The PI3Kδ inhibitor roginolisib (IOA-244) preserves T-cell function and activity

PI3K inhibitors (PI3Ki) have shown promise in some hematological cancers, but further development has been hampered by reports of serious immune-related adverse effects. Thus, identification of effective PI3Ki lacking these adverse effects is desirable. Here, we evaluated the in vitro effects of the investigational PI3Ki roginolisib (IOA-244) and the approved PI3Ki idelalisib on immune cells and leukemic cells. Roginolisib inhibited chronic lymphocytic leukemia cell signaling and viability in a manner comparable to idelalisib. Both drugs specifically inhibited PI3K-signaling in T cells, validating their on-target effects. Both idelalisib and roginolisib reduced regulatory T-cell frequency in a concentration-dependent manner, with idelalisib demonstrating greater potency. Both inhibitors also reduced T-cell activation and proliferation, but to differing extents. However, only idelalisib induced a pronounced impairment of CD8⁺ T-cell cytotoxic function. Furthermore, idelalisib treatment promoted differentiation of conventional CD4⁺ T cells into Th1, Th2, and Th17 subsets-a response not observed with roginolisib. In summary, roginolisib functions as an effective PI3K Inhibitor on leukemic cells while preserving T-cell functions, posing it as an alternative to current PI3K inhibitors.

CD4+ T helper cell; CD8+ cytotoxicity; PI3K inhibitor; T‐cell function; chronic lymphocytic leukemia; regulatory T cells.