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A gut microbiota rheostat forecasts responsiveness to PD-L1 and VEGF blockade in mesothelioma.

ABSTRACT: Malignant mesothelioma is a rare tumour caused by asbestos exposure that originates mainly from the pleural lining or the peritoneum. Treatment options are limited, and the prognosis is dismal. Although immune checkpoint blockade (ICB) can improve survival outcomes, the determinants of responsiveness remain elusive. Here, we report the outcomes of a multi-centre phase II clinical trial (MiST4, NCT03654833) evaluating atezolizumab and bevacizumab (AtzBev) in patients with relapsed mesothelioma. We also use tumour tissue and gut microbiome sequencing, as well as tumour spatial immunophenotyping to identify factors associated with treatment response. MIST4 met its primary endpoint with 50% 12-week disease control, and the treatment was tolerable. Aneuploidy, notably uniparental disomy (UPD), homologous recombination deficiency (HRD), epithelial-mesenchymal transition and inflammation with CD68⁺ monocytes were identified as tumour-intrinsic resistance factors. The log-ratio of gut-resident microbial genera positively correlated with radiological response to AtzBev and CD8⁺ T cell infiltration, but was inversely correlated with UPD, HRD and tumour infiltration by CD68⁺ monocytes. In summary, a model is proposed in which both intrinsic and extrinsic determinants in mesothelioma cooperate to modify the tumour microenvironment and confer clinical sensitivity to AtzBev. Gut microbiota represent a potentially modifiable factor with potential to improve immunotherapy outcomes for individuals with this cancer of unmet need.

SUBMITTER: Zhang M

PROVIDER: S-EPMC11339264 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature

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A gut microbiota rheostat forecasts responsiveness to PD-L1 and VEGF blockade in mesothelioma.

Zhang Min M Bzura Aleksandra A Baitei Essa Y EY Zhou Zisen Z Spicer Jake B JB Poile Charlotte C Rogel Jan J Branson Amy A King Amy A Barber Shaun S Kamata Tamihiro T Dzialo Joanna J Harber James J Greystoke Alastair A Nusrat Nada N Faulkner Daniel D Sun Qianqian Q Nolan Luke L Hahne Jens C JC Scotland Molly M Walter Harriet H Darlison Liz L Morgan Bruno B Bajaj Amrita A Brookes Cassandra C Hollox Edward J EJ Lubawska Dominika D Jama Maymun M Griffiths Gareth G Nakas Apostolos A Kutywayo Kudzayi K Luo Jin-Li JL Klampatsa Astero A Cooper Andrea A Halder Koirobi K Wells-Jordan Peter P Zhou Huiyu H Dudbridge Frank F Thomas Anne A Richards Catherine Jane CJ Pritchard Catrin C Yang Hongji H Barer Michael M Fennell Dean A DA

Nature communications 20240821 1

Malignant mesothelioma is a rare tumour caused by asbestos exposure that originates mainly from the pleural lining or the peritoneum. Treatment options are limited, and the prognosis is dismal. Although immune checkpoint blockade (ICB) can improve survival outcomes, the determinants of responsiveness remain elusive. Here, we report the outcomes of a multi-centre phase II clinical trial (MiST4, NCT03654833) evaluating atezolizumab and bevacizumab (AtzBev) in patients with relapsed mesothelioma. W ...[more]

PMID: 39168966

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Project description:PurposeThe treatment of glioblastoma (GBM) poses challenges. The use of immune checkpoint inhibition (ICI) has been disappointing as GBM is characterized by low mutational burden and low T-cell infiltration. The combination of ICI with other treatment modalities may improve efficacy.Patient and methodsPatients with recurrent GBM were treated with avelumab, a human IgG1 antibody directed against PD-L1 (part A), or avelumab within a week after laser interstitial thermal therapy (LITT) and continuation of avelumab (part B). Bevacizumab was allowed to be combined with ICI to spare steroid use. The primary objective was to characterize the tolerability and safety of the regimens. The secondary objectives included overall survival, progression-free survival (PFS), signatures of plasma analytes, and immune cells.ResultsA total of 12 patients (median age 64; range, 37-73) enrolled, five in part A and seven in part B. Two serious adverse events occurred in the same patient, LITT treated, not leading to death. The median survival from enrollment was 13 months [95% confidence interval (CI), 4-16 months] with no differences for part A or B. The median PFS was 3 months (95% CI, 1.5-4.5 months). The decrease in MICA/MICB, γδT cells, and CD4+ T cell EMRA correlated with prolonged survival.ConclusionsAvelumab was generally well tolerated. Adding bevacizumab to ICI may be beneficial by lowering cytokine and immune cell expression. The development of this combinatorial treatment warrants further investigation. Exploring the modulation of adaptive and innate immune cells and plasma analytes as biomarker signatures may instruct future studies in this dismal refractory disease.SignificanceOur phase I of PD-L1 inhibition combined with LITT and using bevacizumab to spare steroids had a good safety profile for recurrent GBM. Developing combinatory treatment may help outcomes. In addition, we found significant immune modulation of cytokines and immune cells by bevacizumab, which may enhance the effect of ICI.

Dataset Information

A gut microbiota rheostat forecasts responsiveness to PD-L1 and VEGF blockade in mesothelioma.

Publications

A gut microbiota rheostat forecasts responsiveness to PD-L1 and VEGF blockade in mesothelioma.

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