Abstract
Intermittent dosing of PI3Kδ inhibitors (PI3Kδi) reduces tumor growth and immune-related adverse events.
Major Finding: Intermittent dosing of PI3Kδ inhibitors (PI3Kδi) reduces tumor growth and immune-related adverse events.
Concept: Continuous dosing of PI3Kδi reduces systemic regulatory T cells, contributing to chronic inflammation.
Impact: This alternative dosing regimen could limit toxicity and allow use of these inhibitors for cancer treatment.
Inhibitors of phosphoinositide 3-kinase δ (PI3Kδi) have demonstrated immunomodulatory effects that contribute to the immune-related adverse events (irAE) observed upon clinical use of these inhibitors. Specifically, it is thought that PI3Kδi inhibit regulatory T cells (Treg), but, to date, no trials have been conducted to investigate this concept in humans. Eschweiler and colleagues addressed this through a phase II clinical trial using the PI3Kδi AMG319 in 33 patients with treatment-naïve head and neck squamous cell carcinoma. Whole-tumor RNA sequencing revealed significant decreases in transcript levels of FOXP3 in the PI3Kδi-treated group in addition to a reduction to intratumoral Tregs rapidly after treatment. Conversely, induction of cytotoxicity genes as well as a modest clonal expansion of CD4+ and CD8+ T cells was also observed. In murine solid tumor models, the antitumor effects of these inhibitors were found to be dependent on immune cells, specifically CD8+ T cells. Furthermore, these inhibitors exhibited systemic effects on the number of Tregs, specifically in the tumor, spleen, and colon. As gastrointestinal toxicity represents a major PI3Kδi-induced irAE, specific investigation into this phenotype revealed that Tregs within the colon were depleted with a more rapid progression to colitis as well as a more severe disease phenotype occurring in mice treated with PI3Kδi as compared to placebo. In an attempt to mitigate these irAEs, three different dosing regimens—continuous, intermittent, and infrequent—were used, with all showing a reduction in tumor growth but only the continuous regimen showing changes to T-cell populations. RNA sequencing of the different T-cell populations from these different dosing regimens indicated uncoupling of the antitumor effects and irAEs upon intermittent dosing. Thus, this work defines the mechanisms behind the PI3Kδi-mediated changes to the tumor microenvironment and provides a rationale for the testing of an intermittent dosing regimen of these inhibitors in future clinical trials to mitigate these irAEs.
Note:Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
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