iOnctura, a clinical stage biotechnology company developing cancer therapies, has published non-clinical research on roginolisib in the AACR journal Cancer Research Communications. Roginolisib is a first-in-class, non-ATP-competitive, allosteric modulator of PI3Kd which prevents tumour proliferation and breaks immune tolerance in patients with solid and haematological tumours.
PI3Kδ inhibition in solid tumours has recently emerged as a novel approach to treating cancer because of its potential in targeting multiple tumour survival pathways. First-generation PI3Kδ inhibitors are used to treat haematological tumours, but safety concerns and limited target selectivity have curbed their clinical usefulness.
Safety concerns are even more aggravated in patients with solid malignancies where rapid onset of toxicities have been observed. Conversely, roginolisib has a favourable toxicity profile with less than 5% Grade 3/4 toxicities at the biologically effective dose. Importantly, these toxicities were transient in nature without the need for dose reductions.
The research published in Cancer Research Communications reinforces the conclusion that roginolisib inhibits regulatory T cell proliferation while having limited anti-proliferative effects on conventional CD4+ T cells and no effect on CD8+ T cells. This process unveils the tumour to the immune system whilst retaining normal immune function. Importantly, treatment of CD8+ T cells with roginolisib during activation favours the differentiation of memory-like, long-lived CD8+ T cells, known to have increased anti-tumour capacity. Consistent with first-generation PI3Kd inhibitors, roginolisib inhibits the in vitro growth of lymphoma cells. In contrast to these other PI3Kd inhibitors, roginolisib activity is correlated with the expression levels of PIK3CD, suggesting cancer cell-intrinsic effects of the drug.
The research also highlights roginolisib has immune-modulatory properties that can be exploited in solid tumours. In CT26 colorectal and LLC lung cancer models, roginolisib sensitised the tumours to anti-PD-1 (Programmed cell death protein 1) treatment, with similar activity in the Pan-02 pancreatic and A20 lymphoma syngeneic mouse models. Roginolisib reshaped the balance of tumour infiltrating cells, favouring infiltration of CD8+ and NK cells, while decreasing suppressive immune cells. Roginolisib presented no safety concerns in animal studies, or in Phase I human studies, and is currently in clinical Phase Ib/II investigation in solid and haematological tumours.
Professor Francesco Bertoni, Head of the Lymphoma Genomics group at Institute of Oncology Research in Bellinzona, Switzerland, said: “This research differentiates roginolisib from other PI3Kd inhibitors and adds to the growing body of nonclinical and clinical evidence that modulation of PI3Kd through an allosteric non-ATP competitive mechanism can be achieved safely and effectively.”
Catherine Pickering, Chief Executive Officer of iOnctura, said: “We are excited that our ground-breaking research has been published by Cancer Research Communications highlighting the potential of our lead clinical program, roginolisib in both solid and haematological cancers. We anticipate returning this key anti-tumour mechanism to physician’s tool-boxes for haematological cancers as well as offering new value for patients with solid tumours.”