CAR T-Cell Therapy for Mesothelioma

What Is CAR T-Cell Therapy?

A new experimental way to treat mesothelioma is a type of immunotherapy called CAR T-cell therapy. This treatment uses a person’s own immune cells, known as T cells, to fight the cancer. Doctors take some of the person’s T cells and change them in a lab. 

They give the cells new instructions so they can make something called a chimeric antigen receptor. This special receptor, or CAR, helps the T cells find and attack cancer cells. CAR T-cell therapy is a type of adoptive cell transfer. This means it uses a person’s own cells to help fight cancer. 

CAR T-cell therapy is already approved for some blood cancers like leukemia and lymphoma. But for mesothelioma, it’s still being tested and is only available in clinical trials. Researchers hope that helping T cells better find mesothelioma cells will improve outcomes for people in the future.

How Does CAR T-Cell Therapy Work for Mesothelioma?

CAR T-cell therapy helps T cells target mesothelin, a protein mainly found in mesothelioma. This allows them to distinguish cancer cells from healthy ones. 

Boosting Immunity Against Mesothelioma

• Multiplying T cells: The modified T cells are grown into millions of copies in the lab. These armies of CAR T cells are then infused back into the patient’s bloodstream to hunt down and kill cancer cells.
• Reprogramming T cells: Scientists reprogram the patient’s T cells with CARs. This gives T cells a “target map” to find and attach to the mesothelioma tumors.

After adding the CAR, doctors grow T cells in a lab until there are millions of them. Then, they’re injected back into your body through a blood infusion. After reinfusion, they circulate and attach to mesothelioma cells via their new receptor, like a magnet finding metal. 

This binding acts like a key turning a lock. It activates the T cells to release toxic chemicals that destroy the cancer cell. Additionally, CAR T cells can signal and recruit other parts of the immune system to help in the fight. 

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What to Expect With CAR T-Cell Therapy

CAR T-cell therapy for mesothelioma is still experimental and only accessible through clinical trials. It’s not FDA-approved for this use. No cancer centers provide it outside of research settings. You must join a clinical trial to receive this therapy.

While the therapy is complex and requires several weeks from start to finish, each step is carefully coordinated to maximize your safety and treatment success. Understanding the CAR T-cell therapy process can help you and your family prepare.

The CAR T-Cell Therapy Process

1. T cell collection: Doctors collect your T cells through a process called apheresis. This filters blood to separate out T cells while the rest of your blood is returned to your body
2. T cell engineering: Your T cells are sent to a specialized lab where they’re genetically modified to produce a CAR that acts like a mesothelioma detector.
3. T cell multiplication: After modification, the CAR T cells are multiplied into millions of copies over the course of several days or weeks to ensure there’s enough for your treatment.
4. Preconditioning chemo: You’ll likely have a short course of low-dose chemo to reduce immune cells that might interfere with your CAR T cells.
5. CAR T cell infusion: Your CAR T cells are infused back into your bloodstream. They’ll travel throughout your body to locate and destroy mesothelioma cells.
6. Post-treatment monitoring: You’ll be monitored closely in the hospital for potential side effects. This could include flu-like immune reactions and issues with thinking or movement. Your doctor will schedule follow-up imaging and blood tests to assess your treatment response.

You’ll stay under close medical care for several weeks after the infusion. Side effects can happen right after treatment or sometime later. Careful observation and rapid treatment are critical. CAR T-cell therapy for mesothelioma is still experimental, but it allows trial participants to contribute to research and benefit from new immunotherapy advancements.

Expert Take

Dr. Jacques Fontaine: Emerging Targeted Therapies for Mesothelioma

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In the last few years, I’m happy to say that we’ve made great advances in cancer care, not just for mesothelioma, but for lung cancer, esophagus cancer, and a multitude of cancers. The new treatment concept in cancer is that we need to better define each cancer, get more data on the cancer, get more personal information on that cancer. So that means that we need to do molecular testing, genomic testing. You may hear from your physician that they’re gonna send next gen sequencing.


Some people call it liquid biopsy. Some call it molecular molecular testing, genetic fingerprinting, molecular testing. All these things are trying to get more information about that specific cancer. Are there specific genetic mutations that are driving the growth of that tumor?


That’s called an oncogene, a driver mutation. And now we have medications that target specifically that driver mutation. So if your cancer has that specific medication, now we have an off the shelf medication specifically for that cancer. We also need to look, are there certain proteins that are overexpressed on that tumor?


Meaning is the tumor expressing a certain protein just on itself, but that is not found anywhere else. So that’s kind of like a very specific birthmark than a patient has. So do you have a specific birthmark on you that differentiates you from the million other patients out there that may look like you.


And now we have medications that try to target if you have that very specific birthmark, if you have that very specific protein.


So how does that work? Once we have identified a specific type of protein on the cancer, a protein that’s almost exclusively found on that cancer cell and nowhere else in that patient’s body, then we can target that protein.


How do we target that protein? Well, proteins are also called antigens and antigens bind to antibodies. So you could take an antibody, an antigen or like a key and lock. The antibody will only come and lock to that antigen.


So now on that antibody, you can place chemotherapy bound to it. That’s called an antibody drug conjugate, an ADC.


And this is the frontier in cancer care. So we’re gonna take that antibody that’s gonna lock to that specific antigen and we’re gonna attach to it chemotherapy so that the chemotherapy doesn’t float around the whole body, the whole system, it will come and be delivered specifically to that cancer cell.


But we can take that same antibody and instead of linking to it chemotherapy, we can link to it a radioactive molecule. So it’s basically a miniature smart nuclear bomb radioactive molecule attached to the antibody, and it’s gonna come attached to the antigen on the tumor cell and be able to deliver the payload or that nuclear substance to kill only the cancer cell and nowhere else in the body. So that’s the key, the antigen and the antibody interaction allows the payload to come, whether it’s chemotherapy or radioactive substance, to go only to that antigen, to that cancer cell.

Side Effects of CAR T-Cell Therapy

Like any potent mesothelioma treatment, CAR T-cell therapy can cause side effects. These can include fever, chills or fatigue. Because it supercharges the immune system, many of the side effects are related to an overactive immune response. 

Cytokine release syndrome is a common side effect of CAR T therapy. When CAR T cells activate, they release many chemical signals called cytokines. Too many cytokines can lead to a strong immune reaction. If severe, CRS can lead to dangerously low blood pressure, rapid heartbeat, trouble breathing and organ dysfunction.

Common CAR T-Cell Therapy Side Effects

• Confusion
• Cough
• Cytokine Release Syndrome 
• Diarrhea
• Fatigue
• Fever
• Low blood counts
• Nausea
• Pneumonitis (lung inflammation)
• Rash or skin itching
• Seizures (rare)
• Sleepiness (extreme tiredness)

People receiving CAR T-cell therapy in trials are closely monitored for adverse effects, particularly in the initial days and weeks post-infusion. Some people experience mild symptoms, while others face serious complications. 

CAR T-cell therapy can affect the nervous system. People may experience neurological symptoms like sleepiness, confusion or agitation. Doctors and nurses will manage any issues. Most side effects can be treated effectively if addressed promptly. 

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CAR T-Cell Therapy Research for Mesothelioma

Clinical research is shaping the future of CAR T-cell therapy for mesothelioma. Ongoing trials aim to enhance CAR T-cell design, delivery and effectiveness against tumors. Although results have been promising, many people with mesothelioma still encounter challenges. These include immune resistance and tumor walls that are hard for treatments to cross.

One major clinical trial (NCI-2024-01620) is testing an advanced, experimental type of cell therapy (an autologous logic-gated Tmod™ CAR T-cell product) in subjects with solid tumors, including mesothelioma. This study, happening at the National Cancer Institute, offers patients a new way to fight their cancer using immunotherapy.

Goals of Active CAR T-Cell Therapy Clinical Trials

• Direct delivery approaches: Deliver CAR T cells directly into the pleural or peritoneal cavities, concentrating therapy at the tumor site.
• Enhancing T-cell survival: Improve how long CAR T cells survive and work after infusion to ensure longer-lasting anti-tumor activity.
• Minimizing toxicity: Engineer “safety switches” and optimizing dosing to reduce side effects.
• Overcoming tumor defenses: Combine CAR T cells with drugs like Keytruda (pembrolizumab) to stop tumors from turning off the immune system.
• Targeting multiple proteins: Design CAR T cells that can attack more than one protein on mesothelioma cells to prevent cancer cells from escaping detection.

Researchers at Houston Methodist and Weill Cornell Medicine developed CAR T cells that better target mesothelin. A human trial evaluated a new CAR T-cell design with different message pathways (like DAP12) to target mesothelin. It showed early signs of working safely, like shrinking tumors or stopping growth.

Studies show there are many ways to improve CAR T-cell treatments for mesothelioma. Early results indicate using local delivery, targeting 2 proteins and boosting the immune system can help solve current problems. With continued progress, CAR T-cell therapy may become a long-term treatment option for people with mesothelioma.