Abstract 2692: Preclinical development of a novel, highly selective PI3Kδ inhibitor, IOA-244, for the treatment of solid malignancies

Abstract

The Class I Phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) family is an attractive target class for the treatment of hematological and solid malignancies. In addition to the direct effects of PI3Kδ inhibition on B cell malignancies, inhibiting PI3Kδ preferentially targets regulatory T cells and myeloid derived suppressor cells, thus breaking tumor-induced immune tolerance and restoring anti-tumor immunity. To date, the development of selective inhibitors of the Class I PI3K family has been hampered by the lack of isoform specificity as well as safety issues. IOA-244 is a novel, highly selective, orally bioavailable PI3Kδ inhibitor, with the unique property of being ATP non-competitive; these characteristics make IOA-244 the ideal drug to explore the hypothesis that PI3Kδ inhibition can modulate anti-tumor immunity as a monotherapy and in combination in clinical trials. In mouse models, IOA-244 inhibited tumor growth when combined with either anti-PD-1 or anti-PD-L1. In the CT26 model the composition of the tumour infiltrating lymphocytes showed a marked decrease in the suppressor cell populations, i.e. Tregs and MDSCs, as well as tumor associated macrophages (TAMs). Conversely a concomitant increase in natural killer cells as well as the ratio of cytotoxic CD8+ T cells: Treg cells was observed. Furthermore, in vitro studies using primary human T cells demonstrated a selective and concentration-dependent suppression of Treg cells by IOA-244 whilst leaving CD8+ T cell proliferation intact. In addition to effects on the immune system, we are exploring the potential of IOA-244 to mediate direct anti-cancer effects on solid tumors with a high expression of PIK3CD. IOA-244 induced a concentration-dependent inhibition of p-AKT in MDA-MB-231 cells. Furthermore, we demonstrate strong anti-proliferative activity by IOA-244 on hepatocellular tumor lines in vitro. Activity in these and other cell and patient derived lines is being studied, both in xenograft in vivo studies and in vitro models. Based on GLP toxicology studies, IOA-244 has the potential to be a best-in-class PI3Kδ inhibitor with a safety and pharmacokinetic profile that is amenable for use alone and in combination with immunotherapies for the treatment of solid malignancies. IOA-244 is poised to enter phase I clinical testing in selected cancer indications in the first half of 2019. Citation Format: Katherine Ewings, Amy MacQueen, Pritom Shah, Anna Tsapara, Evangelia Papakonstanti, Lars van der Veen, Michael Lahn, Zoe Johnson. Preclinical development of a novel, highly selective PI3Kδ inhibitor, IOA-244, for the treatment of solid malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2692.

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

“…Additionally, PI3K inhibitors could also cause high blood pressure through insulin-induced vasoconstriction. [106] Because the PI3K-AKT-mTOR signals in healthy cells regulate the basic cell functions, PI3K inhibitors are prone to off-target side effects, [107] which affects the treatment and patient's quality of life. Pan class I PI3K inhibitors act on all type I subtypes.…”

PI3Kδ Inhibitors as Immunomodulatory Agents for the Treatment of Lymphoma Patients

“…In this context, CD8+ CTL can still mediate anti-tumor activity, although an altered balance between regulatory and effector CD4+ T-cells, with effector cells that prevail. Pharmacological targeting of PI3Kδ lead to similar changes compared to genetical inhibition, such as suppression of tumor growth and reduction of immunosuppression, in many cancer models [ 22 , 31 , 82 , 86 , 92 , 93 , 94 , 95 , 96 ]. The PI3Kδ inhibitor parsaclisib has in vivo antitumor activity against the A20 mouse lymphoma cell lines despite no in vitro anti-tumor activity [ 96 ].…”

“…The PI3Kδ inhibitor idelalisib and the PI3Kδ/γ inhibitor duvelisib, but not the dual PI3Kδ/CK1ε inhibitor umbralisib, determined a reduction of Tregs, which was associated with increased immune-mediated toxicities, in the absence of changes in the CD4/CD8 ratio or in the absolute number of T-cells [ 95 ]. In a syngeneic colorectal cancer model, treatment with the PI3Kδ inhibitor IOA-244 increases NK cells, and the ratio of cytotoxic CD8+ T-cells/Tregs [ 31 ]. The last observation is supported by data indicating a selective and concentration-dependent suppression of Treg cells but not of the proliferation of CD8+ T-cells [ 31 ].…”

“…In a syngeneic colorectal cancer model, treatment with the PI3Kδ inhibitor IOA-244 increases NK cells, and the ratio of cytotoxic CD8+ T-cells/Tregs [ 31 ]. The last observation is supported by data indicating a selective and concentration-dependent suppression of Treg cells but not of the proliferation of CD8+ T-cells [ 31 ]. Suppression of Tregs in syngeneic tumors is also reported with the PI3Kα/δ inhibitor copanlisib [ 92 ], and with KA2237 [ 38 ].…”

“…Finally, data collected in syngeneic mouse models mostly suggest that PI3Kδ inhibitors show synergism with immune checkpoint modulators [ 22 , 31 , 92 ]. However, there are also data demonstrating an important suppression of CD8+ T-cells maturation and killing capacity, antagonizing the effect due to immune checkpoint blockade [ 100 ].…”