A Computational Model of Neoadjuvant PD-1 Inhibition in Non-Small Cell Lung Cancer

Mohammad Jafarnejad, Chang Gong, Edward Gabrielson, Imke H. Bartelink, Paolo Vicini, Bing Wang, Rajesh Narwal, Lorin Roskos, Aleksander S Popel

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number79
JournalAAPS Journal
Volume21
Issue number5
DOIs
StatePublished - Sep 1 2019

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Non-Small Cell Lung Carcinoma
Biomarkers
Neoadjuvant Therapy
Antigen Presentation
Clinical Trials
Clinical Protocols
Tumor Burden
T-Lymphocytes
Neoplasms
Blocking Antibodies
Neoplasm Antigens
Regulatory T-Lymphocytes
Immunotherapy
Immunity
Lung Neoplasms
Therapeutics
Pharmacokinetics
Pharmacology
Antigens
Survival

Keywords

  • immune checkpoint inhibitors
  • immuno-oncology
  • immunotherapy
  • non-small cell lung cancer
  • quantitative systems pharmacology

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

A Computational Model of Neoadjuvant PD-1 Inhibition in Non-Small Cell Lung Cancer. / Jafarnejad, Mohammad; Gong, Chang; Gabrielson, Edward; Bartelink, Imke H.; Vicini, Paolo; Wang, Bing; Narwal, Rajesh; Roskos, Lorin; Popel, Aleksander S.

In: AAPS Journal, Vol. 21, No. 5, 79, 01.09.2019.

Research output: Contribution to journalArticle

Jafarnejad, M, Gong, C, Gabrielson, E, Bartelink, IH, Vicini, P, Wang, B, Narwal, R, Roskos, L & Popel, AS 2019, 'A Computational Model of Neoadjuvant PD-1 Inhibition in Non-Small Cell Lung Cancer', AAPS Journal, vol. 21, no. 5, 79. https://doi.org/10.1208/s12248-019-0350-x
Jafarnejad, Mohammad ; Gong, Chang ; Gabrielson, Edward ; Bartelink, Imke H. ; Vicini, Paolo ; Wang, Bing ; Narwal, Rajesh ; Roskos, Lorin ; Popel, Aleksander S. / A Computational Model of Neoadjuvant PD-1 Inhibition in Non-Small Cell Lung Cancer. In: AAPS Journal. 2019 ; Vol. 21, No. 5.
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