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Car-Modified T Cells Capable of Distinguishing Normal Cells from Malignant Cells

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Car-Modified T Cells Capable of Distinguishing Normal Cells from Malignant Cells 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 CAR-MODIFIED T CELLS CAPABLE OF DISTINGUISHING NORMAL CELLS FROM MALIGNANT CELLS Hillary G. Caruso Follow this and additional works at: https://digitalcommons.library.tmc.edu/utgsbs_dissertations Part of the Cancer Biology Commons, Immunity Commons, and the Medicine and Health Sciences Commons Recommended Citation Caruso, Hillary G., "CAR-MODIFIED T CELLS CAPABLE OF DISTINGUISHING NORMAL CELLS FROM MALIGNANT CELLS" (2014). The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access). 457. https://digitalcommons.library.tmc.edu/utgsbs_dissertations/457 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]. CAR-MODIFIED T CELLS CAPABLE OF DISTINGUISHING MALIGNANT CELLS FROM NORMAL CELLS by Hillary Gibbons Caruso, B.S. APPROVED: ______________________________ Laurence Cooper, M.D., Ph.D., Supervisory Professor ______________________________ Oliver Bögler, Ph.D. ______________________________ Bradley McIntyre, Ph.D. ______________________________ Jeffrey Molldrem, M.D. ______________________________ Kimberly Schluns, Ph.D. APPROVED: ____________________________ Dean, The University of Texas Graduate School of Biomedical Sciences at Houston CAR-MODIFIED T CELLS CAPABLE OF DISTINGUISHING MALIGNANT CELLS FROM NORMAL CELLS A DISSERTATION Presented to the Faculty of The University of Texas Health Science Center at Houston and The University of Texas MD Anderson Cancer Center Graduate School of Biomedical Sciences in Partial Fulfillment of the Requirements for the Degree of DOCTOR OF PHILOSOPHY by Hillary Gibbons Caruso Houston, Texas May 2014 Copyright (c) 2014 Hillary Gibbons Caruso. All rights reserved. ii DEDICATION To my best friend, my husband, Andrew For teaching me that “Laughter is timeless, Imagination has no age, And dreams are forever.” - Walt Disney iii ACKNOWLEDGMENTS The road journeyed to complete my doctorate work and dissertation could not have been traveled without the support from those around me. There are many I am eternally grateful to for their unending encouragement. First, my profound appreciation goes to my mentor, Dr. Laurence Cooper. He has been the most enthusiastic, understanding, and supportive mentor one could ask for, and I am glad that I was able to undertake my work in his laboratory. His passion is contagious and necessary for successful pursuit of scientific research, and I am grateful to have studied under his mentorship. Additionally, my sincerest thanks go to Dr. Dean Lee for his input and guidance through my graduate career. Through advice with experimental design to guidance with writing manuscripts, his advice has been invaluable. I would also like to thank all members of my advisory committee, Drs. Oliver Bögler, Brad McIntyre, Jeffrey Molldrem, and Kimberly Schluns, for their insightful input and guidance through this journey. Next, I would like to thank everyone in the Cooper Lab, past and present members included, for the congenial work atmosphere and supportive collaborations through the years. I thank Harjeet Singh for taking on the role of training me in day-to-day lab practices and being my “go-to” guru for input on experimental design and interpretation through the years. I’d also like to thank Sourindra Maiti, Simon Olivares, and Sonny Ang for assistance in designing vectors and molecular biology techniques, David Rushworth and Bipulendu Jena for manufacture and construction of CAR-L, Ling Zhang for sharing her in vitro transcription protocol, and Drew Deniger for assistance with lentiviral transduction. I owe many thanks to Tiejuan Mi, Kirsten Switzer, Lenka Hurton, and Amer Najjar for assistance and valuable company during many long days in the mouse facility. I would also like to thank Lenka Hurton, Denise Crossland, Drew Deniger, and Radhika Thokala for the brainstorming sessions, suggestions, advice and collegial atmosphere within our own little office for the past five years. Working alongside you, learning from you, and sharing our experiences over the past several years have been among some of the most distinguishing joys of this process, and I’m glad to have had you along for the ride. Finally, many, many thanks to Helen Huls, the glue that holds everything together in the Cooper Lab. Between your responsibilities in clinical translation of all of our work and day-to-day guidance and structure to keep our lab afloat, we would be lost without everything you do for us. iv Many funding agencies have supported the work completed in this dissertation. I would like to thank the American Legion Auxiliary for their hard work fundraising for cancer research and their support of this project. I would also like to thank the Cancer Answers and the Sylvan Rodriguez Foundations, who have offered their support through the Andrew Sowell Wade Huggins fellowship. In addition, I offer thanks to the friends and family of R.W. Butcher, who have supported my work through the R.W. Butcher fellowship. And finally, much of this work was supported by the Center for Clinical and Translational Sciences at the University of Texas at Houston Health Science Center, funded through the National Center for Advancing Translational Science of the National Institutes of Health under award number TL1TR000369. I have been fortunate enough to have educators and mentors along the road that encouraged me from a young age to succeed in all I do. First, my sincerest thanks to Jim Dixon. As a young student interested in music, Mr. Dixon had more faith in me than I did in myself. Through his teaching and support, he taught me not only to play the flute, but to have passion and dedication for music, and to work as hard as I could to achieve my goals. Applying the dedication instilled in me at that young age has fueled my progress through graduate school, and I am grateful for all his support. I would not be where I am today without the influence of two wonderful high school teachers, Ms. Janice Pyles and Ms. Hope Stevens. Ms. Pyles saw my enthusiasm for science as a student in her Pre-AP Chemistry class and encouraged me to take not only AP Chemistry II, but AP Biology II. My love for chemistry was immediate, but I only discovered a love for biology through this course, and I wouldn’t be where I am today without her guidance. Ms. Stevens encouraged me to take AP Biology II as a guided independent-study during her off-period, as I was the only enrollee. In usual circumstances, the class would have been canceled, but because I was allowed to study in this manner, I discovered a profound and deep appreciation for biology on the cellular and molecular level, which has lead me to this point in my career. Finally, I have been blessed beyond words with a caring and endlessly supportive family. My parents have been the best role models a child could ask for. They have shown what dedication and hard work can achieve, paramount among those achievements being true happiness and contentment with life. I owe the person I am today, and everything I have accomplished thus far, to their love and support, for they are constantly behind me, my own perpetual cheering section. My brother, Ryan, was among the first people to push me to do my best. His encouragement to achieve pushed my academic endeavors in high v school, which has flowed right through each stage of my education. My entire family has been a network of love and support, which grows from the center of our family, my grandparents. To Maw Maw and Paw Paw, and to Grandma and Grandpa McBrayer, thank you for all you have done for us. I am lucky to have an entire network of in-laws that treat me as family, including my mother-in-law, Diana, father-in-law, Vincent, and brother-in-laws, Vin and Patrick. Thank you for taking me into your family as one of your own; I am lucky to be a member of the Caruso clan. I am also fortunate to have three sister-in-laws that I treasure as my own sisters. Stacey, Melissa, and Lenka, I am so happy to have you not only as family, but as friends. Last, but not certainly not least, my eternal love and gratitude to my own family, my husband, Andrew, and my daughter, Olivia. Andrew, you are the glue that holds our family together. Your constant love and hard work to take care of us, even before yourself, is a perfect example of what a marriage should be. You make me work harder to be a better person every day, and I am beyond blessed to have you as a husband. Olivia, you are the happiness in my every day. You are such a bright, quirky, and cheerful little girl, and I can’t wait to see who you will become. Your smile has given me hope and carried me through more than one hard day, and I am lucky to be your mother. vi CAR-MODIFIED T CELLS CAPABLE OF DISTINGUISHING MALIGNANT CELLS FROM NORMAL CELLS Hillary Gibbons Caruso, B.S. Advisory Professor: Laurence Cooper, M.D., Ph.D. T cells can be redirected to target tumor-associated antigen (TAA) by genetic modification to express a chimeric antigen receptor (CAR), which fuses the specificity derived from an antibody to T-cell activation domains to result in lysis of TAA-expressing cells.
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