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UNIVERSITY of CALIFORNIA Los Angeles Stem Cell Engineered UNIVERSITY OF CALIFORNIA Los Angeles Stem Cell Engineered Invariant Natural Killer T Cells for Cancer Immunotherapy A dissertation submitted in partial satisfaction of the requirements for the degree Doctor of Philosophy in Molecular Biology by Drake John Smith 2017 © Copyright by Drake John Smith 2017 ABSTRACT OF THE DISSERTATION Stem Cell Engineered Invariant Natural Killer T Cells for Cancer Immunotherapy by Drake John Smith Doctor of Philosophy in Molecular Biology University of California, Los Angeles, 2017 Professor Donald Barry Kohn, Chair Cancer immunotherapy is a rapidly developing field that has already shown to be of great clinical value as evidenced by the success of engineered T cell therapies, such as chimeric antigen receptor (CAR) therapies in treating B cell leukemia and T cell receptor (TCR) therapies in treating melanoma, and by checkpoint inhibitor therapies, such as PD-1 and CTLA-4 antibodies, in treating a variety of cancers. This dissertation seeks to add to this growing knowledge base and carve out a niche in the discipline by utilizing a unique combination of immune cell type and method of delivery; a hematopoietic stem cell (HSC) can be genetically engineered using a viral vector in order to generate invariant natural killer T (iNKT) cells in vivo. Several cancer immunotherapy clinical trials have already utilized iNKT cells either by infusion after expansion ex vivo and/or activation of the cells in vivo by dendritic cells loaded ii with the synthetic ligand α-Galactosylceramide (α-GalCer). These trials have demonstrated that the treatments are well tolerated, and while some have shown promising anti-tumor immunity, most have yielded unsatisfactory results. This lack of clinical efficacy has been attributed to the cells’ very low and highly variable number in humans (0.001-1% in peripheral blood) and their rapid depletion after stimulation. Many cancer immunotherapy treatments trend towards a phase of promising tumor regression followed by a disheartening cancer relapse. This may be due to several factors, but a major contributor specific to cancer immunotherapy is thought to be exhaustion of the therapeutic cells by the ex vivo expansion protocol. This protocol drives the therapeutic cells to expand and differentiate into terminally differentiated effector cells. While these effector cells have increased killing efficacy, it comes at the expense of a decreased life span and regeneration. This would explain the initial regression mediated by the effector cells, followed by a relapse when the cells become exhausted. This issue can be addressed by utilizing viral vectors to genetically engineer hematopoietic stem cells to continually generate new therapeutic cells in vivo. This dissertation lays the foundation for combining the genetic engineering of HSCs by viral transduction to generate iNKT cells to be used for cancer immunotherapy. Proof-of- principle experiments in mice and an expansion to the use of the humanized mouse model provided the necessary knowledge and tools for further development to be pursued. Ongoing and future studies aim to demonstrate anti-cancer efficacy in humanized mouse models in order to collect data for an application to utilize these HSC-engineered iNKT cells in a cancer immunotherapy clinical trial. iii The dissertation of Drake John Smith is approved. Lili Yang Yvonne Y. Chen Arnold I. Chin Anna Wu Work Donald Barry Kohn, Committee Chair University of California, Los Angeles 2017 iv DEDICATION This dissertation is dedicated to my grandfather, John David Quinn, whom we lost to cancer in 2015. v TABLE OF CONTENTS Abstract of the Dissertation ii Committee Page iv Dedication Page v List of Figures and Tables vii Acknowledgements ix Vita xii Chapter 1: Engineering Immunotherapy 1 References 13 Chapter 2: Genetic engineering of hematopoietic stem cells to generate invariant 16 natural killer T cells (Smith et al., PNAS 2015) References 22 Chapter 3: Propagating humanized BLT mice for the study of human immunology 26 and immunotherapy (Smith et al., Stem Cells and Dev 2016) References 36 Chapter 4: Invariant natural killer T cells generated in vivo from genetically 38 engineered human hematopoietic stem cells (Smith et al., manuscript in preparation) References 58 Chapter 5: Conclusions and future studies 60 References 63 vi LIST OF FIGURES AND TABLES Chapter 1: No figures. Chapter 2: Figure 2-1: Cloning of invariant natural killer T-cell receptor (iNKT TCR) 18 genes and construction of retroviral delivery vectors Figure 2-2: Generation of functional iNKT cells through TCR gene 19 engineering of hematopoietic stem cells (HSCs) Figure 2-3: Development of the HSC-engineered iNKT cells. B6-miNKT 20 and control B6-mock mice were analyzed for iNKT cell development at 6–8 wk post HSC transfer Figure 2-4: Protection from melanoma lung metastasis by the 21 HSC-engineered iNKT cells Figure S2-1: Titration of the miNKT retroviral vector 24 Figure S2-2: Lineage differentiation of iNKT TCR-engineered HSCs 25 Chapter 3: Figure 3-1: Generation of propagated BLT (proBLT) mice through 30 secondary transfer of bone marrow cells and human thymus implants from primary BLT mice to naïve NSG mice Figure 3-2: Reconstitution of multilineage human immune cells in proBLT 32 mice Figure 3-3: Reconstitution of human thymus and human T cells in proBLT 33 mice vii Figure 3-4: Inheritance of human immune cell genetic traits from BLT to 34 proBLT mice Figure 3-5: Persistence of human immune cell gene modifications from 35 BLT to proBLT mice Chapter 4: Figure 4-1: Cloning of invariant natural killer T (iNKT) cell T cell 45 receptor (TCR) genes and construction of lentiviral delivery vectors Figure 4-2: Generation of functional iNKT cells through TCR gene 47 engineering of hematopoietic stem cells (HSCs) Figure 4-3: Development of genetically engineered HSCs and iNKT cells 50 Figure 4-4: In vitro functionality of engineered iNKT cells 52 Chapter 5: No figures. viii ACKNOWLEDGEMENTS First and foremost, I would like to thank my graduate mentor Dr. Lili Yang. She took a chance on me as her first graduate student as a biochemist who thought he could be an immunologist. She taught me everything I know about immunotherapy and her tireless pursuit in the name of science inspired me to push myself beyond my own limits as well. With her help, I have been able to meet and collaborate with some of the most influential minds in the field and I strive to have as great of an impact on the field as she has had in the years to come. I want to retroactively thank my undergraduate mentor Dr. Joanie Hevel. She also took a chance on me as a freshman when I was straight off the farm and convinced I wanted to pursue a career in research. She taught me how to be a research scientist and to stay tenacious even when it feels like nothing is working. Her words of wisdom have aided in sustaining me through many weeks of negative results; her margarita recipe may have helped on occasion as well. I need to thank all of the members of the Yang lab who I have worked with over the past few years. Their daily support of my research and training have made the pace of my progress possible. I would like to specifically thank my undergraduate student Levina Lin. She quickly became like a second pair of hands and was never afraid to call me out when I’d made a mistake, much to her enjoyment. I must also thank the army of collaborators that I have been so fortunate to work with during my time at UCLA. Without their expertise and dedication, none of this work would have been possible. I want to specifically thank Jessica Scholes and Felicia Codrea of the BSCRC FACS Core for mentoring me in the art of flow cytometry when I was a newly minted graduate student. I also wish to thank Debbie Posner of the CFAR Virology Core not only for her support of my research through providing and processing blood products, but for her support of my ix personal journey through my PhD. Thank you for the words of advice and encouragement on my bad days. I would like to thank the members of my committee for their critical evaluation of my research and their insightful suggestions that have helped me along the way. The advice I have received has aided in directing my research as well my career and life goals. Special thanks go to the chair of my committee, Don Kohn, who agreed to take me on for an early summer lab rotation when I first came to UCLA. I have seen his exemplary mentorship change the lives of many, including my own, and I hope to one day be able to do the same. I have had the pleasure of serving as the President of the Biological Sciences Council for the past two years of my PhD. This has given me the opportunity to work with many motivated scientists who want to help make UCLA a better place for graduate students both now and in the future. Good luck to them as they take on the torch of slogging through bureaucracy. Thank you to my friends for their continued support over the past four years, even when I wouldn’t see them for months at a time. Thanks to Brendan Barry for helping me get through my first year of graduate school and beyond as well as critical reading of this dissertation. Special thanks go to my first graduate mentor at UCLA, Eric Gschweng, who continually pushed me to be a better scientist and still does to this day. I strive to one day live up to his expectations and his example.
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