Abstract :
Byline: Mohammad Jafarnejad (1), Chang Gong (1), Edward Gabrielson (2,3), Imke H. Bartelink (4,5), Paolo Vicini (6), Bing Wang (4,7), Rajesh Narwal (8), Lorin Roskos (8), Aleksander S. Popel (1,2) Keywords: immune checkpoint inhibitors; immuno-oncology; immunotherapy; non-small cell lung cancer; quantitative systems pharmacology Abstract: Immunotherapy and immune checkpoint blocking antibodies such as anti-PD-1 are approved and significantly improve the survival of advanced non-small cell lung cancer (NSCLC) patients, but there has been little success in identifying biomarkers capable of separating the responders from non-responders before the onset of the therapy. In this study, we developed a quantitative system pharmacology (QSP) model to represent the anti-tumor immune response in human NSCLC that integrated our knowledge of tumor growth, antigen processing and presentation, T cell activation and distribution, antibody pharmacokinetics, and immune checkpoint dynamics. The model was calibrated with the available data and was used to identify potential biomarkers as well as patient-specific response based on the patient parameters. The model predicted that in addition to tumor mutational burden (TMB), a known biomarker for anti-PD-1 therapy in NSCLC, the number of effector T cells and regulatory T cells in the tumor and blood is a predictor of the responders. Furthermore, the model simulated a set of 12 patients with known TMB and MHC/antigen-binding affinity from a recent clinical trial (ClinicalTrials.gov number, NCT02259621) on neoadjuvant nivolumab therapy in resectable lung cancer and predicted an augmented durable response in patients with adjuvant nivolumab treatment in addition to the clinical trial protocol of neoadjuvant nivolumab treatment followed by resection. Overall, the model provides a valuable framework to model tumor immunity and response to immune checkpoint blockers to enhance biomarker discovery and performing virtual clinical trials to aid in design and interpretation of the current trials with fewer patients. Author Affiliation: (1) 0000 0001 2171 9311, grid.21107.35, Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA (2) 0000 0001 2171 9311, grid.21107.35, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA (3) 0000 0001 2171 9311, grid.21107.35, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA (4) Clinical Pharmacology, Pharmacometrics and DMPK (CPD), MedImmune, South San Francisco, CA, USA (5) 0000 0004 1754 9227, grid.12380.38, Department of Clinical Pharmacology and Pharmacy, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands (6) 0000 0004 5929 4381, grid.417815.e, Clinical Pharmacology, Pharmacometrics and DMPK, MedImmune, Cambridge, UK (7) Amador Bioscience Inc., Pleasanton, CA, USA (8) grid.418152.b, MedImmune, Gaithersburg, MD, USA Article History: Registration Date: 07/06/2019 Received Date: 01/03/2019 Accepted Date: 07/06/2019 Online Date: 24/06/2019 Article note: Electronic supplementary material The online version of this article (https://doi.org/10.1208/s12248-019-0350-x) contains supplementary material, which is available to authorized users.