CAR-T Cell Therapy for Mesothelioma

What Is CAR-T Cell Therapy?

CAR-T (Chimeric Antigen Receptor T-cell) therapy is a form of immunotherapy that uses a patient’s own immune cells, genetically engineered to recognize and attack cancer. Unlike checkpoint inhibitors that release the “brakes” on the immune system, CAR-T therapy creates an entirely new weapon, T-cells specifically designed to find and kill mesothelioma cells.

This approach has transformed treatment for certain blood cancers (leukemias and lymphomas), with some patients achieving complete remission. Now researchers are adapting this technology for solid tumors like mesothelioma.

How CAR-T Therapy Works

The process involves several steps:

1. Collection (Leukapheresis)

T-cells are extracted from the patient’s blood through a process similar to blood donation. These are the immune cells that will be modified.

2. Engineering

In a laboratory, the T-cells are genetically modified using viral vectors (typically lentivirus) to express a chimeric antigen receptor (CAR). This receptor is designed to recognize a specific protein on cancer cells.

3. Expansion

The modified CAR-T cells are multiplied in the laboratory until there are hundreds of millions of them, enough to mount an effective attack on the tumor.

4. Conditioning

Before receiving CAR-T cells, patients undergo lymphodepleting chemotherapy (typically fludarabine and cyclophosphamide) to make “space” for the new cells and reduce immune suppression.

5. Infusion

The engineered cells are infused back into the patient, where they seek out cancer cells expressing the target protein.

6. Attack

When CAR-T cells encounter their target, they:

• Bind to the cancer cell
• Activate and proliferate
• Release cytotoxic granules (perforin and granzymes)
• Produce interferon-gamma (IFN-γ)
• Directly kill the tumor cell

Why Mesothelin?

Most mesothelioma CAR-T therapies target mesothelin (MSLN), a protein that is:

• Highly expressed on 75–90% of pleural mesothelioma cells
• Minimally present on normal tissues (limited to mesothelial surfaces)
• An ideal target because CAR-T cells attack tumors while largely sparing healthy tissue

Mesothelin is also overexpressed in ovarian cancer, pancreatic cancer, and lung adenocarcinoma, making these therapies potentially applicable to multiple cancer types.

Current Clinical Trials

SynKIR-110 (STAR-101 Study)

FDA Status: Fast-track designation (2023)

SynKIR-110 is an autologous T-cell therapy using a novel KIR-CAR (Killer Immunoglobulin-like Receptor CAR) design that may enhance recognition and killing of mesothelin-expressing cells.

Trial Sites:

• MD Anderson Cancer Center (Houston, TX)
• University of Pennsylvania (Philadelphia, PA)
• University of Wisconsin Carbone Cancer Center (Madison, WI)
• University of Kansas Cancer Center (Westwood, KS)

Eligible Cancers: Mesothelioma, ovarian cancer, cholangiocarcinoma

The FDA fast-track designation recognizes SynKIR-110’s potential to address a serious condition with unmet medical need, allowing for expedited review processes.

A2B694 (EVEREST-2 Study)

A mesothelin-targeting CAR-T therapy being evaluated for mesothelioma, lung cancer, and ovarian cancer.

Status: Currently recruiting Results Expected: 2029

Logic-Gated CAR-T (Tmod Platform)

A seamless Phase 1/2 study evaluates mesothelin-targeting Tmod CAR-T products in patients with recurrent, unresectable, or metastatic solid tumors. The “logic-gated” design may improve specificity and safety.

CAR-T + Checkpoint Inhibitor Combinations

Researchers are combining CAR-T therapy with checkpoint inhibitors (pembrolizumab, nivolumab) to:

• Prevent T-cell exhaustion
• Enhance tumor killing
• Extend duration of response

Engineering Advances

Researchers are developing next-generation CAR-T approaches to overcome solid tumor challenges:

Metabolic Engineering

The tumor microenvironment creates hostile conditions for CAR-T cells through elevated adenosine and nutrient restriction. New approaches include:

• ADA1-expressing CAR-T cells that convert adenosine to inosine, improving cell survival
• Enhanced metabolic flexibility for better persistence
• Reduced exhaustion markers (lower PD-1, TIM-3, LAG-3 expression)

Alternative Cell Sources

NK Cell-Based Approaches:

• Natural killer (NK) cells precomplexed with bispecific engagers
• Cytokine-induced memory-like programming (IL-12/15/18)
• Tumor-penetrating peptides for enhanced infiltration

Armed CAR-T Strategies

• Oncolytic viruses (IL-12-armed HSV-2) to improve tumor microenvironment
• Direct intratumoral injection for better penetration
• Combination with radiation therapy

Early Results

While mesothelioma-specific CAR-T results are still emerging from Phase 1 trials, early data shows promise:

• ~30% tumor reduction observed within weeks in some patients
• Low severe CRS rates compared to blood cancer CAR-T
• Durable responses in select patients

However, mature efficacy data from completed mesothelioma trials is not yet published. Results from ongoing trials will provide clearer guidance on survival benefits.

Potential Side Effects

CAR-T therapy can cause significant side effects that require specialized management:

Cytokine Release Syndrome (CRS)

When CAR-T cells activate, they release inflammatory signals (cytokines) that can cause:

• Fever
• Low blood pressure
• Difficulty breathing
• Organ dysfunction

Management: Tocilizumab (IL-6 blocker), steroids, supportive care

CRS occurs in 70–90% of blood cancer CAR-T patients but may be lower in solid tumor trials.

Neurotoxicity (ICANS)

Immune Effector Cell-Associated Neurotoxicity Syndrome can cause:

• Confusion
• Difficulty speaking
• Tremors
• Seizures (rare)

Usually temporary and reversible with treatment.

Other Considerations

• Infection risk during lymphodepletion and recovery
• Prolonged cytopenias (low blood counts)
• Tumor lysis syndrome (rare in solid tumors)

Challenges in Solid Tumors

CAR-T therapy has been more successful in blood cancers than solid tumors. Mesothelioma presents specific challenges:

Physical Barriers

• Tumors create dense stroma that limits CAR-T infiltration
• Cancer cells may be hard to reach

Immunosuppressive Environment

• Tumors produce factors that exhaust T-cells
• Regulatory cells suppress immune responses

Antigen Heterogeneity

• Not all cancer cells may express the target protein equally
• Tumor cells can downregulate target antigens

Current research specifically addresses these challenges through engineering improvements.

Who May Be Eligible

CAR-T trials for mesothelioma typically require:

• Confirmed diagnosis of malignant mesothelioma
• Mesothelin expression (determined by biopsy)
• Previous treatment (most trials are for relapsed/refractory disease)
• Adequate organ function
• Acceptable performance status
• Specific HLA type (some trials require HLA-A*02)
• Ability to travel to participating centers

Finding CAR-T Trials

Search for mesothelioma CAR-T trials at:

• ClinicalTrials.gov: Search “mesothelioma CAR-T” or “mesothelin CAR”
• NCI Cancer Information Service: 1-800-4-CANCER
• Major cancer centers: Contact MD Anderson, Penn, University of Wisconsin directly

The Future of CAR-T in Mesothelioma

Research is advancing rapidly:

• Off-the-shelf CAR-T (allogeneic) could eliminate manufacturing delays
• Multi-target CARs may prevent tumor escape
• Local delivery (intrapleural injection) could improve penetration
• Combination strategies with checkpoint inhibitors may enhance durability

While CAR-T therapy for mesothelioma remains experimental, fast-track designations and active trials suggest it may become an important treatment option in the coming years.