Type I IFN blockade uncouples immunotherapy-induced antitumor immunity and autoimmune toxicity
Scott R. Walsh, Donald Bastin, Lan Chen, Andrew Nguyen, Christopher J. Storbeck, Charles Lefebvre, David Stojdl, Jonathan L. Bramson, John C. Bell, Yonghong Wan
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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Research Article Autoimmunity

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

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 4

IFN-α/-β signaling couples diabetes with tumor regression.

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IFN-α/-β signaling couples diabetes with tumor regression. (A) Systemic ...
(A) Systemic levels of IFN-α and IFN-β induced by the combination therapy and each component when used alone, assayed in plasma from treated B16-gp33 tumor–bearing RIP-gp mice (n = 4). (B and E) gp33-specific CD8+ T cell responses, (C and F) tumor volume, and (D and G) percentage of mice with diabetes induced by the combination therapy were measured on the indicated dpi. (B–D) n = 10 RIP-gp mice and n = 8 RIP-gp/IFNAR–KO mice; (E–G) n = 10 anti-isotype Ab–treated RIP-gp mice and n = 8 anti-IFNAR Ab–treated RIP-gp mice. Data for B–G represent 1 of 3 experiments and are shown as the mean ± SD. *P < 0.05, **P < 0.01, and ****P < 0.0001, by 1-way ANOVA with Holm-Sidak correction for multiple comparisons (A), 2-tailed Student’s t test (B and E), and log-rank (Mantel-Cox) test (D and G).