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Bringing Til Therapy Beyond Melanoma: Advancing the Treatment of Advanced Pancreatic and Ovarian Cancers

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Bringing Til Therapy Beyond Melanoma: Advancing the Treatment of Advanced Pancreatic and Ovarian Cancers 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 8-2020 BRINGING TIL THERAPY BEYOND MELANOMA: ADVANCING THE TREATMENT OF ADVANCED PANCREATIC AND OVARIAN CANCERS Donald Sakellariou-Thompson Follow this and additional works at: https://digitalcommons.library.tmc.edu/utgsbs_dissertations Part of the Immunotherapy Commons, and the Medicine and Health Sciences Commons Recommended Citation Sakellariou-Thompson, Donald, "BRINGING TIL THERAPY BEYOND MELANOMA: ADVANCING THE TREATMENT OF ADVANCED PANCREATIC AND OVARIAN CANCERS" (2020). The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access). 1022. https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1022 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]. BRINGING TIL THERAPY BEYOND MELANOMA: ADVANCING THE TREATMENT OF ADVANCED PANCREATIC AND OVARIAN CANCERS by Donald Anastas Sakellariou-Thompson, B.S. APPROVED: ______________________________ Chantale Bernatchez, Ph.D. Co-Advisory Professor ______________________________ Patrick Hwu, M.D. Co-Advisory Professor _____________________________ Gregory Lizee, Ph.D. ______________________________ Carlos Antonio Torres-Cabala, M.D. ______________________________ Gheath Al-Atrash, D.O. ______________________________ Roza Nurieva, Ph.D. APPROVED: ____________________________ Dean, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences i BRINGING TIL THERAPY BEYOND MELANOMA: ADVANCING THE TREATMENT OF ADVANCED PANCREATIC AND OVARIAN CANCERS A DISSERTATION Presented to the Faculty of The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences in Partial Fulfillment of the Requirements for the Degree of DOCTOR OF PHILOSOPHY by Donald Anastas Sakellariou-Thompson, B.S. Houston, Texas AUGUST, 2020 ii Dedication The work of this dissertation is dedicated to my parents who always showed me the way and never stopped encouraging me. Σας αγαπώ πάρα πολύ. iii Acknowledgements The work in this dissertation would not have been possible without the tremendous support, guidance, encouragement, and collaboration of the so many wonderful people around me. I owe the greatest debt of gratitude to several people without whom none of this would have been possible. Chantale, your constant patience, encouragement, and support were a calming force that allowed me to keep pushing forward. Dr. Hwu, I appreciate you always challenging me to go further and providing inspiration through your dedication. Thank you both for taking a chance on me and giving me this opportunity. Cara and Marie, thank you for taking me under your wing. Your guidance, knowledge, infinite patience, and unwavering support were invaluable. It was an honor and a privilege to learn from all of you. I would also like to acknowledge the contributions of the rest of the current and former members of the Bernatchez lab, Haymaker lab, and Melanoma TIL Lab who were always willing to provide help, moral support, or have a silly chat, and without whom this experience would have been far less enjoyable. I have been fortunate to work with such amazing people. Thank you to the rest of my Advisory Committee members, past and present, for your commitment, advice, and encouragement. Thank you to all my amazing collaborators throughout MD Anderson, without whom I could not have completed this work. There is no better collaborative environment than here. Thank you to the administration, faculty, and staff at the GSBS for their help and understanding, and for creating a great environment in which to pursue our studies. Finally, to my family and friends, I don’t have the words to convey the depth of my gratitude. I would be nothing without your unconditional love, support, and encouragement. iv Abstract BRINGING TIL THERAPY BEYOND MELANOMA: ADVANCING THE TREATMENT OF ADVANCED PANCREATIC AND OVARIAN CANCERS Donald Sakellariou-Thompson, B.S. Advisory Professors: Chantale Bernatchez, Ph.D. Patrick Hwu, M.D. The success of checkpoint blockade immunotherapy (CBI) has reinvigorated the cancer therapy field, particularly for advanced melanoma which has doubled the survival rates compared to 20 years ago. However, there are many solid tumor types that are yet to receive substantial benefit from this ground breaking therapy, two of which are pancreatic cancer (PDAC) and ovarian cancer (OvCa). As such, the 5-year survival rate for PDAC and OvCa stand at 9% and 28% respectively. Despite the lack of efficacy of CBI so far, there is still evidence for the role of immune control in these cancers as evidenced by presence of tumor- infiltrating lymphocytes (TIL) correlating with increased survival. Since in vivo manipulation of TIL through CBI does not seem to be sufficient to generate a strong clinical response, approaches involving ex vivo manipulation of immune cells, such as adoptive cell therapy (ACT) using autologous TIL, might be able to provide therapeutic benefit. The effectiveness of TIL ACT has been demonstrated in metastatic melanoma with overall response rates around 50%. Given this success and the anti-tumor potential of the immune infiltrate in PDAC and OvCa, I sought to assess the feasibility of TIL ACT in these solid tumors. My work here has demonstrated the feasibility of TIL ACT for PDAC and OvCa by showing that they harbor an activated, anti-tumor CD8+ T-cell infiltrate that can be robustly and reliably expanded using an improved 3-signal culture method consisting of a CD3 stimulation, an v agonistic 4-1BB mAb, and high-dose IL-2. Additionally, these results show that TIL ACT for PDAC and OvCa is viable regardless of primary or metastatic site and regardless of prior chemotherapy. Furthermore, given the difficulty of treating PDAC, single-cell RNA sequencing was used to interrogate the immune landscape to further our understanding of the TIL heterogeneity in PDAC. Paired transcriptomic and T-cell receptor sequencing revealed novel TIL populations with potential prognostic and therapeutic implications. A Phase II clinical trial based on this work has been initiated at MDACC to evaluate the feasibility of the adoptive transfer of autologous TIL in recurrent or refractory PDAC and OvCa (NCT03610490). vi Table of Contents Approval Page ............................................................................................................................ i Title Page .................................................................................................................................. ii Dedication ............................................................................................................................................. iii Acknowledgements ............................................................................................................................... iv Abstract .................................................................................................................................................. v Table of Contents ................................................................................................................................. vii List of Figures ....................................................................................................................................... ix List of Tables .......................................................................................................................................... x Chapter 1: Introduction .......................................................................................................................... 1 1.1: The Immune System and Cancer ................................................................................................. 2 1.1.1 Innate Immunity .................................................................................................................... 3 1.1.2 In between innate and adaptive immunity ............................................................................. 5 1.1.3 Adaptive immunity ................................................................................................................ 6 1.1.4 T-cell differentiation and plasticity ....................................................................................... 9 1.1.5 Initiation of an adaptive immune response .......................................................................... 13 1.1.6 The immune surveillance of cancer ..................................................................................... 16 1.2: Cancer Immunotherapy ............................................................................................................. 18 1.2.1 Cytokine Therapy ................................................................................................................ 19 1.2.2 Immune Checkpoint Inhibitors ...........................................................................................
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