Walsh et al. investigated the balance of antitumor immunity and autoimmunity by treating RIP-gp33 mice (which transgenically express the LCMV gp33 antigen on pancreatic β islet cells) bearing B16-gp33 tumors with gp33-specific TCM cells and a gp33-expressing VSV oncolytic virus (to boost T cell expansion). Tumor regression was coupled with the development of severe diabetes which was associated with elevated plasma IFNα/β levels. Diabetes onset depended on IFNα/β-induced upregulation of MHC-I expression on islet cells and was abrogated in IFNAR1-/- mice or when using a non-inflammatory vaccinia virus without impacting therapeutic efficacy.
Despite showing success in treating melanoma and haematological malignancies, adoptive cell therapy (ACT) has generated only limited effects in solid tumors. This is, in part, due to a lack of specific antigen targets, poor trafficking/infiltration and immunosuppression in the tumor microenvironment. In this study, we combined ACT with oncolytic virus vaccines (OVV) 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 consequence when the antigen targeted was a self-protein. However, modulation of IFNalpha/beta signaling, either by functional blockade or rational choice of an OVV backbone, ameliorated autoimmune side effects without compromising antitumor efficacy. Our study uncovers a pathogenic role for IFNalpha/beta in facilitating autoimmune toxicity during cancer immunotherapy and offers a safe and powerful combinatorial regimen with immediate translational applications.
Author Info: (1) (2) (3) (4) (5) (6) (7) (8) (9) (10)
Author Info: (1) (2) (3) (4) (5) (6) (7) (8) (9) (10)
