CAR T-Cell Therapy for Mesothelioma: A Reason for Hope

Abstract

I have been representing mesothelioma patients for more than 40 years. A client walked into my office recently stating she was cured. She explained she underwent Car T cell Therapy. I immediately began to research. This is what I found out.

Chimeric Antigen Receptor (CAR) T-cell therapy is a form of immunotherapy that reprograms a patient’s own T cells to target cancer-specific proteins. It has revolutionized the treatment of certain blood cancers, but translating this success to solid tumors like mesothelioma has proven challenging . Mesothelioma is a rare, aggressive cancer often caused by asbestos exposure, and it has few effective treatments. Researchers worldwide are exploring CAR T-cell therapy as a new approach to improve mesothelioma outcomes. Early-phase clinical trials indicate that mesothelioma CAR T-cell therapy – most often targeting the tumor-associated antigen mesothelin – can be delivered safely, with some patients experiencing tumor shrinkage or prolonged disease control . In a landmark study, combining mesothelin-targeted CAR T cells with checkpoint inhibitor immunotherapy achieved a one-year survival rate of over 80% in mesothelioma patients . However, efficacy has been modest overall, and significant challenges remain, including the tumor’s protective microenvironment and the risk of immune-related side effects . This paper reviews how CAR T-cell therapy works, its adaptation for mesothelioma, the latest evidence from clinical trials, current treatment centers and trials, obstacles to success, and future directions. While CAR T-cell therapy for mesothelioma is still experimental (with no regulatory approvals yet), recent FDA fast-track and orphan drug designations underscore its potential . Ongoing trials at leading cancer centers and biotech innovations aim to overcome current limitations, offering hope that CAR T cells could become a viable weapon against mesothelioma in the coming years.

Introduction

Mesothelioma is a rare cancer that affects the mesothelial lining of the lungs (pleura) or abdomen (peritoneum), most commonly linked to asbestos exposure . It is notoriously difficult to treat – surgery rarely removes all tumor cells, and the disease tends to resist standard chemotherapy and radiation. Until recently, only a couple of new therapies had been approved for mesothelioma since 2000 . One breakthrough was the 2020 approval of combination immune checkpoint inhibitors (ipilimumab plus nivolumab), which modestly improved survival. Nonetheless, prognosis remains poor, with a median survival often around 12–18 months for advanced pleural mesothelioma even with aggressive treatment.

In this context, there is an urgent need for novel treatments. Immunotherapy approaches are at the forefront of research. One especially promising strategy is CAR T-cell therapy, which has shown dramatic success in certain leukemias and lymphomas. CAR T-cell therapy involves extracting a patient’s T lymphocytes (a type of white blood cell), genetically engineering them to recognize a specific cancer antigen, expanding those cells in the lab, and infusing them back into the patient . The engineered receptor – a chimeric antigen receptor – enables T cells to latch onto cancer cells and destroy them. Unlike traditional T-cell responses, CARs recognize targets independent of HLA molecules, allowing a robust immune attack directly on tumor cells.

For mesothelioma, researchers have identified the protein mesothelin as a prime target for CAR T cells. Mesothelin is highly expressed on mesothelioma tumor cells in the vast majority of patients (especially epithelioid subtype) but is mostly absent or low in normal tissues . This tumor-associated antigen thus offers a hopeful combination of specificity and ubiquity – an “Achilles’ heel” of the cancer that CAR T cells could exploit with minimal collateral damage to healthy cells . Indeed, mesothelin is also over-expressed in several other difficult cancers (such as ovarian, pancreatic, and certain lung cancers), making it an attractive target across solid tumors .

Translating CAR T therapy to solid tumors like mesothelioma does, however, pose unique hurdles. The solid tumor microenvironment creates physical and immunosuppressive barriers that CAR T cells must overcome – challenges not present in the bloodstream where CAR T therapy first succeeded . Mesothelioma tumors can form a thick rind around the lung, with regions of poor T-cell penetration and immunosuppressive signals that cause T cells to shut down or “exhaust.” Furthermore, mesothelioma’s location (often in the chest cavity) raises safety considerations: mesothelin is present at low levels on normal mesothelial cells lining the pleura and peritoneum, so on-target, off-tumor toxicity is a concern . In the sections that follow, we discuss how scientists have adapted CAR T-cell therapy for mesothelioma, examine evidence from clinical trials, identify where this therapy is being tested, outline key challenges, and consider the future outlook for this cutting-edge treatment.

How CAR T-Cell Therapy Works

CAR T-cell therapy harnesses the patient’s own immune cells to fight cancer in a highly targeted way. The process begins with leukapheresis, in which some of the patient’s T cells are collected from the blood. In a specialized laboratory, these T cells are genetically modified – usually via a viral vector – to insert a gene encoding a chimeric antigen receptor. This CAR is an artificial receptor that typically includes: (1) an extracellular antigen-binding domain (often derived from an antibody) that recognizes a protein on cancer cells, and (2) intracellular signaling domains (such as CD3ζ and co-stimulatory domains like CD28 or 4-1BB) that fully activate the T cell when the CAR binds to the target . In essence, the CAR endows T cells with a new “GPS system” and attack mechanism against cells bearing the target antigen.

Once engineered, the CAR T cells are expanded to large numbers and then infused back into the patient’s bloodstream (after a short course of lymphodepleting chemotherapy to make space for them). When these CAR T cells encounter cancer cells expressing their target antigen, they bind strongly and become activated – releasing toxic granules and inflammatory cytokines that kill the cancer cell. CAR T cells can proliferate further upon activation, acting as “living drugs” that persist and patrol the body for some time.

CAR T therapy has achieved remarkable remission rates in certain blood cancers like B-cell acute lymphoblastic leukemia and large B-cell lymphoma. In those diseases, FDA-approved CAR T products (e.g. tisagenlecleucel and axicabtagene ciloleucel) targeting the B-cell antigen CD19 have produced lasting remissions in patients who exhausted other treatments. However, solid tumors present additional difficulties. Unlike free-floating cancer cells in blood or bone marrow, solid tumor cells reside in dense tissue, often surrounded by a suppressive microenvironment of proteins and cells that fend off immune attacks. Moreover, T cells have trouble homing to and penetrating a solid tumor mass. As a result, CAR T cells have struggled to work against solid tumors like mesothelioma in early trials . They may become trapped or deactivated before eliminating the cancer. Thus, while the principle of CAR T therapy is the same for solid tumors, researchers have had to adapt the delivery and design of CAR T cells to improve their chances in solid tumor settings.

CAR T-Cell Therapy in Mesothelioma

Applying CAR T therapy to mesothelioma has required innovative strategies. The target antigen mesothelin (MSLN) has been the focal point of most efforts, due to its high expression on mesothelioma cells and limited presence on normal tissue . Mesothelin is a cell-surface glycoprotein; in healthy individuals it’s found only in low levels on mesothelial linings, but in mesothelioma (and some ovarian, pancreatic, and lung cancers) it is abundant on tumor cells . This makes mesothelin an ideal bullseye for CAR T cells – it’s like a flag that says “attack here” on the cancer cells, with relatively few flags on normal cells.

Early clinical studies at the University of Pennsylvania were among the first to test mesothelin-targeted CAR T cells in humans. To maximize safety, Penn investigators led by Dr. Carl June used a transient CAR T-cell approach: instead of permanently altering T cells, they electroporated mRNA encoding a mesothelin CAR into the cells, creating CAR T cells that would only express the receptor for a few days . These mRNA-engineered CAR T cells (sometimes called “CART-meso”) were given to a small number of mesothelioma patients. The idea was that if any serious side effects occurred, the CAR T cells would naturally fade away quickly. Encouragingly, this trial demonstrated that CAR T cells could be delivered safely to mesothelioma patients, with some signs of tumor response and no severe off-tumor toxicity reported in initial case studies . However, because the CAR T cells were not long-lived, any clinical benefit was short-term – the modified T cells disappeared and the disease eventually progressed.

Subsequent trials have moved to using fully functional, permanent CAR T cells (produced via viral transduction) but with added precautions to improve their activity and safety in solid tumors. A key adaptation in mesothelioma has been the delivery method. Researchers at Memorial Sloan Kettering Cancer Center (MSKCC) pioneered regional CAR T-cell infusion for pleural mesothelioma. Instead of infusing CAR T cells intravenously (through the bloodstream), they injected the cells directly into the pleural cavity where the mesothelioma tumors reside . Dr. Prasad Adusumilli and colleagues at MSKCC reasoned that by putting the CAR T cells right at the tumor site (via a catheter or image-guided needle into the chest), the cells could immediately interact with tumor nodules before dispersing elsewhere . “Mesothelioma almost always stays within the chest,” Dr. Adusumilli explains. “When you infuse T cells specifically to that spot, they seem to recognize the cancer cells right away and start multiplying” . This approach of intrapleural CAR T-cell delivery helps overcome the homing problem – more of the engineered T cells can penetrate the tumor, and systemic side effects may be reduced since the cells remain concentrated in the cavity initially.

Another adaptation has been to combine CAR T cells with other therapies to keep them functional. One combination is with checkpoint inhibitor drugs (like pembrolizumab, which blocks the PD-1 pathway). These drugs “take the brakes off” T cells that have become exhausted or inhibited by the tumor’s microenvironment. In preclinical research, Adusumilli’s team showed that mesothelin CAR T cells tend to tire out in the pleural tumor unless “rescued” by a PD-1 blocking antibody . Therefore, in their clinical trial they administered pembrolizumab (Keytruda) to patients a few weeks after the CAR T-cell infusion, once it was safe to do so . The checkpoint inhibitor effectively revives the CAR T cells, sustaining their attack on the cancer . This dual therapy – CAR T cells followed by an anti-PD-1 drug – is a form of combination immunotherapy tailored for solid tumors.

Researchers are also experimenting with next-generation CAR T designs to make them more potent against mesothelioma. One example is “armored” CAR T cells, which are T cells genetically equipped with additional features beyond the CAR. MSKCC and Atara Biotherapeutics have co-developed an armored CAR T for mesothelioma that not only carries a mesothelin CAR but also expresses a PD-1 dominant-negative receptor (PD1-DNR), essentially a decoy that neutralizes PD-1 signals in the T cell . By blocking the PD-1 pathway within the CAR T cell, this design aims to make the T cell intrinsically resistant to tumor suppression (so that an external checkpoint drug might not even be needed). Additionally, that CAR T (called ATA2271 in the trial setting) uses a tweaked signaling domain (the “1XX” mutation in CD3ζ) to fine-tune activation strength and improve T-cell persistence . Other groups have engineered CAR T cells to secrete immune-modulating agents at the tumor site – for instance, a Chinese research team is testing mesothelin CAR T cells that secrete tiny anti-PD-1 nanobodies directly in the tumor environment, aiming to locally counteract PD-1 without systemic drugs .

Mesothelioma CAR T research has therefore become a proving ground for these advanced concepts: local delivery, combination therapy, and armored CARs. All share the goal of boosting CAR T-cell efficacy in the inhospitable terrain of a solid tumor. The focus remains on mesothelin-targeted CAR T cells, but researchers are aware of antigen heterogeneity and are keeping an eye on other potential targets. (For example, trials have also explored CAR T cells against fibroblast activation protein and podoplanin in mesothelioma, which are other antigens of interest, though these are in earlier stages.) By and large, mesothelin CAR T therapy has led the way.

Clinical Evidence of Efficacy and Safety

Although CAR T-cell therapy for mesothelioma is still experimental, a number of Phase I clinical trials (and a few Phase I/II) have now reported results. These early studies primarily evaluate safety (to ensure no unexpected severe toxicities) and seek hints of efficacy. Below we review the key findings from several landmark trials:

• MSKCC Phase I Intracavitary CAR T Trial (NCT02414269): This was a first-in-human study of intrapleurally delivered mesothelin CAR T cells in patients with malignant pleural mesothelioma. The CAR T product was an autologous second-generation CAR (with a CD28 co-stimulatory domain) targeting mesothelin, and patients received a single infusion into the pleural space. Notably, most patients (18 out of 27) in later cohorts also received pembrolizumab checkpoint therapy about 6 weeks after CAR T-cell infusion . The results, published in 2021, demonstrated encouraging safety and survival outcomes. No dose-limiting toxicities were observed up to the highest dose tested, and there were no cases of off-tumor organ damage despite mesothelin’s presence on normal pleura . The most common side effects were low-grade inflammation in the chest (some patients had temporary pleuritic pain or fluid buildup that was manageable) . In terms of anti-cancer activity, 22 of 23 evaluable mesothelioma patients experienced disease control (defined as tumor shrinkage or stable disease) following CAR T-cell therapy . Tumor metabolic activity on PET scans reduced in many cases. The best responses included two complete responses (disappearance of active tumor on PET imaging) and five partial responses, with additional patients having prolonged stable disease . Although formal RECIST criteria only confirmed partial responses in a minority (around 12.5% of patients had a PR by CT scans) , the overall impact was that patients’ disease progression was significantly delayed. The median overall survival for mesothelioma patients after CAR T infusion was 17.7 months (95% CI, 13.2 months to not reached) . For those who received the CAR T + pembrolizumab combination, median survival extended to 23.9 months, with 83% of those patients alive at 1 year . This is notable given historical 1-year survival rates around 50–60% for advanced mesothelioma with standard therapies. Dr. Adusumilli noted that some patients in the trial achieved long remissions not seen before in this disease. Moreover, the CAR T cells were detected in patients’ blood for up to 200+ days in some cases , indicating the modified T cells can persist for months. These data, while from a small Phase I cohort, strongly suggested that CAR T cells (augmented by checkpoint blockade) can safely produce lasting disease control in mesothelioma . Based on these findings, the investigators have moved to a Phase II trial to further evaluate efficacy .

• University of Pennsylvania (Penn) Trials: Penn’s initial trials with mesothelin CAR T mRNA (transient CAR T cells) provided important proof of concept for safety. In two patients reported, the approach was feasible and safe, though anti-tumor effects were modest. Penn has since advanced to a next-generation product called SynKIR-110, which is a CAR T cell using a dual-chain KIR-based receptor targeting mesothelin (a slightly different design from traditional CARs) with an added DAP12 signaling domain to enhance T-cell activation . SynKIR-110 is now in a first-in-human Phase I trial (launched in 2023) for mesothelioma and other mesothelin-positive tumors. This therapy, developed by a Penn spin-off company (Verismo Therapeutics), garnered FDA Fast Track designation in April 2023 and Orphan Drug designation in 2022 , reflecting its potential in an unmet medical need. While patient outcome data from the SynKIR-110 trial are not yet available, the fact that regulators granted Fast Track status indicates optimism—this status is intended to speed up development and review of promising new treatments . We await results to see if SynKIR-110’s novel design yields higher response rates or longer remissions in mesothelioma.

• TCR² Therapeutics Gavo-cel Trial (NCT03907852): Biotech company TCR² Therapeutics developed gavocabtagene autoleucel (gavo-cel, formerly TC-210), which is not a classical CAR T but a TCR fusion construct (TRuC) T cell therapy. Gavo-cel’s receptor uses a single-domain antibody against mesothelin fused into the natural T-cell receptor complex, aiming to leverage the full TCR signaling machinery for a potent response . Gavo-cel has been tested in a multicenter Phase I/II trial for various mesothelin-expressing solid tumors, including mesothelioma, ovarian cancer, and cholangiocarcinoma. Interim Phase I results reported in 2021–2022 showed promising anti-tumor activity but also highlighted the need for careful dosing. Among 16 heavily pretreated patients in dose escalation (12 of whom had mesothelioma), tumor regression was observed in 15 patients – meaning almost everyone had some reduction in tumor size . The disease control rate (DCR) (tumor response or stable disease) was 81%, and the overall response rate (ORR) was around 31% (about 25–31% of patients achieved a partial response depending on assessment criteria) . Notably, three mesothelioma patients had confirmed partial responses. Median progression-free survival was ~5.9 months, and median overall survival was ~11.2 months in these advanced cases – outcomes that compare favorably to historical controls given these patients had a median of 5 prior therapy lines . However, safety concerns emerged at higher doses. At the highest dose level tested (5×10^8 CAR T cells per square meter), severe toxicities occurred: all three patients at this level experienced Grade 3 cytokine release syndrome (a systemic inflammatory reaction), and one patient suffered a Grade 5 (fatal) bronchoalveolar hemorrhage in the lung . Investigators identified this as a dose-limiting toxicity and established a lower maximum tolerated dose of 1×10^8 cells/m^2 after lymphodepletion . High-grade pneumonitis (lung inflammation) was also noted in 16% of patients overall, though none at the recommended Phase II dose . These events underline the narrow therapeutic window for gavo-cel and the need to balance potency with safety . The trial has since adjusted to a split-dose regimen and continues to Phase II with combination strategies (adding checkpoint inhibitors, etc.) to improve outcomes . Despite the risks, the observed responses across multiple tumor types were encouraging enough that gavo-cel received FDA Orphan Drug status for mesothelin-positive cholangiocarcinoma and mesothelioma . This trial is a valuable demonstration that mesothelin-targeted T cells can shrink solid tumors, but it also highlights the challenge of toxicity – likely related to on-target effects in the lungs or pleura at high cell doses.

• Atara MSKCC Armored CAR (ATA2271) Trial: Building on their Phase I success, MSK and Atara launched a trial of the next-gen ATA2271 armored CAR T (with the 1XX signaling tweaks and PD-1 decoy described earlier). This trial (NCT04577326) started in late 2020, but in 2022 it encountered a setback when a patient treated at the highest dose level died from a serious adverse event . The details were not fully disclosed, but the trial was voluntarily paused for investigation . The patient had advanced disease and comorbidities, and it’s being evaluated whether the death was related to the therapy . Importantly, at lower doses, ATA2271 had shown no dose-limiting toxicities in 6 patients, and the CAR T cells demonstrated good persistence (surviving and expanding) in patients . The pause, however, underscores the potential risks of highly potent CAR T cells – even with local delivery and added safety features, a strong immune response can tip into fatal toxicity in fragile patients. As of the latest updates, the trial’s enrollment remained on hold pending safety review. Atara and MSK are also developing an off-the-shelf (allogeneic) version of this CAR T (ATA3271) using donor-derived T cells and gene edits (including PD1-DNR and 1XX) to treat mesothelioma without needing to harvest the patient’s own cells . Allogeneic CAR T products could make therapy more accessible if safety can be managed.

• Other Notable Studies: In China, at least one mesothelin CAR T trial (NCT04489862) is ongoing at Wuhan Union Hospital, testing CAR T cells engineered to secrete anti-PD-1 nanobodies – effectively combining cell therapy and checkpoint blockade in one package . This trial, initiated in 2022, is still in early phases but reflects global interest in the armored CAR T approach. Additionally, investigators in Japan and Europe have explored CAR T cells targeting podoplanin, another mesothelioma-associated antigen, and early-phase results showed feasibility and some tumor responses, though this research is in its infancy compared to the mesothelin programs.

Overall, the clinical evidence to date suggests that CAR T-cell therapy for mesothelioma can achieve disease control and occasional deep responses, with manageable safety at appropriate doses. Many patients in trials have experienced stable disease or slow progression, which is a meaningful achievement in this aggressive cancer. However, cure or outright tumor eradication remains rare so far – complete responses are very infrequent. The tumor often eventually finds ways to resume growth, indicating that improvements are needed to make CAR T cells more effective and durable in solid tumors. On a positive note, nearly all trials report minimal “on-target/off-tumor” toxicity in terms of attacking healthy tissues that express mesothelin at low levels . This validates mesothelin as a reasonably safe target. The main serious side effects seen (like cytokine release syndrome or pneumonitis) are typically related to the intensity of immune activation, not misguided targeting – in other words, the CAR T cells are hitting the tumor, but the collateral inflammation can affect lungs or other organs. Researchers are actively addressing these issues through dosing strategies and drug prophylaxis.

Hospitals and Trials: Where CAR T is Offered for Mesothelioma

Because mesothelioma CAR T-cell therapy is still experimental, it is only available in clinical trials at specialized centers. Below are some of the prominent institutions and ongoing trials (as of 2025) involved in administering CAR T-cell therapy to mesothelioma patients:

• Memorial Sloan Kettering Cancer Center (New York, USA): MSKCC has been at the forefront of mesothelioma CAR T research. It conducted the first-in-world intrapleural CAR T trial led by Dr. Prasad Adusumilli . MSK continues to run CAR T trials, including the Phase II of mesothelin CAR T with pembrolizumab and the now-paused ATA2271 armored CAR T trial. Patients in MSK trials receive CAR T-cell infusion on site, often followed by immunotherapy. MSK’s Cell Therapy Center, led by experts like Dr. Isabelle Riviere and Dr. Michel Sadelain, is a leading facility for CAR T-cell production .

• National Cancer Institute (Bethesda, Maryland, USA): The NCI (part of NIH) launched a major trial in 2025 testing a novel mesothelin-targeted CAR T product called TNhYP218 . This is a 100-patient Phase I/II trial led by Dr. Raffit Hassan, who is a renowned mesothelioma researcher. The trial is open to mesothelioma and other mesothelin-positive solid tumors and involves engineering patients’ T cells with a TNaïve/SCM CAR construct (details are emerging) . All treatment is being done at the NIH Clinical Center in Bethesda. As a government-sponsored trial, there is no cost to participate, and the NCI can accept patients from across the country who meet eligibility (e.g. tumor must have >50% mesothelin expression) . This trial signals a strong commitment by federal research to advancing CAR T therapy for mesothelioma.

• Abramson Cancer Center of the University of Pennsylvania (Philadelphia, USA): Penn Medicine’s Abramson Cancer Center, where CAR T therapy was first developed for leukemia, is also involved in mesothelioma CAR T work. The SynKIR-110 trial (Verismo Therapeutics) is expected to treat patients at Penn, given the company’s roots as a Penn spinout . Penn’s Abramson Center has a dedicated T-cell therapy program and was one of the first to treat mesothelioma patients with CAR T cells in early studies. Patients seeking CAR T trials in the mid-Atlantic region often go to Penn to inquire about ongoing studies or compassionate use programs.

• MD Anderson Cancer Center (Houston, Texas, USA): MD Anderson was a site for the gavo-cel (TC-210) trial by TCR² Therapeutics. In fact, Dr. David Hong of MD Anderson was a principal investigator who presented interim results . This world-renowned cancer center has extensive immunotherapy and cell therapy clinical trial infrastructure. As of 2023, the gavo-cel trial’s Phase II expansion is continuing, potentially involving MD Anderson and other centers. MD Anderson also has its own research efforts on CAR therapies for solid tumors. Mesothelioma patients in the South Central US have sought out trials at MD Anderson due to its expertise.

• Other US Centers: Besides the above, other hospitals participated in the multi-center gavo-cel trial, such as Massachusetts General Hospital in Boston, Mayo Clinic in Rochester, and Washington University in St. Louis (based on trial site listings). Additionally, Baylor College of Medicine (Houston) has conducted CAR T research for thoracic cancers and may have trials targeting mesothelin or other antigens. Some mesothelioma patients have also been treated in CAR T trials focusing on related cancers (e.g. a lung cancer CAR T trial at Providence Cancer Institute in Oregon allowed mesothelioma patients with mesothelin expression).

• International Centers: In China, as mentioned, Wuhan Union Hospital in Hubei is conducting a CAR T trial for mesothelin-positive solid tumors (including mesothelioma) using PD-1-armored CAR T cells . China has several companies and academic centers actively developing CAR T therapies for solid tumors, so we may see more Chinese trials for mesothelioma in coming years. In Australia, the Asbestos Diseases Research Institute (ADRI) in Sydney and collaborators have been investigating mesothelin-targeted immunotherapies; while Australia’s first CAR T approvals have been in leukemia, plans for mesothelioma CAR T trials are being formulated by research groups there (some of the authors of a 2021 review on mesothelioma CAR T were from ADRI, indicating interest ). In Europe, mesothelioma CAR T trials have been limited so far. However, a clinical program in France is reportedly exploring an allogeneic CAR T for mesothelioma, and the UK’s Cell and Gene Therapy Catapult has partnered with TCR² to enable manufacturing of TRuC-T cells in Europe , which could facilitate future trials in the EU/UK.

It’s important to note that outside of a trial, one cannot receive CAR T-cell therapy for mesothelioma at this time. Patients interested in these therapies must enroll in research studies. Resources like clinicaltrials.gov and cancer center websites are useful for finding active trials. Additionally, mesothelioma patient advocacy groups (e.g. Mesothelioma Applied Research Foundation) can help patients locate trials and even assist with travel arrangements to specialized centers. As of mid-2025, roughly a dozen CAR T trials specific to mesothelioma or mesothelin-positive cancers are ongoing globally, reflecting a growing but still nascent field.

Challenges and Limitations

While the progress to date is encouraging, CAR T-cell therapy faces significant challenges in mesothelioma (and solid tumors generally). These hurdles must be overcome to achieve consistent, life-extending benefits akin to those seen in blood cancers. Key challenges include:

• Tumor Microenvironment (TME) Suppression: The mesothelioma tumor creates an immunosuppressive niche around itself. Within the pleural tumors are regulatory T cells, myeloid-derived suppressor cells, and inhibitory molecules (like TGF-β and IL-10) that collectively dampen T-cell activity. CAR T cells entering this environment often become exhausted or inactive over time . The TME also has high levels of PD-L1 (the ligand for PD-1), which can shut down CAR T cells unless counteracted . This is why approaches such as adding checkpoint inhibitors (to block PD-1/PD-L1) or building PD-1 resistance into CAR T cells are so crucial. Additionally, mesotheliomas are fibrous tumors – a dense stroma can physically limit T-cell infiltration. Some strategies to address this include combining CAR T therapy with drugs that modify the stroma or using local delivery and repeated dosing to flood the tumor with T cells. Preclinical studies are investigating novel combinations, such as CAR T cells with oncolytic viruses (viruses that selectively infect tumors and make them more immunologically “hot”) or with targeted radiation (to inflame the tumor microenvironment and attract T cells). Overcoming the TME is central to improving CAR T efficacy in solid tumors.

• Antigen Heterogeneity and Escape: Mesothelioma tumors, like most cancers, can be heterogeneous – not all cells express the target antigen at high levels. Mesothelin is expressed in a majority of mesothelioma cells, but there can be variability (some cells or regions with lower expression) . There is a risk that if CAR T cells wipe out the mesothelin-high cells, any mesothelin-low cancer cells could survive and grow (“antigen escape”). This phenomenon has been observed in other CAR T settings (e.g. some leukemias lose CD19 to evade CAR T). In mesothelioma, outright antigen loss has not been widely reported yet, but it remains a concern. To counter this, researchers are considering dual-target CAR T cells that can recognize two antigens (for example, mesothelin and a second marker) to reduce the chance of tumor escape. Another approach is sequential or combo therapy – using CAR T cells in combination with other treatments that kill mesothelin-negative cells (such as chemotherapy or another immunotherapy). Continuous monitoring of patient tumor samples before and after CAR T therapy is ongoing to see if antigen patterns change.

• On-Target, Off-Tumor Toxicity: Mesothelin-targeted CAR T cells carry an inherent risk: they could attack normal tissues that have mesothelin. In healthy adults, mesothelin is present at low levels on the lining of the pleura, peritoneum, and pericardium. It’s also found on a fraction of cells in the lungs and other organs at very low levels. CAR T cells, especially if highly avid, might recognize these normal cells as targets, leading to potentially dangerous inflammation in vital organs. In fact, severe “on-target” toxicity has been reported in past trials when using certain high-affinity mesothelin CAR T cells . For example, two patients in an early trial experienced lethal lung failure attributed to CAR T cells attacking normal pleural tissue . More recently, the case of fatal respiratory hemorrhage in the gavo-cel trial (at a high dose) raised concerns that the intense immune response in the pleura/lungs could have been an on-target reaction exacerbated by heavy tumor burden in the chest . To mitigate this risk, scientists are tuning the affinity of CARs – surprisingly, a slightly lower-affinity CAR may be more specific for tumor cells (which have abundant antigen) and spare cells with only a little antigen . A 2024 study demonstrated that ultra-high-affinity mesothelin CARs caused fatal toxicity in mice (by attacking normal tissue), whereas affinity-reduced CARs still killed mesothelin-rich tumors but did not harm normal cells . This finding is influencing CAR design going forward. Moreover, local delivery (like intrapleural infusion) helps concentrate CAR T cells at the tumor, potentially reducing systemic exposure and off-tumor attacks – the MSK trial using regional delivery saw no off-tumor organ toxicities . As an extra safety layer, some CAR T constructs include a “suicide switch” gene, allowing doctors to infuse a benign molecule that triggers self-destruction of the CAR T cells if severe toxicity occurs . Thankfully, across trials to date, side effects attributable to off-tumor mesothelin recognition have been relatively limited, suggesting a workable therapeutic window when dosing and design are optimized.

• Cytokine Release Syndrome (CRS) and Immune Reactions: A common side effect of CAR T therapy is CRS – a systemic inflammatory syndrome with fever, low blood pressure, and potential organ dysfunction caused by a flood of cytokines (immune signaling molecules) released by activated T cells. CRS was observed in several mesothelioma CAR T trials, especially at higher doses. In the gavo-cel trial, for instance, all patients at the highest dose level had severe CRS . Even at moderate doses, some patients experience fevers and inflammation requiring management with drugs like tocilizumab (an IL-6 blocker) or steroids. CRS can usually be managed if promptly recognized, but it adds risk and often necessitates in-hospital monitoring for at least a week post-infusion. Mesothelioma patients often have compromised lung function to start with (due to tumor and prior treatments), so a vigorous inflammatory reaction in the chest can be harder to tolerate. This makes CRS management in mesothelioma CAR T trials particularly important. Research is ongoing into preemptive strategies (for example, using prophylactic tocilizumab or designing CAR T cells that release fewer inflammatory cytokines). Another related phenomenon is immune cell-associated neurotoxicity syndrome (ICANS) – a transient neurotoxic effect seen in some CAR T therapies – though it has been rarely reported in mesothelioma CAR T trials, possibly because the T cells localize to the chest rather than circulating broadly (ICANS is more common when there is high CAR T cell expansion in the bloodstream, affecting the brain). Nonetheless, careful neurological monitoring is part of trial protocols.

• Manufacturing and Logistic Hurdles: CAR T-cell therapy is personalized and complex. Each patient’s T cells must be harvested, engineered in a specialized facility, and tested for quality. This process can take 1–2 weeks or more, during which a mesothelioma patient’s disease might progress. Mesothelioma patients often have had multiple prior therapies and can be in a weakened state; not all patients will have T cells robust enough to expand to a therapeutic dose. Manufacturing failures or delays can occur. Furthermore, access to these trials is limited – patients may have to travel to the trial site and meet strict eligibility criteria. All these factors mean that CAR T is currently not an “off-the-shelf” solution and is only available to a subset of patients. Companies like Atara are working on allogeneic (donor-derived) CAR T cells that could be banked and ready on demand , which might simplify logistics in the future. But for now, the time and resource intensiveness of CAR T-cell production is a limiting factor. On the regulatory side, ensuring consistent product potency and safety is also challenging in multi-center trials.

Despite these challenges, the field is rapidly learning and evolving. Each trial setback – whether toxicity or insufficient efficacy – is met with new ideas to surmount the problem. For instance, the problem of T-cell exhaustion is being addressed not only by PD-1 blockade but also by optimizing T-cell phenotypes: researchers are exploring the use of younger T cells (stem cell memory T cells) to make CAR T products that persist longer and function better . To improve infiltration, teams are testing chemokine-modified CAR T cells that are better at migrating into tumors. And to avoid antigen escape, bispecific CAR T cells (CARs with two different antigen binders) are under development.

In summary, applying CAR T-cell therapy to mesothelioma is not as straightforward as it was in B-cell leukemia. The solid tumor context raises numerous barriers – from the tumor’s defensive tactics to therapy delivery issues – but none of these appear insurmountable. It may require a combination of modifications and adjunct therapies to unlock CAR T cells’ full potential against mesothelioma. The current trials are as much about engineering solutions to these challenges as they are about treating patients.

Future Outlook

The future of CAR T-cell therapy for mesothelioma is one of cautious optimism. While there is much work to be done, the progress over the last decade has established a solid foundation. Looking ahead, several trends and developments are likely to shape the trajectory of this therapy:

• Enhanced CAR Designs: We expect to see next-generation CAR constructs moving into trials. These include CAR T cells that secrete supportive cytokines (so-called “TRUCKs” or T cells redirected for antigen-unrestricted cytokine killing), CAR T cells with genetic “programs” to resist exhaustion, and multi-antigen targeting CARs. For mesothelioma, a conceivable strategy is a CAR T cell that targets mesothelin and a second antigen (perhaps a tumor vasculature marker or another mesothelioma antigen) to prevent tumor escape and simultaneously disrupt the tumor stroma. Preclinical research is also exploring switchable CARs – systems where the CAR T cell is inactive until a small molecule drug is given, which could help control timing and intensity of the immune attack to improve safety. The emphasis will be on improving potency without sacrificing safety, essentially sharpening the spear but also shielding normal tissues. Affinity tuning of CARs (to strike the right balance in recognizing mesothelin) is an active area that will feed into future designs .

• Combination Therapies as Standard: Just as chemotherapy is often combined with radiation or surgery in mesothelioma, CAR T therapy will likely become one component of a multimodal approach. The combination with checkpoint inhibitors has already shown synergy . In the future, we might routinely combine CAR T cells with other immunotherapies – such as oncolytic viruses, cancer vaccines, or agonist antibodies (stimulating T-cell activity) – to boost their effectiveness. For example, an oncolytic virus that infects mesothelioma cells could inflame the tumor and attract CAR T cells to it, enhancing infiltration. Or a localized low-dose radiation to a tumor site before CAR T infusion could act as a beacon by causing tumor cells to release signals that draw CAR T cells in (this concept, sometimes called radiotherapy-induced antigen spreading, is being investigated). The timing and sequencing of such combinations will be critical – e.g., giving CAR T cells time to home to the tumor, then introducing a checkpoint inhibitor to sustain them, as was done in the MSK trial .

• Regulatory Pathways and Approvals: As data accumulates, we anticipate that one or more mesothelioma-directed CAR T therapies could earn FDA Breakthrough Therapy designation if they show substantial improvement in patient outcomes in early trials. (Breakthrough designation would expedite development and review.) As of 2025, none have Breakthrough status yet, but the Fast Track for SynKIR-110 is a step in that direction. Achieving full FDA approval will likely require a successful Phase III trial demonstrating that CAR T therapy improves survival or durable response rates compared to standard care. Given mesothelioma’s rarity, single-arm pivotal trials might suffice if the results are dramatic (with historical controls as comparators), or a randomized trial might be done where one arm is CAR T plus standard care vs. standard care alone. The regulatory agencies (FDA, EMA) are watching these developments closely, and they have shown flexibility in approving innovative treatments for rare, lethal cancers. Orphan Drug designations (already granted to several mesothelin CAR products ) will provide incentives like fee waivers and market exclusivity to developers. If a particular CAR T approach demonstrates, say, a doubling of 1-year survival or a significant subset of complete responders, approval could follow relatively swiftly. A realistic timeline might be within the next 5–7 years for the first approved mesothelioma CAR T therapy, assuming Phase II trials in the next couple of years are positive.

• Commercial Development and Industry Involvement: Multiple biotech and pharmaceutical companies are now invested in mesothelioma CAR T therapy, which should accelerate progress. TCR² Therapeutics (developer of gavo-cel) is advancing its TRuC-T cell platform and may partner or be acquired by a larger company to fund late-phase trials. Atara Biotherapeutics, in partnership with Bayer, is working on both autologous and allogeneic mesothelin CAR T programs (although Bayer recently opted to step back from the collaboration , Atara is continuing development). Verismo Therapeutics and by extension Penn are pushing the novel KIR-CAR design (SynKIR-110). Additionally, major CAR T players like Novartis and Kite/Gilead might enter the fray if proof-of-concept solid tumor CAR T successes emerge – these companies have the manufacturing capability and experience with CAR T approvals in hematologic cancers. There are also companies developing TCR-mimic approaches (targeting intracellular mesothelioma antigens via TCR-engineered cells) and alternative cell therapies (like CAR natural killer cells) for mesothelioma. The involvement of industry is crucial as it brings the resources to run large trials and eventually commercialize a product. For patients, this means more trials will be available and, hopefully, eventual access outside of trials if a therapy gets approved.

• Global Access and Centers of Excellence: We may see the rise of specialized centers (or networks) for delivering cell therapies for mesothelioma. These “centers of excellence” will have the infrastructure to manage CAR T toxicities and the expertise in mesothelioma care. It’s likely that initially, only select major cancer centers in each region will offer an approved CAR T for mesothelioma, given the complexity. Over time, as logistics improve (e.g., with allogeneic products or faster manufacturing), availability could broaden. Importantly, scientists around the world continue to collaborate. Mesothelioma is a rare disease, so global collaboration is necessary to enroll trials and share insights. The future might include international trials that pool patients from multiple countries – something already seen in the nature of authorship on recent studies (for example, the Nature Medicine 2023 interim results for gavo-cel had investigators from the US and Canada and was led in part by NCI’s Dr. Hassan ).

• Patient Outcomes and Quality of Life: If CAR T-cell therapy can induce long-term remissions, it could transform mesothelioma management. Even if not curative for all, extending survival by a year or more with good quality of life would be a major win. One encouraging aspect observed is that patients who respond tend to report feeling better as the tumor burden decreases. Mesothelioma symptoms like chest pain, shortness of breath, and fatigue might improve when CAR T therapy controls the disease. Quality of life will be an important consideration; unlike systemic chemotherapy, CAR T is a one-time (or limited-time) treatment followed by monitoring. Some patients from trials have returned to normal activities during remission, not needing continuous treatment. As CAR T protocols get refined, outpatient administration might become feasible (currently, most patients are hospitalized around the infusion time as a precaution). In the future, we can imagine a scenario where a mesothelioma patient gets diagnosed, undergoes standard debulking surgery or chemo if needed, and then receives CAR T-cell therapy to mop up residual disease and prevent recurrence – thus using CAR T as part of first-line or consolidation therapy, not just as a last resort. That is the hope: to move from end-stage trials to treating earlier in the disease where the chances of long-term cure could be higher.

In conclusion of the outlook, CAR T-cell therapy for mesothelioma is on a promising yet steep trajectory. The next few years will likely bring clearer answers on which approaches yield the best balance of safety and efficacy. Each iteration of clinical trial teaches researchers more about what modifications are needed. It’s a story of incremental engineering improvements that, cumulatively, could result in a therapy that genuinely changes the fate of mesothelioma patients. Beyond mesothelioma, success here would also open doors for CAR T therapies targeting other solid tumors, benefiting the broader cancer field.

Conclusion

CAR T-cell therapy represents a bold and innovative paradigm in the fight against mesothelioma. What began as a daring idea – reprogramming the immune system to attack an aggressive, treatment-resistant tumor – has progressed to tangible clinical reality in the form of multiple ongoing trials worldwide. In this comprehensive review, we have seen that CAR T cells can indeed be marshaled against mesothelioma, with early trials demonstrating safety and instances of tumor regression. The most developed approach targets mesothelin, a protein that mesothelioma wears on its surface like a badge. By aiming for this badge, CAR T cells have managed to infiltrate tumors, trigger cancer cell deaths, and in some patients, hold the disease at bay for many months .

However, the journey from experimental therapy to standard care is not yet complete. Mesothelioma poses unique challenges – a hostile tumor microenvironment, potential antigen escape, and the ever-present concern of harming normal tissues. The clinical experience so far reveals modest efficacy: the majority of patients derive clinical benefit (disease stabilization or minor shrinkage), but deep and lasting remissions are observed in a minority . This tells us that current CAR T strategies hit the target but need a heavier punch. Through ongoing refinements – from arming CAR T cells with intrinsic immune boosters, to combining them with checkpoint inhibitors and other therapies – scientists are aiming to amplify that punch. The example of one trial achieving 2-year survivors in a cancer that often takes lives in a year underscores the potential if we can optimize the approach .

Safety has been encouragingly manageable in most studies, affirming that a properly designed mesothelin CAR T can distinguish cancer from normal tissue. Yet, we have also been reminded of the fine line between an all-out immune attack on the tumor and collateral damage. Cytokine storms and inflammatory side effects must be carefully controlled, and tragically, at least one life was lost in a dose-escalation attempt . Each such event refines our understanding and protocols, ensuring future patients will be safer. The field is moving prudently, with patient safety as the top priority.

From a regulatory and global perspective, the interest in mesothelioma CAR T therapy is accelerating. The FDA and EMA have signaled support by granting special statuses like Fast Track and Orphan Drug to products in development . These not only encourage companies to invest in this rare cancer but also lay groundwork for smoother approval processes if efficacy is proven. Across North America, Europe, Asia, and Australia, leading cancer centers are collaborating on trials – a testament to a unified global effort against this disease.

It is quite possible that in the next decade, a mesothelioma patient might be offered CAR T-cell therapy as part of a standard treatment regimen, especially if diagnosed at an early stage or if the disease recurs after initial therapy. The vision would be turning mesothelioma from a near-certain terminal diagnosis into a more chronic condition or even achieving long-term remissions, using the patient’s own immune cells as a living drug. While we are not there yet, each trial and each scientific innovation brings us one step closer.

In closing, CAR T-cell therapy for mesothelioma stands as a beacon of hope on the horizon of cancer treatment. It exemplifies the power of modern biomedical science – merging immunology, genetics, and engineering – to tackle a formidable foe. The path has challenges, but also clear signs of progress: tumors shrinking, patients living longer, and knowledge expanding. With continued research, smart trial design, and patient participation, the dream of defeating mesothelioma with a patient’s reengineered T cells becomes ever more attainable. This global endeavor may very well yield one of the first effective cell therapies for a solid tumor, transforming outcomes for mesothelioma and paving the way for many other cancers to follow.

References

1. Castelletti L. et al. (2021). “Anti-Mesothelin CAR T cell therapy for malignant mesothelioma.” Biomarker Research, 9:11. Open access review detailing mesothelin-targeted CAR T strategies, clinical trial results, and challenges .

2. Adusumilli PS. et al. (2021). “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, 11(11):2748–2763. First-in-human study at MSKCC showing safety and potential efficacy of intrapleural CAR T with checkpoint inhibitor .

3. Memorial Sloan Kettering Cancer Center – On Cancer Blog (2020). “CAR T Cell Therapy Shows Promise for Treating Mesothelioma.” Interview with Dr. Prasad Adusumilli. Describes how the therapy works, trial outcomes (83% 1-year survival with CAR T + Keytruda), and next steps in research .

4. Johnson V. (2021). “Gavo-Cel Efficacious in Refractory Mesothelin-Expressing Solid Tumors.” CGTLive (October 6, 2021). Reports interim results of TCR² Therapeutics’ gavo-cel (TC-210) trial: 81% disease control rate, partial responses in mesothelioma, and identified toxicity at high doses .

5. Golden D. (2023). “FDA Grants Fast Track Designation to CAR T-cell Therapy for Mesothelioma.” Mesothelioma Guide (April 27, 2023). News of FDA fast track for Verismo’s SynKIR-110 CAR T, with explanation of its mesothelin targeting and prior orphan designation .

6. Rodgers T. (2025). “Clinical Trial to Test New Mesothelioma CAR T-Cell Immunotherapy.” News (July 22, 2025). Announcement of a 100-person NCI trial for mesothelioma using a new CAR T (TNhYP218), including patient eligibility and context that CAR T is not yet standard therapy .

7. Yang YY. et al. (2024). “Affinity-tuned mesothelin CAR T cells demonstrate enhanced targeting specificity and reduced off-tumor toxicity.” JCI Insight, 9(22):e186268. Preclinical study showing high-affinity CARs caused fatal off-tumor effects, whereas lower-affinity CARs were safer and still effective .

8. Hassan R. et al. (2023). “Mesothelin-targeting T cell receptor fusion construct cell therapy in refractory solid tumors: phase 1/2 trial interim results.” Nature Medicine, 29:2099–2109. Interim analysis of the gavo-cel trial across mesothelioma, ovarian, and cholangiocarcinoma patients, detailing 20% ORR (13% confirmed) and 77% DCR, with commentary on a narrow therapeutic window .

9. CGTLive News (2022). “Enrollment Pauses in Mesothelioma CAR T-Cell Therapy Trial.” CGTLive (Feb 22, 2022). Report on the ATA2271 trial pause after a patient death at MSKCC, emphasizing safety review and dose considerations .

10. TCR² Therapeutics Press Release (2019). “TCR² Therapeutics Receives FDA Orphan Drug Designation for TC-210 for Mesothelioma.” (Feb 2019). SEC filing excerpt confirming orphan status for gavo-cel (TC-210) in mesothelioma .