Date Published: June 24, 2019
Publisher: Springer International Publishing
Author(s): Mohammad Jafarnejad, Chang Gong, Edward Gabrielson, Imke H. Bartelink, Paolo Vicini, Bing Wang, Rajesh Narwal, Lorin Roskos, Aleksander S. Popel.
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.
Lung cancer, predominantly non-small cell lung cancer (NSCLC), has been the leading cause of cancer-related mortality worldwide with consistently poor prognosis due to late diagnosis and lack of effective treatment strategies for late-stage cases. Chemotherapy and targeted therapies for NSCLC have shown to improve the survival, but often lack durable response. The approval of immune checkpoint blocking antibodies has revolutionized the treatment strategies for patients with advanced forms of lung cancer in the past few years (1). In particular, approved antibodies against PD-1 (nivolumab (2–4) and pembrolizumab (5–7)), PD-L1 (atezolizumab (8) and durvalumab (9)), and combination of nivolumab and anti-CTLA-4 (ipilimumab) (10) have significantly improved the overall survival of the advanced NSCLC patients. However, effective therapies that can replace or complement the current standard-of-care for early-stage NSCLC are lacking (11). A recent small clinical trial investigated the role of neoadjuvant nivolumab therapy for early-stage resectable NSCLC patients (11). Nivolumab treatment showed major pathological response in 45% of the resected tumor without delaying the surgery and resulted in expansion of T cell clones against the tumor antigens.
Despite the remarkable success of immune checkpoint inhibitors in clinical trials, our understanding of the intricacies associated with anti-tumor immune response is limited. The quantitative systems pharmacology modeling offers valuable insight by integrating various experimental and clinical data to enhance our understanding of the cancer growth and anti-tumor immune response. The model presented in this study aims at including many important biological processes such as cancer cell growth, antigen release, antigen processing and presentation by APC, T cell activation, proliferation and infiltration to tumor, cancer cell killing, and mechanisms of T cell inhibition and exhaustion. In particular, the model includes a detailed expression of the antigen presentation that allows us to directly use patient-specific antigen strength data available from recent clinical trials (11,28). The model was developed and parameterized based on a variety of experimental and clinical data in the literature with extensive emphasis on the use of the data from human sources to build confidence on the use of the model for clinical trials (11,29–31). The model showed to be capable of capturing the variety of the responses observed in the clinical trials. In particular, the model is able to capture the fast response observed within a few months in clinical trials of NSCLC (32). Furthermore, the model was able to point towards less discussed characteristics of the responders in this virtual in silico clinical trial and made predictions about scenarios that were not explored clinically.
In summary, by integrating our knowledge of anti-tumor immune response with detailed inclusion of antigen processing and presentation, we have built a comprehensive QSP model capable of explaining the modes of response based on patient characteristics. The model was calibrated based on the available clinical data on human NSCLC and was able to qualitatively reproduce the available experimental data. This model was utilized to explore the potential response in the patients from NCT02259621 trial that implemented neoadjuvant nivolumab therapy before surgical resection of the NSCLC tumors and showed the relative importance of TMB versus MHC/antigen binding affinity. With the expansion of the data collection in future clinical trials, including combination immunotherapies, this model can be further constrained for individual patients and patient cohorts using the information on tumor size and immune profiles in the blood and tumor samples to increase the patient-specific prediction power of the model.