Mesothelioma DNA Methylation Subtypes Immunotherapy
DNA methylation subtypes in mesothelioma are tumor-level epigenetic patterns that classify malignant pleural mesothelioma (MPM) according to genome-wide CpG methylation density, and they predict response to immune checkpoint inhibitor (ICI) therapy independent of histological subtype.[1] The classification was established in the NIBIT-EPI-MESO study (Calabrò et al., Nature Genetics 2026, PMID 42045690), which analyzed pre-treatment tumor biopsies from 91 pleural mesothelioma patients who received checkpoint inhibitor therapy and identified four methylation subtypes — demethylated, LOW, intermediate, and CIMP (CpG island methylator phenotype) — arrayed along a continuum of increasing global DNA methylation.[1][2] The LOW (hypomethylated) subtype is enriched for ICI responders with a T cell– and B cell–rich tumor microenvironment, while the CIMP (hypermethylated) subtype is enriched for non-responders with an immune-depleted microenvironment.[1][2] Importantly, DNA methylation describes a characteristic of the tumor that predicts how it will respond to immunotherapy — it is not a cause of mesothelioma. The cause of pleural mesothelioma is asbestos exposure.
Educational disclaimer: This page is for medical and scientific education and is not a substitute for individualized advice from a treating oncologist or thoracic-oncology multidisciplinary team. Methylation subtype testing is investigational and is not standard of care for mesothelioma treatment selection as of May 2026.
Executive Summary
Before NIBIT-EPI-MESO, no validated predictive biomarker existed for selecting pleural mesothelioma patients for immune checkpoint inhibitor therapy — and the American Society of Clinical Oncology (ASCO) 2025 mesothelioma guideline explicitly advises against using programmed death-ligand 1 (PD-L1) immunohistochemistry, tumor mutational burden (TMB), or microsatellite instability (MSI) for treatment selection.[3] The NIBIT-EPI-MESO study addressed this gap by performing genome-wide DNA methylation profiling on pre-ICI tumor lesions from 91 pleural mesothelioma patients enrolled in earlier NIBIT clinical trials or treated in routine practice.[1] Four methylation subtypes were identified — demethylated, LOW, intermediate, and CIMP — representing a continuum of increasing global DNA methylation.[1] The LOW (hypomethylated) subtype was enriched for ICI responders and had the longest median overall survival (OS) in the cohort, while the CIMP (hypermethylated) subtype was enriched for non-responders and had the shortest median OS.[1] The classifier operates independently of epithelioid versus non-epithelioid histology, meaning it can identify responder subsets within both histological categories.[1][2] The investigators describe a methylation-based probabilistic decision-making tool as the proposed clinical application; the classifier is not a diagnostic for mesothelioma but a treatment-selection adjunct, and prospective validation in a biomarker-stratified Phase II trial is required before incorporation into ASCO, European Society for Medical Oncology (ESMO), or National Comprehensive Cancer Network (NCCN) guidelines.
At a Glance
- Anchor study and journal: NIBIT-EPI-MESO study by Calabrò and colleagues, published in Nature Genetics (May 2026, PMID 42045690, DOI 10.1038/s41588-026-02580-4).[1]
- Cohort and design: 91 pleural mesothelioma patients in a retrospective multicenter analysis; pre-treatment tumor lesions profiled by genome-wide DNA methylation array.[1]
- Four methylation subtypes identified: demethylated, LOW (hypomethylated), intermediate, and CIMP (CpG island methylator phenotype) — arrayed along a continuum of increasing global methylation.[1][2]
- LOW subtype = best ICI response: enriched for responders to immune checkpoint inhibitors; T cell– and B cell–rich tumor microenvironment; longest median overall survival in the cohort.[1][2]
- CIMP subtype = worst ICI response: enriched for non-responders; depleted immune microenvironment; shortest median overall survival.[1][2]
- Histologic-subtype independent: the methylation classifier identifies responder subsets within both epithelioid and non-epithelioid pleural mesothelioma — a question histology alone cannot resolve.[1][2]
- Clinical-utility status: investigational / research-grade decision-support tool; not yet standard of care; not Food and Drug Administration (FDA)-cleared as a companion diagnostic; not covered by Medicare or private insurance.[3][4]
- Companion immune checkpoint inhibitor regimens: nivolumab + ipilimumab (CheckMate 743, FDA-approved first-line October 2020) and pembrolizumab + pemetrexed/platinum chemoimmunotherapy (KEYNOTE-483).[5][6]
Key Facts
| Metric | Finding (Source) |
|---|---|
| Anchor citation | Calabrò L, Caruso FP, Covre A, Noviello TMR, Lofiego MF, et al. "Tumor DNA methylation subtypes predict immunotherapy outcomes in pleural mesothelioma patients in the NIBIT-EPI-MESO study." Nature Genetics 2026; PMID 42045690; DOI 10.1038/s41588-026-02580-4.[1] |
| Cohort size (N) | 91 pleural mesothelioma patients receiving immune checkpoint inhibitor (ICI) therapy in earlier NIBIT trials or routine practice; retrospective multicenter design.[1] |
| Number of methylation subtypes | 4 — demethylated, LOW (hypomethylated), intermediate, and CIMP (CpG island methylator phenotype).[1] |
| LOW subtype ICI outcome | Enriched for ICI responders; longest median overall survival (OS) in the cohort; T cell– and B cell–rich tumor microenvironment.[1][2] |
| CIMP subtype ICI outcome | Enriched for ICI non-responders; shortest median OS; depleted immune microenvironment with silenced antigen-presentation pathways.[1][2] |
| Independent validation (TCGA-MESO) | In the Cancer Genome Atlas pleural mesothelioma cohort (TCGA-MESO, n=87, Illumina 450K methylation array), CIMP patients had median OS 459 days versus 689 days for LOW patients (log-rank P=0.065 trend).[2][7] |
| Histologic independence | Methylation subtype distribution is independent of epithelioid versus non-epithelioid histotype; principal component analysis shows both histologies distributed across CIMP and LOW.[1][2] |
| Comparison with PD-L1 immunohistochemistry (IHC) | ASCO 2025 mesothelioma guideline advises against using PD-L1, TMB, or MSI to determine therapy choice; methylation subtyping is positioned to fill this predictive-biomarker gap.[3] |
| Interaction with BAP1 and CDKN2A | BRCA1-associated protein 1 (BAP1) is somatically inactivated in ~57–60% of MPM and drives polycomb-mediated histone-methylation reprogramming (H3K27me3); cyclin-dependent kinase inhibitor 2A (CDKN2A) homozygous deletion (HD) occurs in 74% of pleural mesotheliomas; co-segregation with methylation subtypes in NIBIT-EPI-MESO is an open question pending full-text data.[8][9] |
| Companion immune checkpoint inhibitor (ICI) regimens predicted | Nivolumab + ipilimumab (FDA-approved October 2, 2020, first-line unresectable MPM, CheckMate 743) and pembrolizumab + pemetrexed/platinum (KEYNOTE-483 chemoimmunotherapy).[5][6] |
| CheckMate 743 anchor outcomes | Median OS 18.1 mo (95% CI 16.8–21.5) for nivolumab + ipilimumab versus 14.1 mo for chemotherapy in unresectable pleural mesothelioma; hazard ratio (HR) 0.74; P=0.002.[6][5] |
| Validation cohort status | Internal validation in NIBIT-EPI-MESO and TCGA-MESO (n=87, 450K methylation array); external prospective biomarker-stratified validation not yet completed (anticipated 2027 outlook).[2][7] |
What the NIBIT-EPI-MESO Study Found
The NIBIT-EPI-MESO study is the first systematic demonstration that tumor DNA methylation profiling can stratify pleural mesothelioma patients into immunotherapy-responsive and immunotherapy-resistant subsets, independent of histological classification.[1] The investigators — led by Luana Calabrò at the University of Ferrara and senior author Michele Maio at the University of Siena Center for Immuno-Oncology — analyzed pre-ICI therapy tumor lesions from 91 patients enrolled in earlier NIBIT Foundation (Network Italiano per la Bioterapia dei Tumori) clinical trials or treated in routine oncology practice.[1] Multi-omics analysis — including genome-wide DNA methylation profiling, transcriptomic analysis, and tumor microenvironment deconvolution — defined four methylation subtypes that correlated with ICI response status, median overall survival, three-year overall survival rate, and the cellular composition of the immune infiltrate.[1] The investigators then derived a probabilistic decision-making classification tool intended to predict ICI treatment outcomes based on the methylation profile.[1]
This is a retrospective discovery-cohort study, not a prospective randomized trial — an important distinction for the weight of evidence. Under the European Society for Medical Oncology Scale for Clinical Actionability of molecular Targets (ESCAT), a retrospective predictive-biomarker study at this sample size would typically map to ESCAT Tier II-B (hypothesis-generating evidence requiring prospective validation), and under the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) framework, it would be classified as Low-quality evidence pending replication.[1] Nature Genetics selection signals editorial confidence in the multi-omics methodology and potential clinical impact, but practice-changing recommendations require a Phase II or III biomarker-stratified prospective trial.
What Are the Four Methylation Subtypes?
DNA methylation is an epigenetic modification — chemically distinct from somatic gene mutation — in which a methyl group is added to the 5-carbon position of cytosine residues at CpG dinucleotides, silencing gene expression without altering the underlying DNA sequence.[2] When promoter-region CpG islands become methylated, transcription factor binding is blocked and the downstream gene is silenced. The four methylation subtypes identified in NIBIT-EPI-MESO represent positions along a continuum of progressively increasing global methylation.[1][2]
| Subtype | Methylation level | ICI outcome enrichment | Tumor microenvironment (TME) phenotype |
|---|---|---|---|
| Demethylated | Lowest global methylation | Likely favorable (inferred from continuum) | Immune-rich (inferred)[1] |
| LOW | Hypomethylated | Best response — enriched for responders; longest median overall survival (OS); highest 3-year OS rate | T cell– and B cell–rich; tertiary-lymphoid-structure-associated pathways enriched[1][2] |
| Intermediate | Intermediate methylation | Intermediate | Intermediate immune composition[1] |
| CIMP | Hypermethylated (CpG island methylator phenotype) | Worst response — enriched for non-responders; shortest median OS | Depleted immune infiltrate; antigen-presentation pathways silenced[1][2] |
In the NIBIT group's earlier preclinical study (Lofiego et al., 2025, PMID 39966970), the CIMP–LOW dichotomy was validated in 14 mesothelioma cell lines profiled on the Illumina Infinium MethylationEPIC BeadChip (850K array) and applied to the publicly available TCGA-MESO cohort (n=87) using 450K methylation array data.[2] The TCGA-MESO analysis confirmed differential overall survival between CIMP and LOW classifications (median OS 459 days versus 689 days, log-rank P=0.065 trend) and significantly higher B-cell and neutrophil infiltration in the LOW group.[2]
Why DNA Methylation Predicts Immunotherapy Response in Mesothelioma
The mechanistic basis for the predictive performance of methylation subtyping lies in how widespread CpG hypermethylation silences immune-activating gene programs within the tumor. In CIMP pleural mesothelioma, multiple pathways critical for immune surveillance are transcriptionally silenced by promoter methylation:[2]
- Antigen processing and Major Histocompatibility Complex (MHC) class I and II presentation pathways — downregulated, reducing tumor visibility to cytotoxic T lymphocytes
- T cell receptor and B cell receptor signaling — inhibited
- Interferon-gamma (IFN-γ) and type I interferon (IFN-α/β) signaling — suppressed
- Antigen presentation signatures (Immunologic Constant of Rejection [ICR], IMPRES, MIRACLE, viral mimicry, IFN-γ response, and T-cell inflammation scores) — broadly depleted in CIMP relative to LOW
The practical consequence is that CIMP tumors present an immune-cold or immune-excluded microenvironment that lacks the T cell and B cell infiltrate that checkpoint inhibitors require to generate productive antitumor responses.[2] LOW tumors show the opposite phenotype: enrichment for T cells, B cells, cytotoxic lymphocytes, myeloid dendritic cells, and tertiary lymphoid structure-associated pathways — a constellation associated with effective ICI engagement.[2]
Mesothelioma has among the lowest tumor mutational burdens of any cancer in the The Cancer Genome Atlas (TCGA) — fewer than 2 non-synonymous mutations per megabase in all but one sample in TCGA-MESO — which is one reason TMB is not a useful predictive biomarker in this disease.[7] Methylation-based classification captures a complementary axis of biology: the epigenetic state of the tumor's immune-related transcriptional programs.[2]
A separate body of background literature documents how immune-cold solid tumors generally pose barriers to adoptive cellular therapies as well, with the immunosuppressive tumor microenvironment limiting effector-cell penetrance and persistence; for example, in the Adusumilli et al. (2021) phase I trial of regional mesothelin-targeted CAR-T plus pembrolizumab in malignant pleural disease, CAR-T cell persistence in peripheral blood was detected beyond 100 days in only 39% of patients, illustrating the same general principle that immune-suppressed solid-tumor environments — of which CIMP mesothelioma is one example — present barriers to immune-effector therapies beyond checkpoint inhibition alone.[10]
The therapeutic implication is that DNA methyltransferase (DNMT) inhibitors such as guadecitabine, decitabine, and 5-azacitidine can reactivate silenced immune-related genes and endogenous retroviral elements (ERVs), generating cytosolic double-stranded RNA that activates innate immune sensing through the melanoma differentiation-associated protein 5 (MDA5) and cyclic GMP-AMP synthase – stimulator of interferon genes (cGAS-STING) pathways — a phenomenon termed "viral mimicry."[2][11] In NIBIT-group preclinical experiments, guadecitabine treatment of CIMP pleural mesothelioma cells specifically activated cGAS-STING signaling, restored MHC class I and II antigen presentation, increased natural killer cell signaling, and induced interferon-stimulated gene expression, converting immune-cold CIMP cells toward a phenotype more permissive to checkpoint inhibition.[2]
How Does Methylation Subtyping Compare to PD-L1 IHC?
Programmed death-ligand 1 (PD-L1) immunohistochemistry (IHC) has not performed reliably as a predictive biomarker in pleural mesothelioma. In CheckMate 743, patients with PD-L1 tumor proportion score (TPS) ≥1% had a hazard ratio (HR) of 0.69 for nivolumab + ipilimumab versus chemotherapy, while PD-L1-negative patients showed no significant benefit — but the PD-L1 threshold was not prospectively validated as a stratification factor, and the resulting clinical recommendation reflects this limitation.[6] The ASCO 2025 mesothelioma guideline explicitly advises that PD-L1 expression, tumor mutational burden, and microsatellite instability should not be used to determine the choice between chemotherapy and immunotherapy in pleural mesothelioma.[3]
This guideline position creates the predictive-biomarker vacuum that DNA methylation subtyping is positioned to fill. Whereas PD-L1 IHC measures a single immune-checkpoint ligand on the tumor cell surface at one point in time, methylation profiling captures a stable, genome-wide epigenetic state that integrates the transcriptional regulation of dozens of immune-related gene programs simultaneously.[2] The NIBIT-EPI-MESO data suggest that methylation subtyping adds predictive information beyond what histology and PD-L1 IHC provide.[1] Head-to-head area-under-the-curve comparisons of methylation subtyping versus PD-L1 IHC within the NIBIT-EPI-MESO cohort are referenced in the abstract; complete quantitative results require full-text confirmation.[1]
For comparison, BRCA1-associated protein 1 (BAP1) loss detected by IHC also correlates with an immune-inflamed tumor microenvironment in pleural mesothelioma, and BAP1-deficient tumors show increased T cell infiltration and closer T cell proximity to tumor cells.[9] Whether BAP1 mutational status co-segregates with the CIMP or LOW methylation subtype in NIBIT-EPI-MESO is an important open question awaiting full-text data; the mechanisms are mechanistically adjacent (BAP1 loss drives polycomb-mediated H3K27 histone trimethylation, whereas methylation subtyping captures CpG methylation), but the downstream consequence — gene silencing — is shared.[9]
What This Means for Treatment Decisions Today (and the 2027 Validation Outlook)
As of May 2026, DNA methylation subtype testing is not standard of care for pleural mesothelioma treatment selection and is not endorsed by ASCO, ESMO, or NCCN guidelines for this indication.[3] The Illumina MethylationEPIC array used in NIBIT-EPI-MESO is sold as Research Use Only (RUO) and is not FDA-cleared as a clinical in vitro diagnostic.[4] Translation into routine practice requires:
- Analytical validation of the EPIC array assay as a laboratory-developed test (LDT) in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory under 21 Code of Federal Regulations (CFR) Part 809
- Prospective clinical validation in a biomarker-stratified Phase II trial pre-specifying methylation subtype as a stratification factor
- Companion-diagnostic FDA premarket approval (PMA) or 510(k) clearance co-developed with an approved therapeutic indication per FDA companion-diagnostic guidance
- Coverage determination from the Centers for Medicare and Medicaid Services (CMS) and private payers — currently absent for this indication
The expected next step from the NIBIT group is a prospective biomarker-stratified Phase II trial pre-selecting patients by methylation subtype: LOW patients proceeding directly to standard nivolumab + ipilimumab and CIMP patients enrolling in epigenetic priming arms (DNMT inhibitor followed by ICI).[2] The Lofiego et al. 2025 preclinical work explicitly positions guadecitabine as the DNMT inhibitor candidate for CIMP-targeted priming.[2] A 2027 outlook for first prospective biomarker-stratified results is realistic given the NIBIT consortium's track record (NIBIT-MESO-1, NCT02588131) and existing European Reference Network on Rare Adult Solid Cancers (EURACAN) infrastructure for mesothelioma tissue collection.
For patients newly diagnosed with unresectable pleural mesothelioma today, the practical pathway is unchanged from the ASCO 2025 framework — nivolumab + ipilimumab remains the first-line standard for unresectable disease, with chemoimmunotherapy (pembrolizumab + pemetrexed/platinum from KEYNOTE-483) as an additional first-line option for epithelioid histology, and pemetrexed + platinum with or without bevacizumab as alternative chemotherapy options.[3][6] Patients whose treating institution participates in NIBIT-aligned or EURACAN epigenomic protocols may have access to methylation-profiled clinical-trial pathways; ClinicalTrials.gov and the National Cancer Institute trial search remain the primary mechanisms for identifying biomarker-stratified opportunities. See Mesothelioma_Survival_Statistics for the underlying pleural-mesothelioma survival reference data that frame the magnitude of potential biomarker-stratified gains.
Companion ICI Regimens and Mesothelioma Standard of Care
The immune checkpoint inhibitor regimens against which methylation subtyping is benchmarked are the current and emerging standards of care for pleural mesothelioma:
- Nivolumab (anti–programmed cell death protein 1 [PD-1]) plus ipilimumab (anti–cytotoxic T-lymphocyte–associated antigen 4 [CTLA-4]) — FDA-approved October 2, 2020 as first-line treatment for unresectable malignant pleural mesothelioma based on the CheckMate 743 trial (ClinicalTrials.gov identifier NCT02899299, N=605).[5][6] Median overall survival was 18.1 months (95% CI 16.8–21.5) for nivolumab + ipilimumab versus 14.1 months for platinum + pemetrexed chemotherapy; hazard ratio 0.74; P=0.002.[6] The survival benefit was substantially larger in non-epithelioid disease (HR 0.46, 95% CI 0.31–0.68) than in epithelioid disease (HR 0.86, 95% CI 0.69–1.08, not statistically significant) — a histology asymmetry that methylation subtyping may help to resolve by identifying responder subsets within epithelioid pleural mesothelioma that current histology-based selection misses.[6]
- Pembrolizumab (anti–PD-1) plus pemetrexed/platinum — investigated in the KEYNOTE-483 trial as chemoimmunotherapy for first-line pleural mesothelioma, reporting an objective response rate of 67% versus 47% with chemotherapy alone in epithelioid disease.[6]
- Durvalumab (anti–programmed death-ligand 1 [PD-L1]) plus tremelimumab (anti-CTLA-4) — studied in the NIBIT-MESO-1 Phase II trial (NCT02588131); the durvalumab + tremelimumab combination is not FDA-approved for pleural mesothelioma as of May 2026.[12]
The methylation classifier is most directly relevant to ICI-based regimens; whether methylation subtyping also predicts response to chemoimmunotherapy versus chemotherapy alone is a question for future biomarker-stratified trials.
Limitations and Open Questions
Several limitations of the current evidence base shape how the methylation classifier should be interpreted today.
- Retrospective discovery-cohort design. NIBIT-EPI-MESO is a retrospective multicenter study, not a prospective randomized trial with pre-specified biomarker stratification.[1] Discovery-cohort classifiers carry overfitting risk and require independent prospective validation before clinical use.
- Sample size of 91. While substantial for a rare cancer, 91 patients limits the precision of subgroup hazard ratio estimates and the power to detect interactions between methylation subtype and other molecular variables (BAP1 status, CDKN2A homozygous deletion, NF2 alterations).[1]
- Single-consortium derivation. Patients were drawn from earlier NIBIT trials and routine practice within Italian and European centers; external replication outside the NIBIT/EURACAN network is needed.[1]
- Survival statistics are pleural-specific. The NIBIT-EPI-MESO cohort consists entirely of pleural mesothelioma patients; the classifier has not been derived or validated in peritoneal mesothelioma, and pleural mesothelioma survival figures should not be applied to peritoneal disease, which has a substantially different natural history. Any survival statistics from NIBIT-EPI-MESO or its companion TCGA-MESO analysis refer to pleural mesothelioma exclusively.[1][7]
- Immune-cold solid-tumor barrier extends beyond ICI. Even outside checkpoint inhibition, the immunosuppressive solid-tumor microenvironment that characterizes CIMP-like tumors poses translational obstacles for adoptive cellular therapies and other immune-effector approaches, reinforcing why epigenetic priming strategies are an active area of investigation.
- Companion-diagnostic regulatory pathway is unbuilt. The Illumina EPIC array is Research Use Only; no FDA-cleared methylation-based companion diagnostic exists for mesothelioma ICI selection.[4] Translation will require analytical validation as a CLIA-certified LDT and prospective clinical validation under FDA companion-diagnostic guidance.
- Co-occurrence with BAP1, CDKN2A, NF2. Whether methylation subtypes co-segregate with specific genomic alterations — BAP1 loss, CDKN2A homozygous deletion (74% of pleural mesotheliomas), methylthioadenosine phosphorylase (MTAP) deletion, or NF2 alterations — is an important question for cohort-stratified analyses and for designing combination trials with EZH2 inhibitors (tazemetostat) or PRMT5 inhibitors.[8][9]
- Liquid-biopsy translation. Cell-free DNA methylation profiling from blood or pleural fluid could enable non-invasive subtype classification. A 2025 ASCO abstract reported feasibility of methylation-based liquid biopsy in pleural mesothelioma, but tissue-EPIC-array remains the reference methodology in NIBIT-EPI-MESO.
See Also
- Mesothelioma_Recurrence_After_Pleurectomy_Decortication
- Mesothelioma_Survival_Statistics
- Veterans_Asbestos_Exposure
- Statute_of_Limitations_by_State
- CheckMate_743
- BAP1_Germline_Mutations
References
- ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 1.15 1.16 1.17 1.18 1.19 1.20 1.21 1.22 1.23 1.24 1.25 1.26 1.27 1.28 1.29 1.30 1.31 1.32 1.33 1.34 Calabrò L, Caruso FP, Covre A, Noviello TMR, Lofiego MF, et al. "Tumor DNA methylation subtypes predict immunotherapy outcomes in pleural mesothelioma patients in the NIBIT-EPI-MESO study." Nature Genetics 2026. PMID 42045690. DOI 10.1038/s41588-026-02580-4. PubMed: pubmed.ncbi.nlm.nih.gov/42045690/.
- ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 2.13 2.14 2.15 2.16 2.17 2.18 2.19 2.20 2.21 2.22 2.23 2.24 2.25 2.26 Lofiego MF, Tufano R, Ferraro L, Noviello TMR, Caruso FP, et al. "DNA methylation status classifies pleural mesothelioma cells according to their immune profile: implications for precision epigenetic therapy." 2025. PMID 39966970. PubMed: pubmed.ncbi.nlm.nih.gov/39966970/. PMC: pmc.ncbi.nlm.nih.gov/articles/PMC11834541/.
- ↑ 3.0 3.1 3.2 3.3 3.4 3.5 American Society of Clinical Oncology (ASCO) 2025 Pleural Mesothelioma Guideline Update. Published in Journal of Clinical Oncology 2025; no PD-L1, tumor mutational burden, or microsatellite instability biomarker should be used to determine choice of chemotherapy versus immunotherapy in pleural mesothelioma. PubMed: pubmed.ncbi.nlm.nih.gov/?term=ASCO+mesothelioma+guideline+2024.
- ↑ 4.0 4.1 4.2 Illumina Infinium MethylationEPIC BeadChip (850K array): sold as Research Use Only (RUO), not cleared as a clinical in vitro diagnostic by the FDA. Validation for fresh-frozen and formalin-fixed paraffin-embedded (FFPE) tissue described in published methylation-array validation literature.
- ↑ 5.0 5.1 5.2 5.3 U.S. Food and Drug Administration, Approval Summary: Nivolumab in Combination with Ipilimumab for First-Line Treatment of Unresectable Malignant Pleural Mesothelioma, Clinical Cancer Research 2022. PubMed identifier (PMID) 34462287.
- ↑ 6.0 6.1 6.2 6.3 6.4 6.5 6.6 6.7 6.8 Baas P, Scherpereel A, Nowak AK, et al. First-line nivolumab plus ipilimumab in unresectable malignant pleural mesothelioma (CheckMate 743): a multicentre, randomised, open-label, phase 3 trial. The Lancet 2021. ClinicalTrials.gov identifier NCT02899299.
- ↑ 7.0 7.1 7.2 7.3 Hmeljak J, Sanchez-Vega F, Hoadley KA, et al. "Integrative Molecular Characterization of Malignant Pleural Mesothelioma." Cancer Discovery / TCGA-MESO 2018. PMID 30322867. PubMed: pubmed.ncbi.nlm.nih.gov/30322867/.
- ↑ 8.0 8.1 Illei PB, Rusch VW, Zakowski MF, Ladanyi M. "The use of CDKN2A deletion as a diagnostic marker for malignant mesothelioma in body cavity effusions." Homozygous deletion of CDKN2A in >70% of pleural mesothelioma tumors. Cancer 2003. PubMed identifier (PMID) 12589646.
- ↑ 9.0 9.1 9.2 9.3 "BAP1 Deficiency Inflames the Tumor Immune Microenvironment and Is a Candidate Biomarker for Immunotherapy Response in Malignant Pleural Mesothelioma." PMC: pmc.ncbi.nlm.nih.gov/articles/PMC11070913/.
- ↑ Adusumilli PS, Zauderer MG, Rivière I, et al. "A Phase I Trial of Regional Mesothelin-Targeted CAR T-cell Therapy in Patients With Malignant Pleural Disease, in Combination with the Anti-PD-1 Agent Pembrolizumab." Cancer Discovery 2021;11(11):2748–2763. PMID 34266984. DOI 10.1158/2159-8290.CD-21-0407. PubMed: pubmed.ncbi.nlm.nih.gov/34266984/. First-in-human phase I trial of regionally delivered, autologous, mesothelin-targeted CAR-T (iCasp9 M28z construct) in malignant pleural disease; CAR-T persistence detected in peripheral blood for >100 days in 39% of patients — exemplifying solid-tumor CAR-T persistence barriers relative to hematologic indications.
- ↑ Roulois D, Loo Yau H, Singhania R, et al. "DNA-demethylating agents target colorectal cancer cells by inducing viral mimicry by endogenous transcripts." Cell 2015;162(5):961–973 — foundational cross-disciplinary reference establishing the DNMT-inhibitor → endogenous-retroviral-element → cGAS-STING viral mimicry mechanism subsequently applied to mesothelioma by the NIBIT group.
- ↑ Calabrò L, Morra A, Bertocci E, Giannarelli D, et al. NIBIT-MESO-1 study, ClinicalTrials.gov identifier NCT02588131 — tremelimumab combined with durvalumab in patients with pleural mesothelioma; four-year survival outcomes reported by the NIBIT group.
Informational and editorial purposes only. This page synthesizes peer-reviewed research and regulatory references for educational use. It is not medical advice and does not replace individualized recommendations from a treating oncologist, thoracic-oncology multidisciplinary team, or genetic counselor. DNA methylation subtype testing is investigational for mesothelioma treatment selection and is not standard of care as of May 2026. Patients should discuss specific treatment options with their care team and consider clinical trial enrollment where appropriate.