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Novel Immunotherapeutic Strategies For NOVEL IMMUNOTHERAPEUTIC STRATEGIES FOR CHRONIC LYMPHOCYTIC LEUKEMIA DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Kyle Beckwith, B.S. Graduate Program in Biomedical Sciences The Ohio State University 2016 Dissertation Committee: John Byrd MD (Co-Advisor) Natarajan Muthusamy DVM, PhD (Co-Advisor) Michael Caligiuri MD Abhay Satoskar MD, PhD Copyright by Kyle A. Beckwith 2016 ABSTRACT Chronic lymphocytic leukemia (CLL) is malignancy characterized by the progressive accumulation of neoplastic B-cells that are phenotypically mature, but functionally incompetent. It is the most prevalent adult leukemia in the United States, and has an incidence of approximately 18,000 new cases per year. The introduction of CD20-targeted monoclonal antibody rituximab dramatically altered how this disease is managed, and immunotherapeutic strategies have become a mainstay of CLL therapy ever since. Newer immunotherapies approved by the FDA include anti-CD52 alemtuzumab and two anti-CD20 antibodies with improved activity. Due to expression of CD52 on T-cells, alemtuzumab therapy puts an already immunocompromised population at greater risk for infection (which is already the most common cause of CLL patient death). Unfortunately current therapeutics are not curative, and resistance/relapse is inevitable. Given the limitations of these therapies, particularly when confronted with the challenge of treating relapsed/refractory disease, it is important to expand our immunotherapeutic arsenal beyond targeting CD20. Therefore, the overall aim of this thesis is to develop novel approaches to CLL immunotherapy that can be successfully translated to the clinic. One of the most promising alternative targets for immunotherapy is CD37. This tetraspanin protein is largely B-cell restricted and highly expressed in CLL and Non-Hodgkins Lymphoma. Furthermore, the single agent clinical activity of anti- CD37 otlertuzumab in CLL validates this therapeutic target. A number of CD37-targeted therapies have been developed recently, but our ability to study them preclinically is significantly hampered by the lack of suitable animal models that can accurately ii recapitulate CLL. Ideally we would use the TCL1 mouse model of CLL, which has been extensively characterized as a drug development tool, but the antibodies targeting human CD37 (hCD37) do not cross react with murine CD37. This problem was addressed by developing a model of murine leukemia expressing hCD37, crossing hCD37 transgenic mice developed by our laboratory with the TCL1 mouse. These hCD37xTCL1 mice facilitated the in vivo study of IMGN529, a CD37-targeting antibody- drug conjugate. Using our new model, I demonstrate that IMGN529 can not only improve overall survival, but is also capable of eliminating the proliferative subset of CLL B-cells within lymphoid tissues. I go on to investigate combination strategies that can improve the efficacy of anti-CD37 therapeutics, including addition of a phosphoinositide 3-kinase (PI3K) inhibitor, which improves cytotoxicity against primary CLL B-cells (and is equally effective against cells from high risk patients). I also investigate whether a CD37- targeted bispecific antibody can effectively recruit T-cells to kill malignant B-cells, despite the profound T-cell defects observed in CLL. Unfortunately, it appears to be inferior to bispecific antibody formats and is only effective at high effector-to-target ratios. Finally, I use a model of CD37-deficient CLL to explore the function of this tetraspanin in B-cell malignancy. These mice exhibit decreased survival that suggests a tumor suppressor role in this context. Overall, this thesis represents a comprehensive inquiry into both the function of CD37, and a wide variety of approaches to targeting CD37 which provide valuable information relevant to future clinical trials. iii DEDICATION This dissertation is dedicated to my family and to my current and former mentors. iv ACKNOWLEDGMENTS First, I would like to acknowledge Dr. Michael Uhler for his mentorship while I was at the University of Michigan. His trust and encouragement to seek out answers to my own questions fostered a love of research I did not discover until very late in college. Without his mentorship and the (relative) freedom he afforded me, it is unlikely I would have continued to pursue laboratory research. This experience encouraged me to continue to seek out research opportunities in medical school, which led me to Dr. Phillip Popovich’s laboratory. The short time I spent in this lab working closely with John Gensel ultimately prompted me to delay entrance to Med 3 to pursue additional research opportunities. I would like express my deepest thanks to my mentors Dr. John Byrd and Dr. Raj Muthusamy for their guidance and support. Without the opportunity to pursue a Pelotonia fellowship in the lab, I would not be seeking a PhD. Your neverending enthusiasm for science and mentorship inspires me. If I train future students half as well as you have, it would be considered a major success. To all members of the Byrd lab (past and present) who have helped or provided insight along the way – thank you. I am grateful to many faculty members at OSU for providing their expertise and support, but I would like to specifically extend thanks to Dr. Michael Caligiuri and Dr. Abhay Satoskar for taking the time to be part of my committee. Thank you for your support and feedback throughout this entire process. v I would also like to thank my parents for their amazing support over the many years of my education. Finally, I am especially thankful to my brilliant wife Puneet for her endless support, insight, patience, and encouragement. You make me strive to be a better person and scientist. vi VITA 2009 ............................................................. B.S. Biochemistry, with distinction University of Michigan 2009 to present ........................................... Graduate/Medical Student Ohio State College of Medicine Biomedical Sciences Graduate Program PUBLICATIONS 1. *Fraietta JA, *Beckwith KA, Patel PR, Ruella M, Zheng Z, Barrett DM, Lacey SF, Melenhorst JJ, McGettigan SE Cook DR, Zhang C, Xu J, Do P, Hulitt J, Kudchodkar SB, Cogdill AP, Gill S, Porter DL, Woyach JA, Long M, Johnson AJ, Maddocks K, Muthusamy N, Levine BL, June CH, *Byrd JC and *Maus MV. Ibrutinib Enhances Chimeric Antigen Receptor T-cell Engraftment and Efficacy in Leukemia. Blood. Pre-published online January 26, 2016. doi: http://dx.doi.org/10.1182/blood-2015-11-679134. Asterisk (*) indicates equal contribution by these authors. 2. Gensel JC, Wang Y, Guan Z, Beckwith KA, Braun KJ, Wei P, McTigue DM, Popovich PG. Toll-Like Receptors and Dectin-1, a C-Type Lectin Receptor, Trigger Divergent Functions in CNS Macrophages. J Neurosci. 35(27):9966-76, 2015. doi: 10.1523/JNEUROSCI.0337-15.2015 3. Beckwith KA, Byrd JC, and Muthusamy N. Tetraspanins as therapeutic targets in hematological malignancy: a concise review. Front. Physiol. 6:91, 2015. doi: 10.3389/fphys.2015.00091 [Review article] 4. Hing ZA, Mantel R, Beckwith KA, Guinn D, Williams E, Smith L, Williams KE, Johnson AJ, Lehman A, Byrd JC, Woyach JA, Lapalombella R. Selinexor is effective in acquired resistance to ibrutinib and synergizes with ibrutinib in chronic lymphocytic leukemia. Blood. 125(20):3128-32, 2015. doi: 10.1182/blood- 2015-01-621391 vii 5. Liu T, Ling Y, Woyach JA, Beckwith K, Yeh Y, Hertlein E, Zhang X, Lehman A, Awan F, Jones JA, Andritsos LA, Maddocks K, MacMurray J, Salunke SB, Chen C, Phelps MA, Byrd JC, Johnson AJ. OSU-T315: a novel targeted therapeutic that antagonizes AKT membrane localization and activation of chronic lymphocytic leukemia cells. Blood. 125(2):284-95, 2015. doi: 10.1182/blood- 2014-06-583518 6. Beckwith KA, Frissora FW, Stefanovski MR, Towns WH, Cheney C, Mo X, Deckert J, Croce CM, Flynn JM, Andritsos LA, Jones JA, Maddocks KJ, Lozanski G, Byrd JC, and Muthusamy N. The CD37-targeting antibody-drug conjugate IMGN529 is highly active against human CLL and in a novel CD37 transgenic murine leukemia model. Leukemia. 28(7): 1501-10, 2014. 7. Zhong Y, El-Gamal D, Dubovsky JA, Beckwith KA, Harrington BK, Williams KE, Goettl VM, Jha S, Mo X, Jones JA, Flynn JM, Maddocks KJ, Andritsos LA, McCauley D, Shacham S, Kauffman M, Byrd JC, Lapalombella R. Selinexor suppresses downstream effectors of B-cell activation, proliferation and migration in chronic lymphocytic leukemia cells. Leukemia. 28(5): 1158-63, 2014. 8. Hertlein E, Beckwith KA, Lozanski G, Chen TL, Towns, WH, Johnson AJ, Lehman A, Ruppert AS, Bolon, B, Lozanski A, Rassenti L, Zhao W, Jarvinen T, Senter L, Croce CM, Symer DE, de la Chapelle A, Heerema N, Byrd JC. Characterization of a new chronic lymphocytic leukemia cell line for mechanistic in vitro and in vivo studies relevant to disease. PLoS One. 8(10), 2013. 9. Dubovsky JA, Beckwith KA, Natarajan G, Woyach JA, Jaglowski S, Zhong Y, Hessler JD, Liu T, Chang BY, Larkin KM, Stefanovski MR, Frissora FW, Smith LL, Smucker KA, Flynn JM, Jones JA, Andritsos LA, Maddocks KJ, Lehman AM, Furman R, Sharman J, Mishra A, Caligiuri MA, Satoskar AR, Buggy JJ, Muthusamy N, Johnson AJ, and Byrd JC. Ibrutinib is an irreversible molecular inhibitor of ITK driving a Th1 selective pressure in T-lymphocytes. Blood. 122(15): 2539-49, 2013. FIELDS OF STUDY Major Field: Biomedical Sciences Specialization: Immunology viii TABLE OF CONTENTS Abstract ............................................................................................................................
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