Tumour extrinsic neutrophil regulation in mesothelioma correlates with responsiveness to AXL and PD1 inhibition in MIST3, a phase IIA clinical trial
Year: 2026
Type: preprint
Abstract: Immune checkpoint blockade (ICB) with ipilimumab and nivolumab is a front- line standard of care in patients with mesothelioma. However, only a minority of patients respond. The tyrosine receptor kinase AXL is a putative ICB resistance factor. We evaluated AXL and programmed death 1 (PD1) inhibition (AXL-PD1) with bemcentinib and pembrolizumab respectively, in a phase IIA clinical trial in patients with ICB naïve-relapsed mesothelioma (MIST3, NCT03654833 ). The study met its primary endpoint with a 12-week disease control rate of 46.2%, 90% confidence interval 29.2-63.8%. Grade 3 or greater adverse events occurred in 53.9% of patients. Multiomic analyses identified tumour-intrinsic and tumour extrinsic features linked to response to AXL-PD1 inhibition. Responders exhibited greater NF2 loss, heightened immune response signalling, and epithelial mesenchymal transition, which was lower in biopsies obtained at the time of acquired drug resistance. Neutrophil- related transcriptional programmes were associated with response to AXL-PD1 inhibition. Neutrophil regulating erythroblast transformation specific (ETS) transcription factors SPI1, ETS2, FLI1 were differentially activated in responding tumours. Gut microbiota rheostat differed between responders and non-responders and positively correlated with neutrophil- associated transcription program, IRF3 and TLR2. In summary, our findings support a hypothesis linking gut microbiota composition, neutrophil- associated tumour biology and response to AXL-PD1 inhibition in mesothelioma.
Source: medRxiv
Authors: Dean A. Fennell, Joanna Dzialo, Min Zhang, Aleksandra Bzura, Charlotte Poile, Essa Y. Baitei, Maurice Dungey, Amy Branson, Amy King, Shaun Barber, Marina Antoniou, Fatihme Maarawi, Maymun Jama, Liz Darlison, Molly Scotland, Clare Belcher, Amrita Bajaj, Bruno Morgan, Cassandra Brookes, Daniel Faulkner, Jan Rogel, Peter Wells-Jordan, Catherine Jane Richards, Jin-Li Luo, Emma Darlington, Louise Carter, Martin Little, Alastair Greystoke, Anne Thomas, Max Luckett, Mohammad Abdullah, Jens C. Hahne, Zisen Zhou, Hongji Yang, Sean Dulloo, Koirobi Haldar, Michael Barer, Gareth Griffiths, Sean Ewings, Kayleigh Hill, Eugene Tulchinsky, Nada Arabi Nusrat, Nathaniel C. Kuse, James Monkman, Rafael Tubelleza, Aaron Kilgallon, Arutha Kulasinghe, David Micklem, James B. Lorens, Matthew G. Krebs
Institutions: University of Leicester, University Hospitals of Leicester NHS Trust, NIHR Leicester Biomedical Research Centre, Novogene Bioinformatics Institute, University College London, King Faisal Specialist Hospital & Research Centre, The Christie NHS Foundation Trust, University of Manchester, Newcastle upon Tyne Hospitals NHS Foundation Trust, Cancer Research UK, NIHR Southampton Biomedical Research Centre, University of Southampton, Nazarbayev University, The University of Queensland, Wesley Hospital, Wesley Research Institute, BerGenBio (Norway), University of Bergen
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7214390431