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. <br>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