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Full text release has been delayed at the author's request until December 15, 2029

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Understanding the Impact of Immune Populations on Anti-PD1 mAb Pharmacokinetics and Efficacy in Murine Models of Immune Checkpoint Inhibitor Resistance

Thomas, Justin
http://orcid.org/0000-0002-6496-6387
http://rave.ohiolink.edu/etdc/view?acc_num=osu1730734376055543

Abstract Details

2024, Doctor of Philosophy, Ohio State University, Pharmaceutical Sciences.
Immune checkpoint inhibitors (ICIs), and immunotherapy as a whole, have been the at the forefront of cancer research for the past two decades. They have revolutionized the oncology field, and their efficacy has helped cure cancer patients, not just treat them. However, for reasons unknown, only 25-45% of patients respond to treatment. Mechanisms of ICI resistance are poorly understood and there are few biomarkers available to identify patients that will respond. Two factors associated with ICI resistance are cancer cachexia-associated increases in exogenous mAb clearance (CL) and the sex-dependent differences in nuclear hormone signaling. In this dissertation, I describe novel immune-intrinsic cancer-induced fluctuations in expression of the neonatal Fc receptor (FcRn). I also determined that in mice absent FcRn:ICI binding, cachexia-associated increased ICI CL disappears, suggesting the role of this receptor in cachexia-induced elevated ICI CL. In a separate tumor model of ICI resistance, female mice were treated with anti-PD1 in combination with two structurally distinct estrogen receptor beta (ERβ) agonists – OSU-ERβ-12 and LY500307. Tumor growth was limited in the combination treatment groups, and in a dose-dependent fashion in the OSU-ERβ-12-treated mice. Splenic immunophenotyping suggests the synergistic effects of the ERβ agonists and anti-PD1 in modulating tumor growth were due to immune activation, rather than direct action on the tumor. Together, these studies advance our knowledge of immune checkpoint inhibitor resistance mechanisms and how to overcome them.
Christopher Coss (Advisor)
Emanuele Cocucci (Committee Member)
Thomas Mace (Committee Member)
Mitch Phelps (Advisor)
160 p.
Pharmaceuticals; Pharmacology
Immunotherapy; Pharmacokinetics; Anti-PD1; Drug Resistance; Estrogen Receptor Beta; FcRn

Recommended Citations

Citations

  • Thomas, J. (2024). Understanding the Impact of Immune Populations on Anti-PD1 mAb Pharmacokinetics and Efficacy in Murine Models of Immune Checkpoint Inhibitor Resistance [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1730734376055543

    APA Style (7th edition)

  • Thomas, Justin. Understanding the Impact of Immune Populations on Anti-PD1 mAb Pharmacokinetics and Efficacy in Murine Models of Immune Checkpoint Inhibitor Resistance. 2024. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1730734376055543.

    MLA Style (8th edition)

  • Thomas, Justin. "Understanding the Impact of Immune Populations on Anti-PD1 mAb Pharmacokinetics and Efficacy in Murine Models of Immune Checkpoint Inhibitor Resistance." Doctoral dissertation, Ohio State University, 2024. http://rave.ohiolink.edu/etdc/view?acc_num=osu1730734376055543

    Chicago Manual of Style (17th edition)

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© 2024, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.
Release 3.2.12