Author ORCID Identifier
https://orcid.org/0000-0002-7744-2478
Date Available
7-20-2027
Year of Publication
2025
Document Type
Doctoral Dissertation
Degree Name
Doctor of Philosophy (PhD)
College
Pharmacy
Department/School/Program
Pharmaceutical Sciences
Faculty
Val R. Adams
Faculty
David J. Feola
Abstract
Cancers must evade the immune system to proliferate. Immune checkpoints are a system of receptors that attenuate immune response and is sometimes used by cancers to escape immune detection. Immune checkpoint inhibitors (ICIs) are a class of cancer medicines that block immune checkpoints receptors, thereby allowing immune cells to attack cancers.
Unfortunately, immune checkpoint receptor expression in cancers can be heterogenous throughout a tumor and change over time, making it challenging to predict response to ICI therapy. Determining whether a patient will benefit from ICI therapy is challenging and remains an unsolved problem.
Metabolic syndrome is associated with chronic inflammation involving obesity and dysregulation of blood pressure, blood sugar, cholesterol, and triglycerides. Some components are associated with cancers expressing more immune checkpoint receptors. Another form of chronic inflammation is chronic obstructive pulmonary disease (COPD) and is associated with immune cells that produce more immune checkpoint receptors.
We hypothesize that patients with chronic inflammation will experience greater benefit from immunotherapy versus patients without inflammatory disease.
We tested our hypothesis using a retrospective cohort study design. Diagnosis with COPD and-or metabolic syndrome was used as a measure of chronic inflammation. Time to treatment discontinuation (TTD) was used as a measure of benefit. Chronic inflammation, TTD, and potential confounders were abstracted from Marketscan, an insurance claims database. Disease risk score (DRS) adjustment was used to account for potential confounders. For each cohort, Cox regression was used to create a model predicting TTD for subjects who had neither COPD nor metabolic syndrome. The model was then applied to all subjects, and the log-hazard served as the DRS. The hazard ratio for chronic inflammation on TTD was then computed while adjusting for the DRS.
The effect of chronic inflammation on TTD was measured in seven cohorts: two for non-small cell lung cancer: nivolumab monotherapy and pembrolizumab monotherapy; two for advanced renal cancer: nivolumab monotherapy and nivolumab plus ipilimumab combination therapy and three for unresectable or metastatic melanoma: nivolumab monotherapy, nivolumab plus ipilimumab combination therapy, and pembrolizumab monotherapy.
Chronic inflammation was associated with benefit from immunotherapy in the nivolumab monotherapy cohort for subjects with unresectable or metastatic melanoma. This result was both statistically significant (HR=0.68 95% CI 0.49-0.93) and clinically important since the median time to therapy discontinuation was prolonged by approximately two months. Little or no association between chronic inflammation and benefit from immunotherapy were identified in the other cohorts.
Digital Object Identifier (DOI)
https://doi.org/10.13023/etd.2025.287
Funding Information
The research was supported in part from Bristol Myers Squibb and
The Center for Clinical and Translational Science (NIH grant # UL1TR001998)
The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. https://www.ccts.uky.edu/about-ccts/cite-ccts
Recommended Citation
Vanghelof, Joseph C., "Effect of Chronic Inflammation on Immunotherapy Benefit" (2025). Theses and Dissertations--Pharmacy. 169.
https://uknowledge.uky.edu/pharmacy_etds/169
