Integrating Systems Biology and an Ex Vivo Human Tumor Model Elucidates PD-1 Blockade Response Dynamics
Munisha Smalley,
Michelle Przedborski,
Saravanan Thiyagarajan,
Moriah Pellowe,
Amit Verma,
Nilesh Brijwani,
Debika Datta,
Misti Jain,
Basavaraja U. Shanthappa,
Vidushi Kapoor,
Kodaganur S. Gopinath,
D.C. Doval,
K.S. Sabitha,
Gaspar Taroncher-Oldenburg,
Biswanath Majumder,
Pradip Majumder,
Mohammad Kohandel,
Aaron Goldman
Affiliations
Munisha Smalley
Integrative Immuno-Oncology Center, Mitra Biotech, Woburn, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA; Division of Engineering in Medicine, Brigham and Women's Hospital, Boston, MA, USA
Michelle Przedborski
University of Waterloo, Department of Applied Mathematics, Waterloo, ON N2L 3G1, Canada
Saravanan Thiyagarajan
Integrative Immuno-Oncology Center, Mitra Biotech, Woburn, MA, USA
Moriah Pellowe
University of Waterloo, Department of Applied Mathematics, Waterloo, ON N2L 3G1, Canada
Amit Verma
Max Super Speciality Hospital, New Delhi, India
Nilesh Brijwani
Integrative Immuno-Oncology Center, Mitra Biotech, Woburn, MA, USA
Debika Datta
Integrative Immuno-Oncology Center, Mitra Biotech, Woburn, MA, USA
Misti Jain
Integrative Immuno-Oncology Center, Mitra Biotech, Woburn, MA, USA
Basavaraja U. Shanthappa
Integrative Immuno-Oncology Center, Mitra Biotech, Woburn, MA, USA
Vidushi Kapoor
Integrative Immuno-Oncology Center, Mitra Biotech, Woburn, MA, USA
Kodaganur S. Gopinath
Bangalore Institute of Oncology, Bangalore, India
D.C. Doval
Rajiv Gandhi Cancer Institute & Research Centre, New Delhi, India
K.S. Sabitha
Kidwai Memorial Institute of Oncology, Bangalore, India
Gaspar Taroncher-Oldenburg
Gaspar Taroncher-Oldenburg Consulting, Philadelphia, PA, USA
Biswanath Majumder
Integrative Immuno-Oncology Center, Mitra Biotech, Woburn, MA, USA
Pradip Majumder
Integrative Immuno-Oncology Center, Mitra Biotech, Woburn, MA, USA
Mohammad Kohandel
University of Waterloo, Department of Applied Mathematics, Waterloo, ON N2L 3G1, Canada; Corresponding author
Aaron Goldman
Department of Medicine, Harvard Medical School, Boston, MA, USA; Division of Engineering in Medicine, Brigham and Women's Hospital, Boston, MA, USA; Corresponding author
Summary: Ex vivo human tumor models have emerged as promising, yet complex tools to study cancer immunotherapy response dynamics. Here, we present a strategy that integrates empirical data from an ex vivo human system with computational models to interpret the response dynamics of a clinically prescribed PD-1 inhibitor, nivolumab, in head and neck squamous cell carcinoma (HNSCC) biopsies (N = 50). Using biological assays, we show that drug-induced variance stratifies samples by T helper type 1 (Th1)-related pathways. We then built a systems biology network and mathematical framework of local and global sensitivity analyses to simulate and estimate antitumor phenotypes, which implicate a dynamic role for the induction of Th1-related cytokines and T cell proliferation patterns. Together, we describe a multi-disciplinary strategy to analyze and interpret the response dynamics of PD-1 blockade using heterogeneous ex vivo data and in silico simulations, which could provide researchers a powerful toolset to interrogate immune checkpoint inhibitors.
