rejection of a systemically distributed CD19+ leukemia. The potential for sustained immunity against B-cell malignancies was shown as, in the absence vi of antigen, mIL15-CAR T cells were long-lived and adopted a desirable CD45ROnegCCR7+ “low-differentiation” state with a memory-like molecular profile and phenotype. These results have direct implications for the design of an adoptive immunotherapy clinical trial evaluating mIL15-CAR T cells in the setting of MRD and warrants further investigation of mIL15 to engineer T cells targeting other tumor cells that have sequestered or low levels of TAA. vii TABLE OF CONTENTS Page APPROVAL.......................................................................................................................... i TITLE PAGE ....................................................................................................................... ii DEDICATION ....................................................................................................................
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    Supplementary Material DNA Methylation in Inflammatory Pathways Modifies the Association between BMI and Adult-Onset Non- Atopic Asthma Ayoung Jeong 1,2, Medea Imboden 1,2, Akram Ghantous 3, Alexei Novoloaca 3, Anne-Elie Carsin 4,5,6, Manolis Kogevinas 4,5,6, Christian Schindler 1,2, Gianfranco Lovison 7, Zdenko Herceg 3, Cyrille Cuenin 3, Roel Vermeulen 8, Deborah Jarvis 9, André F. S. Amaral 9, Florian Kronenberg 10, Paolo Vineis 11,12 and Nicole Probst-Hensch 1,2,* 1 Swiss Tropical and Public Health Institute, 4051 Basel, Switzerland; [email protected] (A.J.); [email protected] (M.I.); [email protected] (C.S.) 2 Department of Public Health, University of Basel, 4001 Basel, Switzerland 3 International Agency for Research on Cancer, 69372 Lyon, France; [email protected] (A.G.); [email protected] (A.N.); [email protected] (Z.H.); [email protected] (C.C.) 4 ISGlobal, Barcelona Institute for Global Health, 08003 Barcelona, Spain; [email protected] (A.-E.C.); [email protected] (M.K.) 5 Universitat Pompeu Fabra (UPF), 08002 Barcelona, Spain 6 CIBER Epidemiología y Salud Pública (CIBERESP), 08005 Barcelona, Spain 7 Department of Economics, Business and Statistics, University of Palermo, 90128 Palermo, Italy; [email protected] 8 Environmental Epidemiology Division, Utrecht University, Institute for Risk Assessment Sciences, 3584CM Utrecht, Netherlands; [email protected] 9 Population Health and Occupational Disease, National Heart and Lung Institute, Imperial College, SW3 6LR London, UK; [email protected] (D.J.); [email protected] (A.F.S.A.) 10 Division of Genetic Epidemiology, Medical University of Innsbruck, 6020 Innsbruck, Austria; [email protected] 11 MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, W2 1PG London, UK; [email protected] 12 Italian Institute for Genomic Medicine (IIGM), 10126 Turin, Italy * Correspondence: [email protected]; Tel.: +41-61-284-8378 Int.