Abstract
BACKGROUND PF-06840003 is a highly selective and active IDO1 inhibitor, presumed to cross the blood brain barrier. IDO1, produced by cancer or immune cells, by affecting tryptophan catabolism, producing immunosuppressive metabolites such as kynurenine, inhibits proliferation of T cells, induces T cell anergy and apoptosis and promotes generation and activity of regulatory T cells and MDSCs. IDO1 is involved in malignant glioma immunosuppression, playing a key role in acquired resistance to PD-1/PD-L1 or CTLA-4 inhibition; their combination with IDO1 inhibition can lead to more efficacious antitumor immunity. Preclinical studies show high PF-06840003 CNS penetration and in the GL261 murine glioma model a synergistic effect in combination with PD-1/PD-L1 blockade, CTLA-4 inhibition, radiation therapy and temozolomide. This ongoing multi-center clinical trial aims to assess the safety, PK and PD activity of PF-06840003 in malignant glioma, confirm CNS penetration and verify its effectiveness in combination.
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