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Development and Characterization of Immunogenic Genetically Engineered Mouse Models of Pancreatic Cancer

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Development and characterization of immunogenic genetically engineered mouse models of pancreatic cancer By Laurens J. Lambert MSc, Medical Biology Radboud University, 2014 Submitted to the Department of Biology in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy at the MASSACHUSETTS INSTITUTE OF TECHNOLOGY September 2020 © 2020 Massachusetts Institute of Technology. All rights reserved. Signature of Author………………………………………………………………………………. Laurens J. Lambert Department of Biology June 16, 2020 Certified by………..………………………………………………………………………………. Tyler Jacks David H. Koch Professor of Biology Investigator, Howard Hughes Medical Institute Thesis Supervisor Accepted by………………………………………………………………………………………. Stephen Bell Uncas and Helen Whitaker Professor of Biology Investigator, Howard Hughes Medical Institute Co-Director, Biology Graduate Committee 2 Development and characterization of immunogenic genetically engineered mouse models of pancreatic cancer By Laurens J. Lambert Submitted to the Department of Biology on June 16, 2020 in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy in Biology Abstract Insights into mechanisms of immune escape have fueled the clinical success of immunotherapy in many cancers. However, pancreatic cancer has remained largely refractory to checkpoint immunotherapy. To uncover mechanisms of immune escape, we have characterized two preclinical models of immunogenic pancreatic ductal adenocarcinoma (PDAC). In order to dissect the endogenous antigen-specific T cell response in PDAC, lentivirus encoding the Cre recombinase and a tumor specific antigen LSL-G12D/+; flox/flox (SIINFEKL, OVA257-264) was delivered to Kras Trp53 (KP) mice. We demonstrate that KP tumors show distinct antigenic outcomes: a subset of PDAC tumors undergoes clearance or editing by a robust antigen-specific CD8+ T cell response, while a fraction undergo immune escape. Subsequently, we have developed an immunogenic pancreatic tumor organoid orthotopic transplant model. In this model, immunogenic pancreatic tumors manifest divergent tumor phenotypes; 40% of tumor organoids do not form tumors (“non- progressors”), whereas 50% of organoids form aggressive tumors despite maintaining antigen expression and a demonstrable T cell response (“progressors”). Additionally, a subset (10%) of tumors show an intermediate phenotype, possibly reflective of an immune equilibrium state. We have further phenotypically and transcriptionally characterized the CD8+ T cell response to understand immune escape in this model. Our analyses reveal unexpected T cell heterogeneity, and acquisition of T cell dysfunctionality. Therapeutic combinatorial targeting of co-inhibitory receptors identified on dysfunctional antigen-specific CD8+ T cells led to dramatic regression of aggressive pancreatic tumors. Finally, we demonstrate that human CD8+ T cells isolated from pancreatic tumors co-express co-inhibitory receptors, suggesting that T cell dysfunction may be operational in human disease. This is the first demonstration of immunoediting in an autochthonous and organoid- based model of pancreatic cancer. Further characterization of these preclinical model systems will enable rational design of novel clinical immunotherapeutic strategies for treatment of this devastating disease. Thesis Advisor: Tyler Jacks Title: Professor of Biology 3 Curriculum vitae Laurens J. Lambert Education 2014 - MASSACHUSETTS INSTITUTE OF TECHNOLOGY (CAMBRIDGE, MA, Present USA) PhD, Department of Biology, The Jacks Lab 2009 - 2014 RADBOUD UNIVERSITY (NIJMEGEN, NETHERLANDS) Bachelor of Science in Biology Master of Science in Medical Biology, Cum Laude Professional Experience May 2015- The David Koch Institute for Integrative Cancer Research, MIT (Tyler Present Jacks Laboratory) PhD Student § Developed novel pancreatic cancer mouse models and characterized the T cell response in these models. § Discovered a therapeutic checkpoint combination with clinical § translatability. § Co-led a pancreas research team in the Jacks lab and coordinated with internal and external collaborators (Koch Institute, DFCI). § Authored a chapter in a major textbook and submitted a manuscript to Nature (under review). Jan. 2020- MPM Capital (Cambridge, MA) Present Consultant § Supported key company-formation activities through the technical evaluation of scientific fields and identification of high priority development candidates. § Presented progress in weekly strategy meetings with the founding team at MPM Capital. April 2019- Vida Ventures (Boston, MA) Dec. 2019 Fellow § Evaluated the scientific evidence, clinical paradigms, and commercial landscape to support 15+ investment decisions for the team at the Boston office. § Performed technical diligence on a Vida investment (Kinnate Biopharma, Series B closed Dec. 2019). 4 Fall 2018 Merrimack Pharmaceuticals (Cambridge, MA) Graduate Intern § Participated in the selective “Research Experience in Biopharma” course and interned at Merrimack Pharmaceuticals for the semester. § Assisted in target validation of the TNFRII preclinical immuno- oncology program (MM-401). Scientific Publications Freed-Pastor W*, Lambert LJ*, Mercer K, Pattada N, Garcia A, Ely Z, Hwang W, Lin L, Eng G, Westcott P, Yilmaz O, Jacks T (2020). Immunogenic models of pancreatic adenocarcinoma reveal the therapeutic benefit of novel checkpoint combinations. Manuscript under review (Nature). *Co-authors Lambert LJ, Muzumdar MD, Rideout III WM, Jacks T (2017). Chapter 15: Harnessing the Mouse for Biomedical Research, in Basic Science Methods for Clinical Researchers, ed. Jalali M, Saldanha FYL and Jalali M, Academic Press Wefers C, Lambert LJ, Torensma R, Hato SV (2015). Cellular immunotherapy in ovarian cancer: Targeting the stem of recurrence. Gynecologic Oncology 137(2) Lambert LJ, Walker S, Feltham J, Lee HJ, Reik W, Houseley J (2013). Etoposide Induces Nuclear Re-Localisation of AID. PLoS ONE 8(12) Teaching & Leadership Experience Sep. 2018- Co-Director, Industry Initiative team Present MIT Biotech Group (MBG) Fall 2017 Teaching Assistant, Hallmarks of Cancer (7.45/7.85), MIT Fall 2015 Teaching Assistant, Introductory Biology (7.016), MIT Awards & Grants • Koch Institute Graduate Fellowship (2018) • Praecis Pharmaceuticals MIT Presidential Fellowship (2014) • Radboud University Excellence Grant (2012) • Erasmus Lifelong Learning Training Grant (2011) 5 Acknowledgments I am extremely grateful for the past 6 years in the Jacks Lab. I have grown tremendously as a scientist, as a mentor, as an educator, and most of all as a person during my PhD. I firmly believe that the skills and life lessons instilled through my graduate training have prepared me well as I pursue the next chapter in my career. In the Jacks Lab, I have had the privilege to work alongside an amazing group of smart and passionate people. I have benefited so much from the experience and scientific knowledge shared, and the friendships formed along the way. Without the tireless dedication of many people in and outside the lab, support and advice from many colleagues, friends and loved ones, the work in this thesis would not have been possible. I have many people to thank… First and foremost, I would like to thank my thesis supervisor, Tyler, for letting me join the lab and for incredible mentorship during my graduate studies. From the early days in the lab, you have given me the freedom to pursue my interests in immunotherapy, trusted me to fail and succeed when I needed to, and through it all challenged me to think “two steps ahead”. I have also appreciated that you have always had my career at heart, and have allowed me to explore my interests in biotech while completing my PhD. Your leadership, thoughtfulness, rigor and generosity are truly inspiring to me, and are qualities I will strive for in the rest of my career. I would also like to thank my thesis committee members, Matt and Jackie. I have benefited tremendously from your scientific insights, guidance and mentorship during my time at MIT. It was always a pleasure to share the latest updates on my science with you during my committee meetings, and I will truly miss having these stimulating conversations moving forward. The classes I took as a TA in 7.45/7.85 Cancer Biology were one of the most memorable courses I took while at MIT-- thank you making them so fun and interactive, Matt. I would also like to thank Vijay Kuchroo for agreeing to be my external thesis defense member, and I look forward to discussing pancreatic tumor immunology with a true leader in the field. I would like to thank Will, for being an amazing collaborator and a great friend. Your incredible drive, intellect, and dedication has pushed our shared science to greater heights. Thank you for always being willing to do the crazy experiments, for challenging the status quo, and for your unrelenting excitement when making new discoveries. I will miss our comradery, wide-ranging discussions on anything pancreatic or immunology- related, and yes maybe even 4 am scRNA-seq harvests. Those were days... I would like to thank the Jacks Lab members who keep our lab running: Judy, Karen, Kate, Kim, and Margaret. Thank you for helping me with countless things during my time in the lab, and for your selfless efforts to make sure the lab is clean, continued to operate 6 smoothly and remained in stable financial waters. I really appreciate everything you have done. Thank you to Kim for your generosity, support, and friendship. Your dedication to the mouse colony and
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