Abstract

BACKGROUND: Concomitant tumor necrosis factor (TNF) neutralization in combination with immune checkpoint inhibitors (ICIs) reduces clinical immune-related adverse events (irAEs) and appears to improve antitumor efficacy in preclinical tumor models. Agonistic antibodies targeting costimulatory receptors such as CD40 represent an additional strategy to boost antitumor immune response and potentiate the activity of ICIs. However, the dose-limiting toxicities observed in anti-CD40-treated cancer patients have hindered its clinical development. METHODS: ) mice, transient depletion of T regulatory cells (Tregs) prior to immunotherapy with additional immunomodulatory antibodies, lowered immune self-tolerance, resulting in the development of a spectrum of physical and biochemical irAEs similar to that reported clinically. In MC38 and 4T1.2 tumor models, following transient Treg depletion, we evaluated the impact of anti-CD40 on antitumor efficacy and the development of irAEs and the impact of concomitant or delayed TNF blockade on both these parameters. Physical irAEs were scored and biochemical irAEs were measured in the serum (ALT and cytokine levels). Histopathological liver and colon tissue analysis were performed to assess immune cell infiltration and tissue damage. RESULTS: mice. Delaying TNF blockade in these mice reduced biochemical but not physical irAEs while preserving antitumor efficacy. CONCLUSIONS: Our results suggest concomitant rather than delayed anti-TNF is most effective in reducing biochemical and physical irAEs induced by anti-CD40, although it had the potential to negatively impact antitumor efficacy. Furthermore, our findings highlight the utility of our mouse model to assess the severity of irAEs induced by novel immunotherapeutic agents and evaluate whether their toxicity and antitumor efficacy can be uncoupled.

Authors	Jacoberger-Foissac, Celia; Blake, Stephen J; Liu, Jing; McDonald, Elizabeth; Triscott, Hannah; Nakamura, Kyohei; Smyth, Mark J; Teng, Michele Wl
Journal	Journal for immunotherapy of cancer
Pages
Volume	8
Date	1/11/2020
Grant ID	1159655
Funding Body	NH&MRC Career Development Fellowship
URL	http://www.ncbi.nlm.nih.gov/pubmed/?term=10.1136/jitc-2020-001687
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