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Type I IFN blockade uncouples immunotherapy-induced antitumor immunity and autoimmune toxicity
Scott R. Walsh, … , John C. Bell, Yonghong Wan
Scott R. Walsh, … , John C. Bell, Yonghong Wan
Published November 13, 2018
Citation Information: J Clin Invest. 2019;129(2):518-530. https://doi.org/10.1172/JCI121004.
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Research Article Autoimmunity

Type I IFN blockade uncouples immunotherapy-induced antitumor immunity and autoimmune toxicity

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Abstract

Despite its success in treating melanoma and hematological malignancies, adoptive cell therapy (ACT) has had only limited effects in solid tumors. This is due in part to a lack of specific antigen targets, poor trafficking and infiltration, and immunosuppression in the tumor microenvironment. In this study, we combined ACT with oncolytic virus vaccines (OVVs) to drive expansion and tumor infiltration of transferred antigen-specific T cells and demonstrated that the combination is highly potent for the eradication of established solid tumors. Consistent with other successful immunotherapies, this approach elicited severe autoimmune consequences when the antigen targeted was a self-protein. However, modulation of IFN-α/-β signaling, either by functional blockade or rational selection of an OVV backbone, ameliorated autoimmune side effects without compromising antitumor efficacy. Our study uncovers a pathogenic role for IFN-α/-β in facilitating autoimmune toxicity during cancer immunotherapy and presents a safe and powerful combinatorial regimen with immediate translational applications.

Authors

Scott R. Walsh, Donald Bastin, Lan Chen, Andrew Nguyen, Christopher J. Storbeck, Charles Lefebvre, David Stojdl, Jonathan L. Bramson, John C. Bell, Yonghong Wan

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Figure 3

VSV-induced inflammation is required for diabetes and features excessive systemic IFN-α/-β levels.

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VSV-induced inflammation is required for diabetes and features excessive...
(A) Schematic representation of the experimental protocol and phenotypic analysis of gp33-tetramer–positive CD8+ T cells in the transferred cell population. (B) The quantity of gp33-specific CD8+ T cells in the circulation 1 day after T cell infusion into B16-gp33 tumor–bearing RIP-gp mice was determined by IFN-γ staining. Tumor volume (C) and diabetes development (D) were assessed on the indicated days post transfer (dpt) (**P = 0.0027). Data for B–D represent 1 of 3 experiments (n = 5 per group) and are shown as the mean ± SD. Data were analyzed using a 2-tailed Student’s t test (B) and a log-rank (Mantel-Cox) test (D).

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