Immunotherapy for Mesothelioma

Immunotherapy Treatment Profile
Immune Checkpoint Inhibitor Therapy
Category	Medical / Treatment
FDA Approval	October 2, 2020
Approved Regimen	Nivolumab + Ipilimumab
Brand Names	Opdivo + Yervoy
Median OS	18.1 months
3-Year OS Rate	23% (vs. 15% chemo)
Pivotal Trial	CheckMate 743

Executive Summary

Immunotherapy has fundamentally changed the treatment landscape for malignant pleural mesothelioma (MPM). On October 2, 2020, the FDA approved the combination of nivolumab (Opdivo) plus ipilimumab (Yervoy) as the first-line treatment for adults with unresectable MPM — the first new systemic therapy approved for mesothelioma in approximately 16 years, since pemetrexed plus cisplatin gained approval in 2004.

The approval was based on the CheckMate 743 trial, which demonstrated that the nivolumab-ipilimumab combination significantly improved overall survival compared to standard chemotherapy, with a median overall survival of 18.1 months versus 14.1 months. The benefit was particularly striking in patients with non-epithelioid (sarcomatoid and biphasic) histology, where immunotherapy more than doubled survival compared to chemotherapy.

Nivolumab is a PD-1 checkpoint inhibitor and ipilimumab is a CTLA-4 checkpoint inhibitor, both manufactured by Bristol-Myers Squibb. These drugs work by releasing the brakes on the immune system, allowing T cells to recognize and attack mesothelioma tumor cells.

At a Glance

Immunotherapy for mesothelioma at a glance:

• Patients receiving immunotherapy survive 4 months longer than those on chemotherapy — median overall survival of 18.1 months vs. 14.1 months in the CheckMate 743 trial
• Non-epithelioid patients benefit far more from immunotherapy than epithelioid patients — five-year overall survival was 12% versus 1% on chemotherapy in sarcomatoid and biphasic subtypes (HR 0.48; 95% CI 0.33–0.68), against 14% versus 8% in epithelioid disease
• More immunotherapy patients than chemotherapy patients were alive at 3 years — 23% vs. 15% three-year survival rate
• Dual checkpoint blockade improved survival over chemotherapy as first-line treatment — the CheckMate 743 combination improved overall survival in previously untreated patients; in a separate setting, previously treated patients, the PROMISE-meso trial of pembrolizumab alone did not improve survival over chemotherapy
• Serious side effects occurred at similar rates on immunotherapy and chemotherapy — grade 3-4 treatment-related adverse events in 30% vs. 32% of patients
• Immunotherapy before surgery is being studied in resectable disease — in a phase 2 trial of patients with resectable epithelioid or biphasic mesothelioma, 14 patients given nivolumab plus ipilimumab before surgery had a median overall survival of 28.6 months
• Combination immunotherapy replaced a 16-year-old standard of care — nivolumab plus ipilimumab became the first new first-line approval since pemetrexed plus cisplatin in 2004
• Some patients who stopped immunotherapy early because of side effects kept responding for years — in a post hoc analysis, patients who discontinued for treatment-related adverse events had a median OS of 25.4 months, and 34% of responders maintained their responses for 3 years or more after stopping
• Immunotherapy responders maintain benefits years after treatment ends — 34% of responders sustained their response for three or more years after stopping therapy, compared to 0% ongoing response in the chemotherapy arm
• Financial assistance can reduce immunotherapy costs from nearly $300,000 to $0 per infusion — BMS Access Support co-pay programs cover eligible commercially insured patients, offsetting the $196,604 incremental cost over chemotherapy

Key Facts

Metric	Finding
FDA Approval	October 2, 2020 — nivolumab + ipilimumab for unresectable MPM, the first new systemic therapy in 16 years
CheckMate 743 Enrollment	605 patients randomized (303 immunotherapy, 302 chemotherapy) across multiple international centers; lead investigator Paul Baas, Netherlands Cancer Institute
Median Overall Survival	18.1 months (immunotherapy) vs. 14.1 months (chemotherapy); HR 0.74 (96.6% CI: 0.60–0.91), representing a 26% reduction in risk of death
3-Year Overall Survival	23% (immunotherapy) vs. 15% (chemotherapy); 3-year PFS rate 14% vs. 1%
Non-Epithelioid Subtype Benefit	Five-year OS 12% vs. 1% (HR 0.48; 95% CI 0.33–0.68) for sarcomatoid and biphasic histology
Epithelioid Subtype Benefit	Five-year OS 14% vs. 8% (HR 0.85; 95% CI 0.69–1.03) — a modest improvement favoring immunotherapy
Objective Response Rate	40% (immunotherapy) vs. 43% (chemotherapy); however, 28% of immunotherapy responders had ongoing response at 3 years vs. 0% for chemotherapy
Grade 3-4 Adverse Events	30% (immunotherapy) vs. 32% (chemotherapy); treatment discontinued for adverse reactions in 28% vs. 19%; nivolumab can cause immune-mediated colitis, hepatitis, pneumonitis
CONFIRM Trial (Second-Line)	First randomized trial to show improved PFS with nivolumab vs. placebo in relapsed mesothelioma (PFS co-primary endpoint met); the final analysis at 37.2-month follow-up did not reach statistical significance for overall survival (HR 0.81, 95% CI 0.64–1.04; p=0.093 unadjusted, p=0.096 adjusted); PD-L1 was not predictive or prognostic
Perioperative Immunotherapy	Neoadjuvant nivolumab + ipilimumab before surgery: median OS 28.6 months, median PFS 19.8 months (Nature Medicine 2025 phase 2 trial)
Active Recruiting Trials (2026)	32 immunotherapy trials among 93 total mesothelioma trials actively recruiting; 52 US-based; 5 CAR-T cell therapy trials recruiting
Treatment Cost	Approximately $292,319 (immunotherapy) vs. $95,715 (chemotherapy); incremental cost of $196,604 for 0.53 additional QALYs; BMS co-pay assistance may reduce patient cost to $0

What Is the FDA-Approved Immunotherapy for Mesothelioma?

The FDA-approved immunotherapy regimen for unresectable malignant pleural mesothelioma consists of two immune checkpoint inhibitors given in combination:

Nivolumab (Opdivo): A PD-1 checkpoint inhibitor administered at 3 mg/kg intravenously every 2 weeks. PD-1 is a protein on T cells that normally acts as an "off switch" — when tumor cells express PD-L1 (the ligand for PD-1), they can deactivate attacking T cells. Nivolumab blocks this interaction, allowing T cells to remain active against tumor cells.

Ipilimumab (Yervoy): A CTLA-4 checkpoint inhibitor administered at 1 mg/kg intravenously every 6 weeks. CTLA-4 is another immune checkpoint that normally dampens T cell activation early in the immune response. By blocking CTLA-4, ipilimumab enhances and broadens the T cell response against the tumor.

Treatment continues for up to 24 months or until disease progression or unacceptable toxicity. Prior to this approval, the only FDA-approved first-line systemic therapy was the chemotherapy combination of pemetrexed plus cisplatin, approved in 2004.

What Did the CheckMate 743 Trial Show?

CheckMate 743 (NCT02899299) was the open-label, multicenter, randomized phase 3 trial that led to FDA approval. It was the first immunotherapy trial to demonstrate improved overall survival in first-line mesothelioma treatment.

Trial Design

A total of 605 patients were randomized: 303 to nivolumab plus ipilimumab and 302 to standard chemotherapy (pemetrexed plus cisplatin or carboplatin). The study was powered at 90% to detect a hazard ratio of 0.72 with a 5% type-I error. The primary endpoint was overall survival. Lead investigator was Paul Baas of The Netherlands Cancer Institute.

Primary Results

Outcome	Nivolumab + Ipilimumab	Chemotherapy
Median Overall Survival	18.1 months (95% CI: 16.8–21.4)	14.1 months (95% CI: 12.4–16.2)
Hazard Ratio	0.74 (96.6% CI: 0.60–0.91) — 26% reduction in death risk
2-Year OS Rate	41%	27%
3-Year OS Rate	23%	15%
3-Year PFS Rate	14%	1%
Objective Response Rate	40%	43%

At three years, 28% of responders in the immunotherapy arm had an ongoing response, versus 0% in the chemotherapy arm. Patients who discontinued immunotherapy due to adverse events still had a favorable median OS of 25.4 months, and 34% of responders maintained their responses for three or more years after discontinuation.

Histology-Specific Results

The most clinically significant finding was the dramatically different benefit by histological subtype:

Epithelioid subtype: Five-year overall survival 14% vs. 8% (HR 0.85; 95% CI 0.69–1.03) Non-epithelioid subtype: Five-year overall survival 12% vs. 1% (HR 0.48; 95% CI 0.33–0.68)

This finding is particularly important because non-epithelioid mesothelioma (sarcomatoid and biphasic subtypes) has historically been poorly responsive to chemotherapy. Immunotherapy demonstrated its greatest relative benefit in this difficult-to-treat population, making it the clear treatment of choice for non-epithelioid disease.

Safety Profile

Grade 3-4 treatment-related adverse events occurred in 30% of immunotherapy patients versus 32% of chemotherapy patients. The types differed: nivolumab can cause immune-mediated colitis, hepatitis and pneumonitis, while anemia was more common with chemotherapy (75% vs. 43% of patients on laboratory testing). Treatment was discontinued because of adverse reactions in 28% of immunotherapy patients and 19% of chemotherapy patients.

A key biomarker finding from the 3-year update: a high score of a 4-gene inflammatory expression signature appeared to correlate with improved survival benefit from immunotherapy, potentially offering a patient selection tool for future clinical practice.

Real-World Results: The Meso-Immune Cohort (France)

The French Meso-Immune study (GFPC 04-2021) is a nationwide retrospective analysis of patients who received nivolumab plus ipilimumab for unresectable pleural mesothelioma through an early-access program in France. Its 2026 update included 204 patients with a median age of 75 years; 152 (75%) had epithelioid and 52 (25%) non-epithelioid disease.

At a median follow-up of 30 months, median overall survival was 20.2 months, and 23.5% of patients were alive at 30 months. Median real-world progression-free survival was 6.3 months. Overall survival was longer for epithelioid than for non-epithelioid disease (22.3 versus 14.3 months).

Side effects were common. Immune-related adverse events occurred in 68.6% of patients, at grade 3 or higher in 24.2% and grade 5 (fatal) in 6.4%. Toxicity led to treatment discontinuation in 39.3% of patients and hospitalization in 34.3%. The authors concluded that the combination provided long-term clinical benefit comparable to CheckMate 743 despite an older population. Because Meso-Immune followed a single treatment, it had no chemotherapy comparison group, so its figures show how patients fared outside a trial rather than how much the combination added over chemotherapy.

What Other Immunotherapy Trials Have Been Conducted?

See also: Bemcentinib Plus Pembrolizumab for Mesothelioma

CONFIRM Trial (Phase 3, Second-Line)

The CONFIRM trial was a randomized phase 3 study comparing nivolumab versus placebo in patients with relapsed mesothelioma (both pleural and peritoneal) who had received at least one prior line of platinum-based chemotherapy. The trial's 2021 preliminary report, at an earlier data cutoff, described improved overall survival, and that report is the source of the claim as it has commonly been repeated. The final analysis at 37.2 months of follow-up met only the progression-free survival co-primary endpoint: overall survival was numerically longer with nivolumab than placebo (9.49 versus 6.77 months) but did not reach statistical significance (HR 0.81, 95% CI 0.64–1.04; p=0.093 unadjusted, p=0.096 adjusted). A September 2026 re-analysis of the published Kaplan–Meier data from CONFIRM and PROMISE-meso found that the early CONFIRM overall-survival signal coincided with short follow-up and a differential censoring pattern consistent with post-progression censoring; the updated CONFIRM dataset, with longer follow-up, showed no overall-survival benefit and no evidence of post-progression censoring. When general differential censoring was addressed in sensitivity analyses, both the progression-free survival effect and the overall-survival advantage in CONFIRM lost statistical significance. The authors conclude that post-progression censoring is an under-recognized source of bias that may have contributed to the initial CONFIRM findings, which were based on a premature early data lock; while a modest treatment effect in a biologically defined subgroup cannot be excluded, they describe the current evidence as inconclusive. Notably, PD-L1 was not found to be predictive or prognostic in CONFIRM, suggesting that PD-L1 testing should not be used to select patients for second-line nivolumab. For the full relapsed-setting systemic therapy landscape beyond immunotherapy — including RAMES, the nivolumab-ramucirumab HCRN trial, the negative anetumab ravtansine trial, and ASCO/ESMO guideline positioning — see Second-Line_Systemic_Therapy_for_Pleural_Mesothelioma.

PROMISE-meso Trial (Phase 3, Second-Line)

The PROMISE-meso trial compared pembrolizumab (200 mg fixed dose every 3 weeks) versus single-agent chemotherapy (gemcitabine or vinorelbine) in 144 patients with relapsed MPM. This trial was negative — pembrolizumab did not improve progression-free survival or overall survival compared to chemotherapy in an unselected patient population. The result highlighted that single-agent PD-1 blockade is insufficient as monotherapy in second-line unselected mesothelioma and reinforced the importance of combination approaches or biomarker-driven selection. PROMISE-meso is not the only relapsed-setting trial to report a negative result — see Second-Line_Systemic_Therapy_for_Pleural_Mesothelioma for the phase 2 anetumab ravtansine trial, which similarly failed to beat its comparator.

Tremelimumab Monotherapy (Phase 2, Second-Line)

Before the combination era, tremelimumab — an anti-CTLA4 antibody — was tested on its own. This open-label, single-arm phase 2 trial enrolled 29 patients with unresectable mesothelioma who had progressed after first-line platinum-based chemotherapy, dosing tremelimumab at 15 mg/kg intravenously every 90 days. The study did not reach its primary endpoint: no patient had a complete response and two (7%) had a durable partial response, against a target response rate of 17%. Disease control was recorded in nine patients (31%), median progression-free survival was 6.2 months and median overall survival 10.7 months. Grade 1-2 treatment-emergent adverse events occurred in 27 patients (93%), most often rash, pruritus, colitis or diarrhoea, with grade 3-4 events in four patients (14%). This is a monotherapy result and should not be read against the durvalumab-plus-tremelimumab combination arms described elsewhere on this page: different intervention, different trial.

Cytokine Immunotherapy Before Checkpoint Blockade

Immunotherapy for mesothelioma did not begin with checkpoint inhibitors. A phase 2 study of interleukin-2 (IL-2) treated 31 consecutive patients with unresectable malignant pleural mesothelioma complicated by pleural effusion, giving repeated intrapleural instillation of 9 million IU IL-2 twice weekly for four weeks after thoracentesis, followed in non-progressing patients by 3 million IU subcutaneously three times weekly for up to six months. Twenty-eight of 31 patients (90%) had no further or only minimal asymptomatic fluid collection, and pleurisy relapsed in only one of those 28. Objective tumour response was seen in seven patients (one complete, six partial; 22%), ten had stable disease and 14 progressed; median overall survival was 15 months. Grade 3 toxicity with intrapleural IL-2 was fever in six patients (19%) and cardiac failure in one (3%). The authors concluded the approach was feasible and active both in palliating effusion and against the primary tumour, and called for randomized study — which the field did not pursue before checkpoint blockade arrived.

DREAM and PrE0505 Trials (Phase 2, First-Line)

The DREAM trial (Australia) and PrE0505 trial (United States) were single-arm phase 2 trials that tested durvalumab (anti-PD-L1) combined with standard chemotherapy (cisplatin plus pemetrexed) as first-line treatment. Both showed promising results — DREAM reported median OS of 18.4 months with a 48% objective response rate, while PrE0505 reported median OS of approximately 20.4 months with a 56.4% partial response rate. These results provided the rationale for DREAM3R, a phase 3 trial. Its registry record lists durvalumab plus chemotherapy against two control arms, chemotherapy alone and nivolumab plus ipilimumab, and shows the trial as completed with 214 patients enrolled.

BEAT-meso Trial (Phase 3)

The BEAT-meso trial was an international randomized phase 3 trial comparing atezolizumab (anti-PD-L1) plus bevacizumab plus chemotherapy versus bevacizumab plus chemotherapy alone in 400 patients. The primary endpoint was not met — median OS was 20.5 months versus 18.1 months (HR 0.84, p=0.14, not significant). However, the addition of atezolizumab did significantly improve progression-free survival (9.2 vs. 7.6 months; HR 0.72, p=0.0021). Benefit was histology-dependent. In the trial's pre-specified analysis by histology, the overall survival hazard ratio was 1.01 (95% CI 0.77–1.32) in epithelioid patients, indicating no benefit, versus 0.51 (95% CI 0.32–0.80) in non-epithelioid patients, with a P value for interaction of 0.012. Quality of life was maintained with the atezolizumab arm, with no clinically meaningful differences from the control arm.

KEYNOTE-483 Trial (Pembrolizumab + Chemotherapy)

The KEYNOTE-483 trial (also designated CCTG IND.227, NCT02784171) was a randomized, open-label, phase 2/3 trial of pembrolizumab (Keytruda) combined with pemetrexed and platinum chemotherapy as first-line treatment for unresectable MPM, conducted at 51 hospitals in Canada, Italy, and France. The trial enrolled 440 patients (222 pembrolizumab + chemo; 218 chemo alone).

Endpoint	Pembrolizumab + Chemo	Chemo Alone	HR (95% CI)
Median OS	17.3 months (95% CI 14.4–21.3)	16.1 months (95% CI 13.1–18.2)	0.79 (0.64–0.98); p=0.0324
ORR (BICR)	52%	29%	p<0.00001
2-Year OS	39%	33%	—
3-Year OS	25%	17%	—

On September 17, 2024, the FDA approved pembrolizumab in combination with pemetrexed and platinum chemotherapy as first-line treatment for unresectable MPM — the third-ever systemic therapy approved for mesothelioma, following cisplatin/pemetrexed (2004) and nivolumab/ipilimumab (2020). Like nivolumab/ipilimumab, the benefit was most pronounced in non-epithelioid histology (HR 0.57; non-epithelioid median OS 12.3 vs. 8.2 months) compared to epithelioid disease (HR 0.89). The addition of pembrolizumab increased grade 3–4 adverse events to 27% versus 15% with chemotherapy alone.

Clinicians now have two FDA-approved immunotherapy options for first-line mesothelioma: nivolumab plus ipilimumab (CheckMate 743, approved 2020) and pembrolizumab plus chemotherapy (KEYNOTE-483, approved 2024). No head-to-head trial comparing these regimens exists. The 2025 ASCO guideline update recommends nivolumab plus ipilimumab as the first-line treatment for newly diagnosed non-epithelioid disease, and says pembrolizumab plus pemetrexed and platinum chemotherapy may be offered as a first-line option for either epithelioid or non-epithelioid disease.

What Role Do BAP1, TMB, and Other Biomarkers Play?

BAP1 Mutations

BAP1 (BRCA1-associated protein 1) is the most commonly mutated gene in mesothelioma, found in approximately 45.6% of cases. Other common mutations include CDKN2A (21.7%), TP53 (17.1%), and NF2 (14.3%).

BAP1 deficiency has been found to enrich immune pathways in the tumor microenvironment, increasing interferon-alpha and interferon-gamma signatures, activating dendritic cells, and increasing checkpoint receptor expression. BAP1-deficient mesothelioma tumors may therefore be more responsive to immunotherapy, though this relationship requires further prospective validation.

Tumor Mutational Burden

Mesothelioma has a low tumor mutational burden (TMB) compared to other cancers that respond well to immunotherapy, such as melanoma or non-small cell lung cancer. Despite this low TMB, the CheckMate 743 results demonstrate that combination immunotherapy can still be effective. In the NIBIT-MESO-1 trial, patients with TMB higher than the median of 8.3 mutations per megabase had significantly longer survival (41.3 months vs. 17.4 months; p=0.02), suggesting TMB may help identify patients most likely to benefit.

What Is CAR-T Cell Therapy for Mesothelioma?

Chimeric antigen receptor T-cell (CAR-T) therapy is an emerging form of cellular immunotherapy that engineers a patient's own immune cells to recognize and attack cancer. While CAR-T therapy has achieved remarkable success in blood cancers — with six FDA-approved products achieving complete response rates up to 90% in certain leukemias and lymphomas — its application in solid tumors like mesothelioma remains in early clinical stages. As of early 2026, no CAR-T therapy is FDA-approved for mesothelioma, and all programs remain in Phase 1 or Phase 1/2 trials. However, early results from Memorial Sloan Kettering Cancer Center have generated significant interest, with a 23.9-month median overall survival and 83% 1-year survival rate in mesothelioma patients receiving intrapleural CAR-T cells combined with pembrolizumab (mRECIST-assessed best response: 12.5% partial response, 56.3% stable disease).

How Does CAR-T Work?

CAR-T therapy involves collecting a patient's T cells through a blood draw (leukapheresis), then genetically engineering those T cells in a laboratory to express a synthetic chimeric antigen receptor (CAR) on their surface. This receptor enables the T cells to recognize a specific protein (antigen) on tumor cells. The modified cells are then expanded to millions of copies over 1–3 weeks and infused back into the patient, where they seek out and destroy cancer cells bearing the target antigen.

Unlike conventional T cells, which require antigen presentation through the major histocompatibility complex (MHC), CAR-T cells recognize surface antigens directly. This is an important advantage in mesothelioma, where tumor cells can downregulate MHC to evade immune detection. CAR-T cells are sometimes described as a "living drug" because they can persist in the body, expand when they encounter tumor cells, and provide ongoing surveillance against cancer recurrence.

Why Is Mesothelin the Target?

Mesothelin (MSLN) is a cell-surface glycoprotein normally expressed at low levels on the mesothelial cells lining the pleura, peritoneum, and pericardium. In mesothelioma, mesothelin is overexpressed in more than 80% of epithelioid tumors, making it an attractive target because the difference between tumor and normal expression is large enough to allow selective targeting. An immunohistochemical study of 1,562 tumors found mesothelin positivity in 75% to 78% of malignant mesotheliomas, depending on the antibody used, with 81% to 84% of epithelioid tumors staining positive compared to 65% of biphasic and 20% of sarcomatoid tumors.

Mesothelin is the most frequently targeted antigen in solid-tumor CAR-T trials worldwide, accounting for 13.4% of all registered solid-tumor CAR-T clinical trials as of 2025. Other potential CAR-T targets for mesothelioma under preclinical or early clinical investigation include fibroblast activation protein (FAP), HER2, and MUC16.

How Does CAR-T Differ from Checkpoint Inhibitors?

CAR-T therapy and checkpoint inhibitors like nivolumab and ipilimumab represent fundamentally different approaches to immunotherapy:

Feature	CAR-T Cell Therapy	Checkpoint Inhibitors (Nivo + Ipi)
Mechanism	Engineers new cancer-targeting T cells	Releases brakes on existing T cells
FDA Approval for Mesothelioma	Not approved (Phase 1/2 trials only)	Approved (October 2020)
Administration	Single infusion (intrapleural or IV) after cell manufacturing	IV infusions every 2–6 weeks for up to 2 years
Manufacturing	Patient-specific; 3–5 week vein-to-vein time	Off-the-shelf pharmaceutical
PD-L1 Dependence	No — targets mesothelin regardless of PD-L1	No PD-L1 requirement for approval
Key Advantage	Directly targets tumor antigen; "living drug" persists	Proven OS benefit; established safety profile

Emerging evidence suggests that combining CAR-T with checkpoint inhibitors may be more effective than either approach alone — the MSKCC trial's 23.9-month median OS was achieved by adding pembrolizumab to rescue exhausted CAR-T cells.

What Have CAR-T Trials Shown So Far?

The most advanced CAR-T program for mesothelioma is led by Dr. Prasad Adusumilli at Memorial Sloan Kettering Cancer Center. His team pioneered the concept of delivering CAR-T cells directly into the pleural cavity (intrapleurally) rather than intravenously, which achieves higher concentrations of therapeutic cells at the tumor site while reducing systemic toxicity.

In a Phase I/II trial (NCT02414269), 18 mesothelioma patients received intrapleural mesothelin-targeted CAR-T cells combined with pembrolizumab:

• Median overall survival from CAR-T infusion: 23.9 months (95% CI 14.7 months to not estimable)
• 1-year overall survival: 83%
• Best radiologic response (mRECIST): 12.5% partial response, 56.3% stable disease in 16 evaluable patients, with 2 complete metabolic responses on PET scan
• CAR-T cells were detectable in peripheral blood for over 100 days in 39% of patients
• Only grade 1–2 adverse events; no severe cytokine release syndrome or on-target/off-tumor toxicity
• PD-L1 expression did not predict response — 6 of 8 responses occurred in PD-L1-low patients

These results represent the most encouraging solid-tumor CAR-T data published to date. However, the study was a Phase I/II trial with a small sample size, and larger trials are needed to confirm these findings.

A current-generation successor trial (NCT04577326) is evaluating a next-generation CAR construct — M28z1XXPD1DNR — that incorporates a built-in PD-1 decoy receptor, potentially eliminating the need for concurrent checkpoint inhibitor therapy. This trial is actively recruiting at MSKCC.

Other notable CAR-T programs for mesothelioma include:

• University of Pennsylvania huCART-meso (NCT03054298): Fully humanized mesothelin-targeted CAR-T cells using a 4-1BB signaling domain. In 20 patients (5 with mesothelioma, 14 with ovarian cancer and 1 with lung adenocarcinoma), stable disease was achieved in 60% (12/20), but no objective responses per RECIST criteria were observed. Median OS was 26.1 weeks.
• NCI TNhYP218 trial (NCT06885697): A novel construct targeting a different region of mesothelin using stem cell memory T cells for improved persistence. Led by Dr. Raffit Hassan at the National Cancer Institute; launched July 2025.
• EVEREST-2 / A2B694 (NCT06051695): A logic-gated "Tmod" CAR-T that activates only against tumor cells that have lost specific HLA markers, designed to eliminate on-target/off-tumor toxicity. Phase 1/2 by A2 Biotherapeutics.
• STAR-101 / SynKIR-110 (NCT05568680): A KIR-based CAR platform by Verismo Therapeutics. Recruiting sites: Moffitt Cancer Center, University of Pennsylvania, MD Anderson Cancer Center, and University of Wisconsin Carbone Cancer Center; University of Kansas Cancer Center is active, not recruiting. Has received FDA Orphan Drug and Fast Track designations for mesothelioma.

What Are the Challenges of CAR-T for Mesothelioma?

Despite promising early results, CAR-T therapy faces significant barriers in solid tumors like mesothelioma that have not been encountered in blood cancers:

Immunosuppressive tumor microenvironment: The mesothelioma tumor microenvironment contains TGF-β, regulatory T cells, and myeloid-derived suppressor cells that actively impair CAR-T function. This is why combining CAR-T with checkpoint inhibitors or engineering checkpoint-resistant CARs is being pursued.

Antigen heterogeneity: Not all mesothelioma cells express mesothelin — particularly sarcomatoid tumors (0% positivity) and a substantial portion of biphasic tumors (28% positivity). Tumor cells that lack the target antigen can escape CAR-T killing and potentially drive relapse.

T-cell exhaustion: Prolonged exposure to the hostile tumor environment causes CAR-T cells to become functionally impaired, losing their ability to kill cancer cells. Next-generation constructs like the MSKCC M28z1XXPD1DNR address this by incorporating built-in checkpoint resistance.

Manufacturing complexity: CAR-T cells are manufactured individually for each patient, requiring specialized facilities and 3–5 weeks of production time. For a rapidly progressing cancer like mesothelioma, this wait can be clinically significant. Rapid-manufacturing platforms producing CAR-T cells in 24–48 hours are under development.

What Next-Generation Checkpoint Targets Are Being Studied?

The approved regimens block two immune checkpoints — PD-1 and CTLA-4 — but many patients gain limited or no benefit, and there is no validated immunotherapy once first-line treatment fails. Research has therefore turned to a newer generation of inhibitory checkpoints, chiefly TIGIT and LAG-3, now being tested in mesothelioma-specific programs.

TIGIT. In a 2025 preclinical study from Australia's Asbestos and Dust Disease Research Institute, adding an anti-TIGIT antibody to anti-PD-1 produced an objective response in 90% of treated animals — compared with 60% for the standard anti-PD-1 plus anti-CTLA-4 combination — with complete tumor regression that persisted beyond 300 days and fewer adverse effects than the standard doublet. The authors presented this as a rationale for testing anti-PD-1 plus anti-TIGIT in mesothelioma patients. That approach has reached the clinic: the academic IMMUNORARE5 platform (NCT06790706) includes a peritoneal-mesothelioma cohort treated with domvanalimab (anti-TIGIT) plus zimberelimab (anti-PD-1) after failure of platinum chemotherapy. As of this writing its status is active, not recruiting (Phase 2).

LAG-3. A second inhibitory checkpoint, LAG-3, is the target of the LAG-MAPS trial (NCT07234058), a French Phase 2 study pairing fianlimab (anti-LAG-3) with cemiplimab (anti-PD-1) and pemetrexed-platinum chemotherapy in treatment-naive pleural mesothelioma. Its status is not yet recruiting, with enrollment planned to begin in 2026.

All of these approaches are investigational. None is FDA-approved for mesothelioma, the TIGIT efficacy data so far come from animal models, and only prospective trials such as IMMUNORARE5 and LAG-MAPS will show whether next-generation checkpoints add to the benefit already established for PD-1/CTLA-4 blockade.

What Immunotherapy Trials Are Currently Recruiting?

As of January 2026, there are 93 mesothelioma clinical trials actively recruiting patients, of which 32 (34%) are immunotherapy trials and 52 are based in the United States.

Key actively recruiting immunotherapy trials include:

Trial	NCT Number	Phase	Intervention
Neoadjuvant Durvalumab + Tremelimumab	NCT05932199	Phase Ib/IIa	Durvalumab + tremelimumab +/- chemo (Baylor)
Immunotherapy Before Surgery for Sarcomatoid Meso	NCT05647265	Phase 2	Neoadjuvant immunotherapy + surgery
Partial Pleurectomy for Unresectable MPM	NCT07126509	—	Surgery +/- immunotherapy
Pembrolizumab + Chemo + Image-Guided Surgery	—	Phase 2	Pembrolizumab + chemo + surgery

CAR-T Cell Therapy Trials

The following CAR-T and cellular therapy trials are actively recruiting mesothelioma patients as of early 2026:

Trial	NCT Number	Phase	Target / Intervention	Institution
M28z1XXPD1DNR Intrapleural CAR-T	NCT04577326	Phase 1	Mesothelin CAR-T with PD-1 decoy receptor (intrapleural)	Memorial Sloan Kettering
TNhYP218 CAR-T	NCT06885697	Phase 1	Novel mesothelin binder; stem cell memory T cells (IV)	NCI / NIH (Dr. Raffit Hassan)
EVEREST-2 (A2B694)	NCT06051695	Phase 1/2	Logic-gated Tmod mesothelin CAR-T (IV)	A2 Biotherapeutics
STAR-101 (SynKIR-110)	NCT05568680	Phase 1	KIR-based mesothelin CAR-T (IV); FDA Orphan Drug + Fast Track	Moffitt, Penn, MD Anderson, Wisconsin (recruiting); Kansas (active)
CAR.70 + NK Cells	NCT05703854	Phase 1/2	CAR.70 engineered natural killer cells	MD Anderson Cancer Center

For detailed information about each trial's mechanism, early results, and eligibility criteria, see the CAR-T section above. Patients can search for currently enrolling trials at ClinicalTrials.gov. Eligibility varies by trial — most require mesothelin expression confirmed by immunohistochemistry, adequate organ function, and ECOG performance status 0–1. Stage 3 and Stage 4 patients are generally eligible for these trials.

Perioperative Immunotherapy (2025 Update)

A phase 2 trial published in Nature Medicine (2025) evaluated neoadjuvant immunotherapy before surgery for resectable mesothelioma. Patients receiving nivolumab plus ipilimumab before surgery (14 patients) had a median PFS of 19.8 months and median OS of 28.6 months; patients receiving nivolumab alone (16 patients) had a median PFS of 9.6 months and median OS of 19.3 months. The two groups were enrolled one after the other rather than randomized, so the trial does not compare them directly. In the combination group, extended pleurectomy/decortication was performed in 9 of the 11 patients who had complete resection (81.8%). The trial met its primary endpoints of safety and feasibility.

What Does Immunotherapy Cost and How Do Patients Access It?

Cost-Effectiveness

A Markov model analysis from a US payer perspective found that the total cost of nivolumab plus ipilimumab treatment was approximately $292,319 compared to $95,715 for chemotherapy — an incremental cost of $196,604 for 0.53 additional quality-adjusted life years (QALYs). At a willingness-to-pay threshold of $207,659 per QALY, the combination was not considered cost-effective unless drug prices were reduced by approximately 34%.

Patient Assistance Programs

BMS Access Support offers benefit investigation, prior authorization assistance, appeal process support, and co-pay assistance programs for eligible commercially insured patients who may pay as little as $0 per infusion, subject to an annual maximum benefit.

"For mesothelioma patients, understanding all available treatment options — including immunotherapy clinical trials — is essential. These advances represent real hope for improved survival, particularly for those with non-epithelioid disease where chemotherapy alone offered limited benefit."

— David Foster, Patient Advocate, Danziger & De Llano

Frequently Asked Questions

Which immunotherapy drugs are FDA-approved for mesothelioma?

Two immunotherapy regimens are FDA-approved for first-line unresectable pleural mesothelioma: nivolumab (Opdivo) plus ipilimumab (Yervoy), approved October 2, 2020 based on CheckMate 743; and pembrolizumab (Keytruda) plus pemetrexed and platinum chemotherapy, approved September 17, 2024 based on KEYNOTE-483. Both are immune checkpoint inhibitors.

Who is eligible for immunotherapy treatment for mesothelioma?

The FDA-approved nivolumab plus ipilimumab combination is indicated for adults with unresectable malignant pleural mesothelioma as a first-line treatment. Patients must have a confirmed MPM diagnosis and disease that cannot be removed by surgery. There is no PD-L1 expression requirement — the CONFIRM trial found that PD-L1 status was not predictive of benefit, so testing is not required for patient selection.

What are the most common side effects of immunotherapy for mesothelioma?

Immunotherapy side effects differ from chemotherapy side effects. Nivolumab can cause immune-mediated adverse events including colitis, hepatitis, and pneumonitis, while anemia is more common with chemotherapy. In CheckMate 743, grade 3-4 treatment-related adverse events occurred in 30% of immunotherapy patients and 32% of chemotherapy patients. Treatment was discontinued because of adverse reactions in 28% of immunotherapy patients and 19% of chemotherapy patients.

Can immunotherapy be combined with surgery for mesothelioma?

Yes. A 2025 phase 2 trial published in Nature Medicine showed that neoadjuvant nivolumab plus ipilimumab given before surgical resection achieved a median overall survival of 28.6 months and median progression-free survival of 19.8 months. Extended pleurectomy/decortication was performed in 9 of the 11 patients who had complete resection (81.8%).

How does immunotherapy compare to chemotherapy for non-epithelioid mesothelioma?

Immunotherapy provides a dramatically greater benefit for non-epithelioid (sarcomatoid and biphasic) mesothelioma than for epithelioid disease. Non-epithelioid patients treated with immunotherapy had a five-year overall survival of 12% versus just 1% on chemotherapy (HR 0.48; 95% CI 0.33–0.68). This makes immunotherapy the clear treatment of choice for non-epithelioid mesothelioma, which historically responded poorly to chemotherapy.

How much does immunotherapy for mesothelioma cost?

A US health economic analysis estimated the total cost of nivolumab plus ipilimumab treatment at approximately $292,319, compared to $95,715 for standard chemotherapy — an incremental cost of roughly $196,604. However, Bristol-Myers Squibb offers patient assistance programs through BMS Access Support, which can reduce co-pays to as little as $0 per infusion for eligible commercially insured patients.

How long does immunotherapy treatment for mesothelioma last?

The FDA-approved regimen continues for up to 24 months or until disease progression or unacceptable toxicity. Nivolumab is administered intravenously at 3 mg/kg every 2 weeks, while ipilimumab is given at 1 mg/kg every 6 weeks. Importantly, patients who stop treatment early due to adverse events still achieve favorable outcomes — a median OS of 25.4 months among those who discontinued for side effects.

Are there clinical trials for mesothelioma immunotherapy currently recruiting?

Yes. As of January 2026, 32 immunotherapy trials are actively recruiting among 93 total mesothelioma clinical trials, with 52 based in the United States. Key trials include neoadjuvant immunotherapy before surgery trials and 5 CAR-T cell therapy trials representing an emerging cellular immunotherapy approach.

Does PD-L1 expression predict immunotherapy response in mesothelioma?

Current evidence suggests PD-L1 expression alone is not a reliable predictor. In the CONFIRM trial, PD-L1 was found to be neither predictive nor prognostic for nivolumab benefit in relapsed mesothelioma. However, a 4-gene inflammatory expression signature identified in the CheckMate 743 three-year update showed correlation with improved immunotherapy benefit, potentially offering a future patient selection biomarker.

What is CAR-T cell therapy and is it available for mesothelioma?

CAR-T (chimeric antigen receptor T-cell) therapy is a form of cellular immunotherapy that engineers a patient's own T cells to recognize and destroy cancer cells bearing a specific target antigen — most commonly mesothelin in mesothelioma. CAR-T is not FDA-approved for mesothelioma as of 2026. All active programs remain in Phase 1 or Phase 1/2 clinical trials. Five CAR-T trials are currently recruiting mesothelioma patients at institutions including Memorial Sloan Kettering, the National Cancer Institute, and the University of Pennsylvania. To qualify, patients typically need confirmed mesothelin expression on tumor biopsy, adequate organ function, and ECOG performance status 0–1.

What is the CART-meso trial?

The CART-meso program refers to the mesothelin-targeted CAR-T clinical trials at Memorial Sloan Kettering Cancer Center, led by Dr. Prasad Adusumilli. The predecessor trial (NCT02414269) tested intrapleural delivery of mesothelin-targeted CAR-T cells combined with pembrolizumab, achieving a median survival of 23.9 months and 83% 1-year OS in 18 mesothelioma patients (mRECIST best response: 12.5% PR, 56.3% SD). The current-generation trial (NCT04577326) is evaluating a next-generation construct called M28z1XXPD1DNR that has a built-in PD-1 decoy receptor. Patients must have malignant pleural disease with mesothelin expression confirmed by immunohistochemistry to be eligible.

What is mesothelin and why is it targeted in mesothelioma?

Mesothelin is a protein found on the surface of mesothelial cells — the cells that line the pleura, peritoneum, and pericardium. In mesothelioma, mesothelin is overexpressed in more than 80% of epithelioid tumors, while normal tissue expression is low. This large difference between tumor and normal expression makes mesothelin an ideal target for CAR-T therapy — the engineered T cells can attack tumor cells while largely sparing healthy tissue. Mesothelin is now the most frequently targeted antigen in solid-tumor CAR-T trials worldwide.

How is CAR-T different from checkpoint inhibitors like nivolumab?

CAR-T and checkpoint inhibitors work through fundamentally different mechanisms. Checkpoint inhibitors like nivolumab and ipilimumab "release the brakes" on the patient's existing immune system, allowing T cells that already recognize the tumor to attack more effectively. CAR-T therapy, by contrast, engineers entirely new cancer-targeting capability by modifying the patient's T cells with a synthetic receptor. Checkpoint inhibitors are FDA-approved for mesothelioma and given as regular infusions over up to 2 years. CAR-T is still investigational, requires patient-specific manufacturing over 3–5 weeks, and is given as a single infusion. Emerging research suggests combining both approaches may be more effective than either alone.

Has CAR-T therapy cured any mesothelioma patients?

No confirmed cures from CAR-T therapy have been reported in published mesothelioma clinical trial data. The most encouraging results come from the MSKCC trial, where 2 of 11 evaluable patients achieved complete metabolic responses on PET scan, and the median overall survival was 23.9 months. However, these are Phase I/II results with small sample sizes and limited follow-up. CAR-T therapy for mesothelioma remains in early development, and while the results are promising, it is too early to determine whether durable complete responses — let alone cures — are achievable. Key challenges include T-cell exhaustion, antigen heterogeneity, and the immunosuppressive tumor microenvironment.

What is pembrolizumab (Keytruda) for mesothelioma — is it FDA-approved?

Yes — pembrolizumab (Keytruda) in combination with pemetrexed and platinum chemotherapy was approved by the FDA on September 17, 2024, for first-line treatment of unresectable malignant pleural mesothelioma. This makes it the third systemic therapy ever approved for mesothelioma. The approval was based on the KEYNOTE-483 trial (n=440), which showed a median overall survival of 17.3 months versus 16.1 months for chemotherapy alone (HR 0.79; p=0.0324). Note that pembrolizumab as a single agent is not approved for mesothelioma — it must be combined with chemotherapy. The nivolumab plus ipilimumab combination (CheckMate 743, approved 2020) remains the other standard first-line immunotherapy option.

Can mesothelioma patients receive both CAR-T and checkpoint inhibitor therapy?

Yes — in fact, the most successful CAR-T results in mesothelioma to date used this exact combination. The MSKCC Phase I/II trial combined intrapleural mesothelin-targeted CAR-T cells with pembrolizumab (a PD-1 checkpoint inhibitor), achieving a 23.9-month median OS and 83% 1-year survival. The rationale is that checkpoint inhibitors can "rescue" CAR-T cells from exhaustion caused by the immunosuppressive tumor microenvironment. Clinical trials combining CAR-T with checkpoint inhibitors are ongoing, and next-generation CAR constructs with built-in checkpoint resistance (such as the M28z1XXPD1DNR construct at MSKCC) aim to achieve the same benefit without requiring separate checkpoint inhibitor therapy.

What is the most promising new immunotherapy approach for mesothelioma in 2026?

Several emerging immunotherapy approaches show promise for mesothelioma in 2026. Perioperative immunotherapy — giving nivolumab plus ipilimumab before surgery — achieved a median survival of 28.6 months in a Phase 2 trial of patients with resectable disease. CAR-T cell therapy targeting mesothelin achieved a 23.9-month median OS at MSKCC, with five trials recruiting patients. TEAD inhibitors like VT3989, which target the Hippo signaling pathway disrupted in many mesotheliomas, achieved an 86% disease control rate in a Phase 1/2 trial and received FDA Fast Track designation. The field is also exploring combinations of these approaches — TTFields plus immunotherapy, CAR-T plus checkpoint inhibitors, and chemoimmunotherapy sequences — to identify the most effective treatment strategies.

External Links

Mesothelioma patients and families can connect with experienced legal and medical advocates:

• Danziger & De Llano can connect families with specialized treatment centers
• Mesothelioma Lawyer Center offers resources on treatment options and legal rights
• Mesothelioma.net provides comprehensive information on immunotherapy and treatment options

Quick Statistics

• 34% of immunotherapy trials focus specifically on mesothelioma — 32 out of 93 actively recruiting mesothelioma trials involve immune checkpoint inhibitors or cellular immunotherapy
• 52 of 93 active mesothelioma clinical trials are based in the United States — giving US patients broader access to experimental immunotherapy regimens
• BAP1 mutations occur in 45.6% of mesothelioma cases — making it the most frequently mutated gene, with potential implications for immunotherapy responsiveness through enhanced immune pathway activation
• Patients with higher tumor mutational burden survived 41.3 months vs. 17.4 months — above-median TMB (greater than 8.3 mutations per megabase) correlated with significantly longer survival in the NIBIT-MESO-1 trial
• DREAM trial reported a 48% objective response rate with durvalumab plus chemotherapy — providing the rationale for the phase 3 DREAM3R trial
• PrE0505 trial achieved 56.4% partial response rate — durvalumab combined with cisplatin and pemetrexed showed a median OS of approximately 20.4 months in US patients
• BEAT-meso quadruple therapy did not meet its primary OS endpoint — median OS 20.5 vs. 18.1 months (HR 0.84, 95% CI 0.66–1.06, p=0.14), though PFS was significantly improved at 9.2 vs. 7.6 months (HR 0.72, 95% CI 0.59–0.89, p=0.0021). Benefit was histology-dependent: in the pre-specified analysis by histology the OS hazard ratio was 1.01 (95% CI 0.77–1.32) in epithelioid disease versus 0.51 (95% CI 0.32–0.80) in non-epithelioid disease (interaction P=0.012)
• 81.8% of patients in the perioperative trial underwent extended pleurectomy/decortication — demonstrating that immunotherapy before surgery does not prevent surgical candidacy in most patients
• Nivolumab plus ipilimumab costs approximately 3 times more than chemotherapy — $292,319 vs. $95,715, yielding 0.53 additional quality-adjusted life years at an incremental cost-effectiveness ratio exceeding standard willingness-to-pay thresholds
• CDKN2A, TP53, and NF2 mutations occur in 21.7%, 17.1%, and 14.3% of mesothelioma cases respectively — behind BAP1, these represent the next most common genomic alterations with potential biomarker implications

Related Resources

• Mesothelioma Types and Histology
• Pleurectomy and Decortication (P/D)
• Mesothelioma Diagnosis and Staging
• Mesothelioma Treatment Options
• Mesothelioma Survival Statistics
• Stage 3 Mesothelioma
• Peritoneal Mesothelioma
• Asbestos Health Effects
• Mesothelioma Settlements