Journal Article

IFN-γ–related mRNA profile predicts clinical response to PD-1 blockade

Murphy, Erin, Loboda, Andrey, Shankaran, Veena, Seiwert, Tanguy Y., Ribas, Antoni, Piha-Paul, Sarina A., McClanahan, Terrill K., Albright, Andrew, Kang, S. Peter, Lunceford, Jared, Kaufman, David R., Cheng, Jonathan D., Ayers, Mark, Yearley, Jennifer, Nebozhyn, Michael

2017

Overview

Programmed death-1-directed (PD-1-directed) immune checkpoint blockade results in durable antitumor activity in many advanced malignancies. Recent studies suggest that IFN-γ is a critical driver of programmed death ligand-1 (PD-L1) expression in cancer and host cells, and baseline intratumoral T cell infiltration may improve response likelihood to anti-PD-1 therapies, including pembrolizumab. However, whether quantifying T cell-inflamed microenvironment is a useful pan-tumor determinant of PD-1-directed therapy response has not been rigorously evaluated. Here, we analyzed gene expression profiles (GEPs) using RNA from baseline tumor samples of pembrolizumab-treated patients. We identified immune-related signatures correlating with clinical benefit using a learn-and-confirm paradigm based on data from different clinical studies of pembrolizumab, starting with a small pilot of 19 melanoma patients and eventually defining a pan-tumor T cell-inflamed GEP in 220 patients with 9 cancers. Predictive value was independently confirmed and compared with that of PD-L1 immunohistochemistry in 96 patients with head and neck squamous cell carcinoma. The T cell-inflamed GEP contained IFN-γ-responsive genes related to antigen presentation, chemokine expression, cytotoxic activity, and adaptive immune resistance, and these features were necessary, but not always sufficient, for clinical benefit. The T cell-inflamed GEP has been developed into a clinical-grade assay that is currently being evaluated in ongoing pembrolizumab trials.

• Publisher: American Society for Clinical Investigation
• Subject: Adaptation / Antibodies, Monoclonal, Humanized - therapeutic use / Antigen presentation / Antineoplastic Agents - therapeutic use / Antitumor activity / Apoptosis / B7-H1 Antigen - metabolism / Biology / Biomedical research / Biopsy / Cancer therapies / Carcinoma - drug therapy / Carcinoma - immunology / Carcinoma, Non-Small-Cell Lung - drug therapy / Carcinoma, Non-Small-Cell Lung - immunology / Chemokines / Clinical trials / Cytokines / Cytotoxicity / Gene expression / Gene Expression Profiling / Gene Expression Regulation, Neoplastic / Head & neck cancer / Humans / Immune checkpoint / Immune System / Immunohistochemistry / Inflammation / Interferon / Interferon-gamma - metabolism / Ligands / Lung cancer / Lung Neoplasms - drug therapy / Lung Neoplasms - immunology / Lymphocytes / Lymphocytes T / Melanoma / Melanoma - drug therapy / Melanoma - immunology / Metastases / Monoclonal antibodies / PD-1 protein / PD-L1 protein / Pilot Projects / Programmed Cell Death 1 Receptor - antagonists & inhibitors / Programmed Cell Death 1 Receptor - metabolism / ROC Curve / Sequence Analysis, RNA / Signal Transduction / Skin Neoplasms - drug therapy / Skin Neoplasms - immunology / Squamous cell carcinoma / Stomach Neoplasms - drug therapy / Stomach Neoplasms - immunology / Targeted cancer therapy / Treatment Outcome / Tumor Microenvironment / Tumors