Balancing the beneficial effects of immunotherapies with their adverse side effects is a key challenge in caring for people with cancer and certain immune disorders. A Nature paper published this month investigated the mechanisms by which immunotherapy for solid cancers trigger immune-related adverse effects, ultimately proposing a better strategy to minimize such effects.
Researchers at La Jolla Institute and Liverpool University evaluated whether phosphoinositide 3-kinase δ (PI3Kδ) inhibitors, which are approved as cancer therapeutics in B-cell malignancies, can serve as immunotherapies for solid cancers. A neoadjuvant, double-blind, placebo-controlled randomized Phase 2 clinical trial was conducted for the PI3Kδ inhibitor AMG319 on patients with head and neck cancer. Although AMG319 leads to antitumor activity, 12 out of 21 patients in the trial reported immune-related adverse effects, and the treatment had to be stopped for these individuals.
The antitumor effects of PI3Kδ inhibition are due to the suppression of regulatory T cell activity, which allows for effector T cells to take over and target cancer cells. However, the side effects in patients suggest drug-induced systemic effects on tumor-infiltrating regulatory T cells. In other words, putting the brakes on regulatory T cells with AMG319 not only affected the tumor but broadly upregulated certain T cell populations throughout the body, causing toxicity in nonmalignant organs.
As such, immunohistochemistry and RNA sequencing of the tumors revealed treatment-associated changes in the tumor microenvironment, including decreased regulatory T cells and enhanced activation, proliferation, or increased cytolytic activity of pathogenic T cell populations.
To understand the mechanisms underlying these adverse effects, the researchers turned to mouse models. Since gastrointestinal toxicity was one of the major adverse effects observed in patients, colon tissue was examined. Mice treated with AMG319 showed heightened sensitivity of particular subsets of T cells in the colon. These changes are thought to underlie the increased susceptibility to colitis, a chronic inflammatory condition in the gut, observed in mice treated with PI3Kδ inhibitors.
One way to minimize the adverse effects of PI3Kδ inhibitors could be altering the dosing regimen. While continuous dosing was shown to drive the pathogenic T cells responsible for inflammation and colitis onset in mice, intermittent dosing of PI3Kδ inhibitors uncoupled the antitumor effects from the adverse effects. Based on this rationale, a future clinical trial will explore different dosing regimens of PI3Kδ inhibitors in humans to optimize these drugs as cancer immunotherapies.