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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 1

Combination TCM cell ACT plus OVV targeting DCT induces complete tumor regression coupled with localized vitiligo.

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Combination TCM cell ACT plus OVV targeting DCT induces complete tumor r...
(A) DCT-specific CD8+ T cell responses were evaluated in B16F10 tumor–bearing C57BL6 mice at the designated time point after administration of the indicated treatment, with 0 dpi representing the day of OV injection and results expressed as the percentage of CD8+ T cells in the peripheral circulation that produced IFN-γ upon stimulation with the immunodominant DCT peptide. (B) Tumor volume (mm3) was assessed on the indicated post-infection days. (C) Survival of the treated mice. (D) Representative image of vitiligo (indicated by white arrows) on the backs of 2 of the treated mice. Data for A–C are representative of 2 independent experiments (n = 5 per group) and are shown as the mean ± SD. **P < 0.01 and ****P < 0.0001, by 1-way ANOVA with Holm-Sidak correction for multiple comparisons (A) and log-rank (Mantel-Cox) test (C).
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