Abstract 3996: KA2237 and KA2507: Novel, oral cancer immunotherapeutics targeting PI3K-p110β/p110δ and HDAC6 with single-agent and combination activity

Two de novo-designed classes of orally-active immunotherapeutics - selectively targeting the PI3K-p110β/p110δ and HDAC6 enzymes - for solid and hematological cancer treatment will be described. The former, exemplified by the clinical candidate KA2237, are uniquely-selective inhibitors of the PI3K-p110β/p110δ isoforms, displaying immunotherapeutic activity and inhibiting primary tumor growth and metastasis. The latter, for which KA2507 is the candidate compound, are HDAC6-specific inhibitors, which inhibit tumor growth through regulation of aggresome formation, and inhibition of PD-L1 expression via decrease of STAT3 phosphorylation. In both cases, selectivity has been achieved over other enzyme superfamily members, with the aim being to minimize mechanism-related toxicity, thereby potentially providing opportunities to enable elevated single dose levels - and broad combination modalities not possible with pan-inhibitors of both enzymes - to be investigated. The PI3K-p110β/p110δ and HDAC6 inhibitors display potent oral activity as single agents in in vivo tumor syngeneic models, impacting on growth inhibition, PD and tumor marker responses; the PI3K-p110β/p110δ inhibitors also inhibit metastatic spread and, following surgical removal of primary tumor, confer promising inhibition of tumor regrowth. Crucially, the inhibitors work in combination with one another, making this co-therapy approach unique in oncology, and potentially important clinically in overcoming resistance mechanisms in both solid and hematological cancer. The rationale for this combination is based upon immunotherapeutic and cell signalling mechanisms, which will be described. KA2237 is entering Phase I studies in patients with lymphoma as a single agent in Q1 2016, with KA2507 scheduled to follow in Q3 to treat multiple myeloma. Further clinical investigations into solid tumor immunotherapy - both single agent- and combination-studies - are planned. Citation Format: Stephen J. Shuttleworth. KA2237 and KA2507: Novel, oral cancer immunotherapeutics targeting PI3K-p110β/p110δ and HDAC6 with single-agent and combination activity. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3996.