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

Our plain-English summary of A gut microbiota rheostat forecasts responsiveness to PD-L1 and VEGF blockade in mesothelioma, by M. Zhang, A. Bzura, E.Y. Baitei, et al (Nature Communications, 2024).

The study

• Authors: M. Zhang, A. Bzura, E.Y. Baitei, Z. Zhou, J.B. Spicer, C. Poile, J. Rogel, A. Branson, A. King, S. Barber, T. Kamata, J. Dzialo, J. Harber, A. Greystoke, N. Nusrat, D. Faulkner, Q. Sun, L. Nolan, J.C. Hahne, M. Scotland, H. Walter, L. Darlison, B. Morgan, A. Bajaj, C. Brookes, E.J. Hollox, D. Lubawska, M. Jama, G. Griffiths, A. Nakas, K. Kutywayo, J.L. Luo, A. Klampatsa, A. Cooper, K. Halder, P. Wells-Jordan, H. Zhou, F. Dudbridge, A. Thomas, C.J. Richards, C. Pritchard, H. Yang, M. Barer, D.A. Fennell
• Journal: Nature Communications
• Published: 2024;15(1):7187
• Cited by: 31 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

© 2024. The Author(s).

In plain English

MIST4, a single-arm phase II trial at three UK centres, gave 26 mesothelioma patients two drugs, atezolizumab and bevacizumab. Most (24 of 26) had pleural mesothelioma; 16 of 26 reported asbestos exposure, and the article did not describe fiber types. At 12 weeks, disease was controlled in 13 of 26 patients (50%, 90% confidence interval 32.7 to 67.3%), meeting the trial's pre-set target. One of 26 patients (3.8%, 95% CI 0.1 to 19.6%) had a partial response. At 24 weeks, 7 of 26 (26.9%, 95% CI 11.6 to 47.8%) had disease control. Adverse events, not all judged treatment-related, occurred in 23 of 26 patients. Eight had grade 3 events; one died of breathlessness due to mesothelioma (grade 5). The researchers also analysed tumour tissue and stool samples. Patients whose tumours shrank had more CD8+ immune cells in their tumours. Tumours that did not shrink showed more signs of genomic instability and more CD68+ cells. A ratio of certain gut bacteria was higher in patients whose tumours shrank. The authors concluded that gut bacteria composition forecasts sensitivity to this treatment. They noted the small sample size and that causal links remain unknown.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Multi-centre, single-stage, single-arm, open-label phase II clinical trial, with added analyses of tumour tissue (exome and RNA sequencing, immune staining) and gut microbiome (16S sequencing of stool)
• Who was studied: 26 patients treated out of 30 consented, January 2020 to June 2021, at three UK centres. Median age 68; 18/26 male; 24/26 with pleural mesothelioma (the rest peritoneal).
• Exposure: The study examined treatment with atezolizumab and bevacizumab (AtzBev). Asbestos exposure was recorded only as patient-reported, in 16/26 patients. No fiber types, jobs or doses were given.
• Main results:
  • Disease control at 12 weeks (primary endpoint) in 13/26 patients (50%, 90% CI 32.7–67.3), meeting the trial's success criterion
  • Partial response in 1/26 patients (3.8%, 95% CI 0.1–19.6)
  • Disease control at 24 weeks in 7/26 patients (26.9%, 95% CI 11.6–47.8)
  • Adverse events of any relatedness in 23/26 patients (88.5%)
  • Of all 130 adverse events, 8/130 (6.2%) were classed as possibly related and 9/130 (6.9%) as probably related to AtzBev
  • Highest adverse event grade per patient: grade 3 in 8/26 (31%) and grade 5 in 1/26 (4%)
  • The single grade 5 event (death) was dyspnoea (breathlessness) due to mesothelioma
  • Among patients with any tumour reduction (R) compared with no reduction (NR), median progression-free survival was 188 days vs 74 days (p = 0.02)
  • Uniparental disomy was more frequent in the NR subgroup (p = 0.01)
  • Homologous recombination deficiency was enriched in the NR subgroup compared with the R subgroup (p = 0.001)
  • Tumour mutation burden and predicted neoantigen burden did not differ between the R and NR subgroups
  • PD-L1 tumour proportion score above 1% in 35% of patients; not enriched in either subgroup (p = 0.7)
  • CD8+ effector T cells were enriched in the R subgroup
  • CD68+ monocytes were enriched in the NR subgroup (p = 0.04)
  • The R subgroup was enriched for gut bacterial genera including Prevotella (p = 0.002)
  • The log ratio of gut genera enriched in the R subgroup to those enriched in the NR subgroup was almost 2 logs greater in the R subgroup (p < 0.0001)
  • The gut bacteria ratio had an area under the receiver operator curve of 0.94 for response (95% confidence limits as printed: 0.82–0.94)
• The authors' conclusion: The authors concluded that gut bacteria composition forecasts sensitivity to immunotherapy in patients with mesothelioma.
• Limitations the authors state:
  • Small phase II sample size; the authors said some findings should be interpreted with caution
  • Tumour and gut factors may vary together with response without being causally linked
  • Causal links between gut bacterial pathways and treatment response remain unknown
  • The 6-colour immune staining captured only part of the tumour immune landscape
  • Whole genome sequencing was not feasible because the diagnostic tissue samples yielded little DNA

Topics

Medical terms in this study, explained in our Lexicon: PD-L1, Mesothelioma, Malignant Mesothelioma, Asbestos Exposure, Peritoneum, Prognosis, Clinical Trial, Atezolizumab (Tecentriq).

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• IFN-γ upregulates membranous and soluble PD-L1 in mesothelioma cells: potential implications for the clinical response to PD-1/PD-L1 blockade — M.P. Pistillo, R. Carosio, et al. (2020)
• Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1-2 trial — B. Geoerger, H.J. Kang, et al. (2020)
• Molecular and immunological features of a prolonged exceptional responder with malignant pleural mesothelioma treated initially and rechallenged with pembrolizumab — A. Minchom, W. Yuan, et al. (2020)
• Impressive clinical response to anti-PD-1 therapy in epithelioid mesothelioma with high clonal PD-L1 expression and EML4-ALK rearrangement — G. Bronte, A. Delmonte, et al. (2020)
• Comprehensive Testing of Chemotherapy and Immune Checkpoint Blockade in Preclinical Cancer Models Identifies Additive Combinations — N. Principe, W.J. Aston, et al. (2022)

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