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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 Vaccines

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 2

Tumor regression is coupled with autoimmune diabetes, and both clinical events are CD8+ T cell dependent.

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Tumor regression is coupled with autoimmune diabetes, and both clinical ...
(A and F) gp33-specific CD8+ T cell responses were evaluated in B16-gp33 tumor–bearing RIP-gp mice at the designated time point after administration of the indicated treatment (0 dpi) and are expressed as the percentage of peripheral circulation CD8+ T cells that produced IFN-γ upon stimulation with the gp33 peptide. (B and G) Tumor volume (mm3) was assessed at the indicated time points. (C and I) Survival of and (D and H) percentage of diabetes in the treated mice. Results of the combination therapy (A–D) and the effect of T cell subset depletion (F–I). Shown in E are representative pancreatic sections from treated mice probed immunohistochemically with an anti-insulin mAb. Scale bars: 20 μm. Data for A–C represent 1 of 3 experiments; n = 4 per group (VSV-gp33) and n = 5 per group (PBS, P14TCM cells, VSV-GFP, P14TCM cells plus VSV-GFP. Data for F–I are representative of 2 independent experiments; n = 5 per group (anti-CD8 [α-CD8] and anti-CD4 [α-CD4]) and n = 4 per group (anti-isotype [α-Isotype]). *P < 0.05 and **P < 0.01, by 1-way ANOVA with Holm-Sidak correction for multiple comparisons (A and F) and log-rank (Mantel-Cox) test (C, D, H, and I).
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