Lauder, Sarah Nihol, Pires, Ana, Somerville, Michelle, Capitani, Lorenzo, Smart, Kathryn, Geary, James, Mills, Emily M., Vanhaesebroeck, Bart, Godkin, Andrew  ORCID: https://orcid.org/0000-0002-1910-7567 and Gallimore, Awen ORCID: https://orcid.org/0000-0001-6675-7004
2026.
Optimising anti-PI3Kd and anti-LAG-3 immunotherapy dosing regimens in a mouse model of triple negative breast cancer improves outcome by removing treatment-related adverse events.
Journal for ImmunoTherapy of Cancer
14
(2)
, e012157.
10.1136/jitc-2025-012157
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Abstract
Background Current immunotherapy regimens most often fail due to an insufficient T cell response and/or immune-related adverse events (irAEs) which lead to treatment discontinuation. Additionally, many cancers likely require combination immunotherapies which may further increase irAE. This is exemplified in our preclinical models of dual targeting of regulatory T cells with a phosphoinositide 3-kinase δ (PI3Kδ) inhibitor and antibodies to LAG-3. Indeed, while this approach in preclinical models of triple-negative breast cancer shows excellent tumor control, treatment is poorly tolerated and results in significant toxicity. Given the emerging relevance of these targets in human breast cancer, we explored strategies to sustain tumor immunity while mitigating toxicity using these therapeutic modalities. Methods Different approaches to combination immunotherapies employing a PI3Kδ inhibitor (PI-3065) with LAG-3 targeting treatments were tested in a mouse model of triple-negative breast cancer to optimize tumor control while limiting irAE. Results Systemic targeting of the LAG-3 ligand FGL1 did not provide additional anticancer benefit but markedly worsened irAE. Localized delivery of anti-LAG-3 antibodies to the tumor microenvironment promoted tumor control while reducing the overall number of animals experiencing severe irAE compared with those receiving systemic LAG-3 blockade. However, intermittent dosing of the PI3Kδ inhibitor in combination with anti-LAG-3 treatment prevented the initial development of irAE and enabled excellent tumor control without systemic adverse effects. Conclusions Our data demonstrated that refining immunotherapy delivery approaches can improve tolerability that ultimately transforms treatment success.
| Item Type: | Article |
|---|---|
| Date Type: | Publication |
| Status: | Published |
| Schools: | Schools > Medicine Research Institutes & Centres > Systems Immunity Research Institute (SIURI) |
| Publisher: | BMJ Publishing Group |
| ISSN: | 2051-1426 |
| Date of First Compliant Deposit: | 15 January 2026 |
| Date of Acceptance: | 10 January 2026 |
| Last Modified: | 04 Feb 2026 15:09 |
| URI: | https://orca.cardiff.ac.uk/id/eprint/183915 |
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