Optimising anti-PI3Kδ and anti-LAG-3 immunotherapy dosing regimens in a mouse model of triple negative breast cancer improves outcome by removing treatment-related adverse events

These datasets are linked to cancer immunotherapy research. Current immunotherapies often fail because they generate inadequate T-cell responses or cause immune-related adverse events (irAE), a problem that can be exacerbated by combination treatments; for example, dual targeting of regulatory T cells with a PI3Kδ inhibitor and LAG-3 antibodies achieves strong tumour control in preclinical triple-negative breast cancer models but with unacceptable toxicity. To sustain antitumour immunity while reducing harm, different strategies combining PI-3065 with LAG-3–targeted approaches were tested in mice. Systemic blockade of the LAG-3 ligand FGL1 did not improve efficacy and worsened irAE, whereas local delivery of anti-LAG-3 to the tumour microenvironment improved tumour control with fewer severe adverse events. Most notably, intermittent dosing of the PI3Kδ inhibitor alongside anti-LAG-3 prevented the development of irAE while maintaining excellent tumour control, demonstrating that optimizing delivery and scheduling can markedly improve tolerability and overall treatment success. Data underpinning each of the figures in doi:10.1136/jitc-2025-012157 can be found in the corresponding tab of the attached file, ‘Data files for Lauder et al.xlsx