Why is the clearance of immune checkpoint inhibitor (ICI) therapies linked to progression-free and overall survival in cancer patients?

For pharmacologists, the answer to this question seems obvious – higher drug clearance leads to lower drug exposure and therefore less effect on the drug target. However, the problem is much more complex with ICIs, which have dramatically changed the clinical landscape over the past decade for many solid tumors where limited effective therapies were available. Despite the advances with ICIs, still only a subset of patients respond, and those who do may develop refractory disease within a short time period. This project aims to discover the underlying mechanisms linking elevated ICI clearance and poor outcomes, which seems to be more prevalent in patients with cancer-associated muscle wasting disease, or cachexia. Within this translational research project we are using murine cancer cachexia models to explore specific pathways involved in antibody drug clearance and acquiring data and samples within IRB approved clinical trials where patients are receiving ICI or other antibody drugs as either standard-of-care or within experimental combination drug regimens. With improved understanding of the underlying mechanisms involved, we hope to be able to identify patients less likely to respond to ICI therapy and develop combination therapies with ICIs and other agents that can improve outcomes in these patients.

Publications related to this project:

1. Castillo AMM, Vu TT, Liva SG, Chen M, Xie Z, Thomas J, Remaily B, Guo Y, Subrayan UL, Costa T, Helms TH, Irby DJ, Kim K, Owen DH, Kulp SK, Mace TA, Phelps MA, Coss CC. Single-dose pembrolizumab in murine cancer-cachexia models replicates elevated catabolic pembrolizumab clearance in humans. JCSM Rapid Communications. https://onlinelibrary.wiley.com/doi/full/10.1002/rco2.32.
2. Jain R, Coss C, Whooley P, Phelps M, Owen DH. The Role of Malnutrition and Muscle Wasting in Advanced Lung Cancer. Curr Oncol Rep. 2020 May 15;22(6):54. doi: 10.1007/s11912-020-00916-9. PMID: 32409907.
3. Liva SG, Tseng YC, Dauki AM, Sovic MG, Vu T, Henderson SE, Kuo YC, Benedict JA, Zhang X, Remaily BC, Kulp SK, Campbell M, Bekaii-Saab T, Phelps MA, Chen CS,  Coss CC. Overcoming resistance to anabolic SARM therapy in experimental cancer cachexia with an HDAC inhibitor. EMBO Mol Med. 2020 Feb 7;12(2):e9910. doi: 10.15252/emmm.201809910. Epub 2020 Jan 13. PMID: 31930715. PMCID: PMC7005646.
4. Badawi M, Coss CC, Phelps MA. Letter to the Editor: Exposure-response or clearance-response relationship in immune checkpoint therapy?-A comment on ‘correlation between nivolumab exposure and treatment outcomes in non-small-cell lung cancer’ by Basak et al. Eur J Cancer. 2019 Jun;114:25-26. Epub 2019 Apr 19. doi: 10.1016/j.ejca.2019.02.017. PMID: 31009820. 
5. Coss CC, Clinton SK, Phelps MA. Cachectic Cancer Patients: Immune to Checkpoint Inhibitor Therapy? Clin Cancer Res. 2018 Dec 1;24(23):5787-5789. Epub 2018 Jul 17. doi: 10.1158/1078-0432.CCR-18-1847. PMID: 30018117. PMCID: PMC6279566.

Relevant Abstracts and Presentations:

1. Vu TT, Castillo AMM, Chen M, Xie Z, Thomas J, Guo Y, Remaily B, Subrayan UL, Costa T, Helms TH, Liva SG, Kulp SK,. Mace TA, Coss CC, Phelps MA. Murine Models of Cancer Cachexia Display Elevated Catabolic Clearance of Pembrolizumab. American Society for Clinical Pharmacology and Therapeutics Annual Meeting, online/virtual, 2021
2. Phelps MA. “Antibody Drug Clearance as a Biomarker for Outcomes with Immune Checkpoint Inhibitor Therapy”. University of Illinois Chicago College of Pharmacy, Department of Pharmacy Practice Research Seminar Series. October 14, 2020. https://www.youtube.com/watch?v=oYPNa23G4OU&feature=youtu.be 
3. SG Liva, A Mortazavi, K Dittmar, AR Walker, CC Hofmeister, MA Phelps, CC Coss. AR-42 pharmacokinetics: estimated versus measured patient body composition. American Association of Pharmaceutical Scientists Annual Meeting, Washington, DC, November 2018. 
4. Hugo Valencia, Herbert Newton, Erinn M. Hade, Douglas W. Sborov, Robert Cavaliere, Ming Poi, Mitch A. Phelps, Christopher C. Coss, Jiang Wang, Soun Khountham, J. Paul Monk, Thomas E. Olencki, Charles L. Shapiro, Richard Piekarz, Craig C. Hofmeister, Michael R. Grever, D. Bradley Welling, Amir Mortazavi. A phase 1 study of AR-42 in patients with advanced solid tumors, including nervous system tumors. American Society of Clinical Oncology Annual Meeting, Chicago, IL, 2016.