Immunomodulatory effects of PI3Kδ inhibition in solid tumors – evaluation in a randomized phase II trial

Abstract

Phosphoinositide 3-kinase δ (PI3Kδ) plays a key role in lymphocytes and inhibitors targeting this PI3K have been approved for hematological malignancies. While studies in hematological and solid tumor models in mice have demonstrated that PI3Kδ inhibitors (PI3Kδi) can induce anti-tumor immunity, the impact of PI3Kδi on solid tumors in humans remains unclear. Here, we assessed the effects of the PI3Kδi AMG319 in patients with resectable head and neck cancer in a neoadjuvant, double-blind, placebo-controlled randomised phase-II trial. We find that PI3Kδ inhibition decreases tumor-infiltrating immunosuppressive TREG cells and causes heightened cytotoxic potential of tumor-infiltrating CD8+ and CD4+ T cells. Loss of intratumoral TREG cells and an increase in the frequency of activated TREG cells in the blood post-treatment are indicative of systemic effects on TREG tissue retention and maintenance. At the tested AMG319 doses, immune-related adverse events caused treatment discontinuation in 12/21 of AMG319-treated patients, further suggestive of systemic effects on TREG cells. Consistent with this notion, in a murine syngeneic tumor model, PI3Kδi decreased TREG cells in both tumor and non-malignant tissues and affected TREG subtype composition, maintenance and functionality. Our data demonstrate the cancer-immunotherapy potential of PI3Kδ inhibition in humans, but its modulation will need to be carefully balanced to harness its anti-tumor capacity while minimizing immune related toxicity.

Treating non-small cell lung cancer by targeting the PI3K signaling pathway

“…[109][110][111] Additionally, corresponding inflammation and autoimmunity are caused by the excessively active immune response of the tissue site exposed to the external immunogen toxicity, presenting as skin rash, colitis, liver toxicity, and pneumonia. In a report of the PI3Kd inhibitor AMG 319, [112] it was found that AMG 319 reduced tumorinfiltrating immunosuppressive Treg cells and enhanced cytotoxic tumor-infiltrating CD8+ and CD4+ T cells. This also leads to immune-mediated adverse reactions.…”

PI3K in T Cell Adhesion and Trafficking

“…In this context, by targeting Treg, PI3Kd inhibitors can unleash potent antitumour immune responses (49). Recent evidence suggests that PI3Kd inhibitors can purge Treg from the tumour microenvironment and into the circulation (50). Hence the capacity of PI3Kd inhibitors to not only affect lymphocyte function, but also to cause redistribution out of lymphoid tissues may underpin the therapeutic effects of PI3Kd inhibitors.…”