A novel mouse model for checkpoint inhibitor-induced adverse events

Abstract

Immune checkpoint inhibitors have demonstrated significant efficacy in the treatment of a variety of cancers, however their therapeutic potential is limited by abstruse immune related adverse events. Currently, no robust animal model exists of checkpoint inhibitor-induced adverse events. Establishing such a model will improve our mechanistic understanding of this process, which in turn will inform design of improved therapies. We developed a mouse model to determine inflammatory toxicities in response to dual checkpoint blockade in the presence of syngeneic tumors. Mice from susceptible genetic backgrounds received intraperitoneal injections of anti-mouse PD-1 and CTLA-4 antibodies. The mice were monitored for weight loss and histologic evidence of inflammation. Blood was collected for basic metabolic panels and titers of anti-nuclear antibodies. In parallel, mice were also treated with prednisolone, which is commonly used to treat immune related adverse events among cancer patients. Among all the genetic backgrounds, B6/lpr mice treated with anti-CTLA-4 and anti-PD-1 antibodies developed more substantial hepatitis, pancreatitis, colitis, and pneumonitis characterized by organ infiltration of immune cells. Mice that developed tissue infiltration demonstrated high serum levels of glucose and high titers of anti-nuclear antibodies. Finally, while administration of prednisolone prevented the development of the inflammatory adverse events, it also abrogated the protective anti-tumor effect of the checkout inhibitors. Genetic background and treatment modalities jointly modified the inflammatory adverse events in tumor bearing mice, suggesting a complex mechanism for checkpoint inhibitor-related inflammation. Future studies will assess additional genetic susceptibility factors and will examine possible contributions from the administration of other anti-inflammatory drugs.

Inhibition of the IL-17A axis Protects against Immune-related Adverse Events while Supporting Checkpoint Inhibitor Anti-tumor Efficacy

“…A primary consideration in the development of strategies to reduce IrAE must be the preservation of anti-cancer effects of ICI. Early efforts using glucocorticoids for IrAE treatment inconsistently reversed autoimmunity or compromised anti-cancer effects 5,19 . In addition, previous studies have shown reduction of thyroid IrAE by elimination of CD4 + T cells 26 , but this is not readily translatable to cancer patients given the importance of CD4 + T cells in cellmediated immunity 36,68 .…”

“…While prior studies have reported autoimmunity in ICI-treated mice, these models on the C57BL/6 (B6) background developed minimal ICI-IrAEs. Augmenting these mild phenotypes required significant manipulation, such as regulatory T cell depletion , genetic knock-in of human checkpoint proteins 24 , chemical stimulants 25 or co-administration of complete Freund's adjuvant 19 .…”

“…To develop ICI therapies with less toxicity while preserving anti-tumor efficacy, we must determine the cause of IrAE. Currently guidelines recommend suspension immunotherapy and high dose glucocorticoid therapy for severe manifestations (grade 3 or 4) of most IrAE 17,18 , which may unnecessarily impair the efficacy of ICI cancer treatment for many patients 5,19 . It is now recognized that high dose glucocorticoid therapy does not attenuate or prevent thyroiditis, hypophysitis, or diabetes, and correlates with shorter overall survival 12,20,21 .…”

Mechanisms of immune checkpoint inhibitor-mediated liver injury

“…Importantly, while ILICI shares some features of autoimmune hepatitis (AIH), the number of plasma cell infiltrates in this study was far less than what is seen in classic AIH 116 . In animal models of ICIs both CD4 + and CD8 + T cells infiltrates have been noted in the liver 117 . Johncilla et al.…”

Emerging Next-Generation Target for Cancer Immunotherapy Research: The Orphan Nuclear Receptor NR2F6

“…This finding strongly suggests that NR2F6 might be an inducible and thus highly localized immune checkpoint at the tumor site. Of note, and in stark contrast, mice treated with a combination of anti-mouse PD-1 and CTLA-4 antibodies have been reported to develop severe diseases characterized by organ infiltration of immune cells [ 64 ].…”