CAR T-cell Therapy for Mesothelioma

What Is CAR T-cell Therapy?

CAR T-cell therapy is a type of cancer treatment within the field of immunotherapy. More specifically, it’s called targeted cancer therapy. CAR is an acronym for “chimeric antigen receptor.”

Tumor Microenvironment and Cancer

Much of oncology in 2021 and beyond is understanding the “tumor microenvironment.” This involves a biological understanding of how tumors form, grow, spread, and are constructed.

The challenge is different cancers’ tumors form, grow, spread and are built in different ways. Mesothelioma is no different, as it’s a metastatic disease where the original tumor multiplies into various smaller tumors, which continue replicating in a sheet-like manner in their growth process.

Each cancer cell has biomarkers to differentiate them from healthy cells or other kinds of cancer cells. These biomarkers could be antigens, or protein receptors. Much of tumor microenvironment analysis is looking for antigens and producing therapies to target the specific ones featured in a cancer case. This is where CAR T-cell therapy fits in.

Altering T cells to Fight Cancer

Doctors adjust your body’s natural T cells to better fight cancer. This is called an adoptive cell therapy since it treats cancer by changing an element of your immune system cells or the cancer cells. Some people call CAR T-cell therapy a type of cancer cell and gene therapy. Immunotherapy and cell and gene therapy are similar to one another.

CAR T-cell therapy is approved by the U.S. Food and Drug Administration (FDA) for specific types of blood cancer: leukemia, lymphoma and myeloma. It is not approved for mesothelioma, lung cancer or any other solid tumors.

What Are CAR T cells?

CAR T cells are genetically modified versions of your T cells, which are a type of white blood cell called lymphocytes. These cells are tasked with fighting off diseases, such as viruses and cancer. Doctors add a chimeric antigen receptor, or CAR, to extracted T cells to make them more focused on finding and killing cancer tumors.

These cells get a CAR focused on a specific protein, or antigen, expressed by the target cancer. This target protein is a sign that you have this specific cancer. The protein is also a way to direct T cells to prioritize looking for cells expressing this specific antigen.

CAR T cells: A Living Drug and Cancer Vaccine

A benefit of CAR T-cell therapy as a treatment for mesothelioma is that many patients only need one infusion of treatment. A single infusion can work for months or years. CAR T cells can continuously replicate within the immune system and create a “living cancer therapy” for years after the treatment is given.

This essentially becomes a cancer vaccine, as the CAR T cells remain active and populated for years to prevent cancer from returning.

This is a significant difference from standard cancer treatment, such as chemotherapy for mesothelioma and even other forms of immunotherapy for mesothelioma. Since these drugs stop working after a few days or weeks, patients need multiple sessions of treatment to keep cancer at bay.

Another Type of T-cell Therapy: Engineered T cells

While not the same as CAR T-cell therapy, engineered T-cell therapy is similar and within the same group called cancer cell and gene therapy. Engineered T-cell therapy, or TCR, involves T cells being removed from patients and receiving a laboratory-created receptor, which helps the T cells find cancer.

All of that is the same as CAR T-cell therapy. The difference is how the T cells look for cancer.

TCR therapies look for peptides, which are fragments of proteins released by cells. These fragments are brought to the surface of cells by the major histocompatibility complex (MHC). The MHC includes human leukocyte antigens (HLA), which is responsible for presenting these fragments to T cells.

If T cells have the engineered receptors that are associated with the peptides, then they’ll label the cells as cancerous.

There is only one engineered T-cell receptor therapy approved by the FDA for cancer. Kimmtrak was approved in 2022 for uveal melanoma, which is a rare skin cancer of the eye.

How to Use CAR T-cells for Mesothelioma

The first step to making CAR T cells is finding a protein to target. It’s easiest if the protein exists on the surface of cancer cells.

Mesothelioma tumors produce a protein called mesothelin on the surface of cells. This protein is expressed on both pleural mesothelioma and peritoneal mesothelioma. CAR T-cell therapy is a possible treatment for both types of mesothelioma.

Ovarian cancer, colorectal cancer and pancreatic cancer also express mesothelin at times, although not as often as mesothelioma.

History of CAR T-cell Therapy

CAR T-cell therapy emerged at the beginning of the 21st century as a cancer treatment. The concept of cell and gene therapy was not well-funded. However, many scientists still believed in the idea of enhancing the body’s T cells by adding a gene that directed them toward cancer tumors.

Dr. Carl June, of Penn Medicine’s Abramson Cancer Center, was one of the scientists who never gave up on this field of cancer treatment. Dr. June created a CAR T-cell therapy and tested it in clinical trials for various blood cancers, including lymphoma and leukemia. He received funding from non-profit organizations, including Alliance for Cancer Gene Therapy, and proved CAR T cells could treat these diseases.

A few of Dr. June’s patients in his 2010 and 2012 clinical trials have reached a decade or more of survival since getting CAR T-cell treatment. Many news outlets reported at the beginning of 2022 that these patients were “cured” of their cancer thanks to CAR T-cell therapy.

The FDA approved the first CAR T-cell therapy in 2017. Five more have followed with approvals since then.

FDA Approvals of CAR T-cell Therapy

There are six CAR T-cell therapies approved by the FDA. They are approved for various blood cancers and only after patients have tried other treatments unsuccessfully.

The six approved CAR T-cell therapies are listed below with their brand names first and generic scientific name in parenthesis:

Steps for Making CAR T-cells

The process of making CAR T cells usually takes 1-2 weeks, although researchers are trying to shorten the time to help patients. There are multiple steps required to enhance T cells to fight cancer:

CAR T-cell Therapy Survival Rates

The survival rate for CAR T-cell therapy depends on the specific CAR T cell and the type of cancer. Since this therapy is only approved for blood cancers, most of the survival data is limited to those types of tumors.

Tecartus, which is approved for mantle cell lymphoma, helped patients reach a median survival of 46.6 months. Tecartus is also in testing for leukemia, leading to a median survival for 25 months.

Mesothelioma survival rates are poor, so CAR T-cell therapy leading to similar results would be a huge improvement in life expectancy of patients.

CAR T-cell Therapy Side Effects

One of the benefits of CAR T-cell therapy compared to chemotherapy is the low rate of side effects. Some side effects may occur but they don’t usually last for as long as chemotherapy.

Cytokine release syndrome is the most common side effect of CAR T-cell therapy. This condition is an overproduction of cytokine, a chemical in your blood. Producing too much cytokine causes nausea, fever, chills, trouble breathing, headaches, dizziness and fatigue. Patients often experience cytokine release syndrome in the days immediately after getting their CAR T cells.

While the side effect is uncomfortable, it’s proof the therapy is working. CAR T cells are multiplying, which is what causes the cytokine overproduction. The effects are also short-lived and medical teams usually can manage it with medication in the hospital.

Another side effect is central nervous system issues: headaches, confusion, seizures, loss of balance, and trouble speaking. CAR T-cell therapy can lead to low blood cell counts, causing infection or bruising, or low potassium or sodium.

The rate of serious side effects from CAR T cells is low. The most serious one usually ends within a few days of receiving treatment.

CAR T-cell Therapy in Clinical Trials for Mesothelioma

A few ongoing mesothelioma clinical trials feature CAR T cells. A few others have completed with positive survival data.

Memorial Sloan Kettering Cancer Center hosted a phase 1 study of CAR T-cell therapy for mesothelioma and other mesothelin cancers. The trial paired CAR T cells with Keytruda, an immunotherapy drug that blocks the protein PD-L1. Their median survival for 18 patients was 23.9 months. The 1-year survival was 83%.

This specific CAR T‑cell therapy, called IcasM28z, includes a fail‑safe gene called Icaspase‑9. If a patient responds negatively to the therapy, this gene kills the CAR T‑cells in the body. This failsafe could prevent serious cytokine release storm and other CAR T-cell side effects.

At the Society for Immunotherapy of Cancer conference in 2021, a cell therapy manufacturing company, Cellectis, reported disease response in mice with mesothelioma or pancreatic cancer thanks to a mesothelin-targeting CAR T-cell therapy. Cellectis’ therapy is called UCARTMESO. It also disrupts three genes: TRAC, CD52 and TGFBR2.

Penn Medicine and the University of Pennsylvania’s Abramson Cancer Center is hosting a phase 1 trial for a mesothelin-targeted CAR T cell. The trial includes pleural mesothelioma and peritoneal mesothelioma.

T-cell Receptor Therapy in Mesothelioma Clinical Trial

T-cell receptor therapy isn’t the same as CAR T-cell therapy, but it’s similar enough and has enough potential to highlight. One clinical trial features a T-cell receptor therapy called gavo-cel, or TC-210, developed by TCR2 Therapeutics. It’s in testing for a few types of cancer, including mesothelioma and lung cancer.

Gavo-cel succeeded in a phase 1 trial. The disease control rate was 77%, meaning this percentage of patients either had their cancer stop growing or shrank thanks to the T-cell therapy. There were 30 patients in the phase 1 study, so 23 out of 30 patients had disease control.

The median overall survival for people with mesothelioma was 11 months. The progression-free survival was 5.6 months. For ovarian cancer, the overall survival was 8.1 months and the progression-free survival was 5.8 months.

The clinical trial is a phase 2 study for people with mesothelin-solid cancers. Mesothelioma cells often express mesothelin, a cancerous protein. Non-small-cell lung cancer and ovarian cancer also often expresses mesothelin.

The phase 2 trial will consist of 75 patients with malignant mesothelioma. Another set will be included with each of the following cancers: ovarian, lung and cholangiocarcinoma. The trial has spots for up to 175 patients.

In addition to the gavo-cel T-cell receptor therapy, mesothelioma patients will also receive one or multiple immunotherapy drugs. Half the patients will receive nivolumab (Opdivo) and the other half will receive nivolumab and ipilimumab (Yervoy). Opdivo and Yervoy are immune checkpoint inhibitor immunotherapies.

Doctors hope the combination of a T-cell enhancing therapy with immune checkpoint inhibitors will help T cells identify cancer cells in multiple ways.

There are a handful of hospitals and cancer centers hosting this clinical trial. A few of them are on the list of the top mesothelioma cancer centers in the world.

The host sites are:

• University of California San Francisco Medical Center
• National Cancer Institute (Bethesda, Maryland)
• Memorial Sloan Kettering Cancer Center (New York)
• Penn Medicine Abramson Cancer Center (Philadelphia)
• University of Texas MD Anderson Cancer Center (Houston)
• Sarah Cannon Research Institute (Nashville, Tennessee)
• Princess Margaret Cancer Center (Toronto, Canada)