A phase one clinical trial that is looking into mesothelin-targeted chimeric antigen receptor (CAR) T-cell therapy has shown promise for treating malignant pleural mesothelioma by reprogramming the body’s T-cells. While it’s still in its early stages, this new therapy has shown researchers that it has the potential to bring about long-term complete remissions.

What Is Mesothelin-Targeted CAR T-cell Therapy?

Mesothelioma is very difficult to treat because the cancer builds up resistance to treatment. This means researchers continuously have to find new targeted mesothelioma therapies to overcome this resistance and get rid of the cancerous cells. One way that scientists can do that is by reprogramming the body’s immune system.

Treatments that teach the body’s immune system how to recognize cancerous cells or how to kill them are called immunotherapy.

Mesothelin-targeted CAR T-cell therapy is a form of immunotherapy. In this particular treatment, the drugs redirect and reprogram the T-cells in mesothelin—a protein found in certain cells. The reason that the researchers chose mesothelin is that it is over-represented in mesothelioma. There are more mesothelin molecules in cancerous cells than there are in healthy cells.

How Does the Therapy Work?

There are two distinct types of blood cells: B-cells (which develop in the bone marrow) and T-cells (which grow in the thymus gland).

As white blood cells, T-cells recognize foreign substances in the body—like mesothelioma cells—and stimulate the production of antibodies. They also activate other T-cells, turn off immune responses, or kill cells that carry antigenic material—toxic substances that work on the immune system.

In mesothelin-targeted CAR t-cell therapy patients are given a drug that activates T-cells, that is, the medication alerts the T-cells to the presence of cancer, and stimulates the production of antibodies to attack and kill the tumor.

Preclinical trials indicated that this process might be even more effective if the patients received treatments that form a programmed death-1 (PD-1) programmed death-ligand 1 (PD-L1) checkpoint blockade. This is because of PD-L1 molecules bond to PD-1 receptors on activated T-cells, which effectively turns the T-cells off.

The current study is looking into whether or not that holds true for humans as well. This is why some of the patients in the phase 1 trial also received anti–PD-1 therapy in addition to the mesothelin-targeted CAR T-cell therapy.

Why Is it Important to Test New Mesothelioma Therapies in Clinical Trials?

When researchers conducted preclinical trials on mice, their studies showed that mesothelin-targeted CAR T-cell therapy could bring about long-term complete remissions.

However, while those trials with mice are very promising, medication can, and often does, react differently inside of a human body. This is one of the reasons why it’s essential for all new drugs and targeted mesothelioma therapy methods to be tested in clinical trials before making them available to the broader population.

Other reasons include:

  • Helping researchers discover what is a safe dosage to give people
  • Learning what dosage of the medication will be effective at shrinking the tumors or killing off the cancerous cells, without giving the patient unbearable or deadly side effects
  • Discovering what some of the common and less common side effects are, so that patients can be fully informed of the risks associated with the treatment and so that doctors can be prepared to deal with the side effects

If the mesothelin-targeted CAR T-cell therapy can make it through the first 3 clinical trial phases, then it can be approved by the FDA as a valid form of treatment for mesothelioma.

The Trial So Far

So far in the phase 1 trial 13 of a planned 36 patients have received mesothelin-targeted CAR T-cell therapy. The patients receive a single dose of the drugs throughout the study. Some patients receive a higher dosage as-the lower dosages prove to be safe, and 6 individuals also received anti–PD-1 agents after the mesothelin-targeted CAR T-cell therapy.

So far, the side effects have been moderate or non-urgent, meaning the patient only requires further treatment if their condition worsens. Although one patient did have severe febrile neutropenia, which means they are at a higher risk of contracting an infection.

By the time the researchers stopped collecting data before presenting their initial findings, 11 of the treated patients were still alive, including a 73-year-old patient who had a complete metabolic response (the patient’s T-cells began to function properly) and the patient has not needed any further treatment.

While not all treatments or therapies make it through the different clinical phases, if this targeted mesothelioma therapy keeps showing promising results, it can be approved by the FDA and offered to more mesothelioma patients so they can have long-term remissions.

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Sources
  1. Abcam. "Cancer immunotherapy and the PD-1/PD-L1 checkpoint pathway. Retrieved from: https://www.abcam.com/cancer/cancer-immunotherapy-and-the-pd1pdl1-pathway. Accessed September 7, 2018.
  2. Adusumilli, P. S., Cherkassky, L., Villena-Vargas, J., Colovos, C., Servais, E., Plotkin, J., … Sadelain, M. (2014). Regional delivery of mesothelin-targeted CAR T cell therapy generates potent and long-lasting CD4-dependent tumor immunity. Science Translational Medicine, 6(261), 261ra151. Retrieved from: http://doi.org/10.1126/scitranslmed.3010162. Accessed September 4, 2018.
  3. Adusumilli, PS. (2016). "Exciting New CAR T Cell Therapy Trial Opens at MSK." Memorial Sloan Kettering Cancer Center. Retrieved from: https://www.mskcc.org/clinical-updates/exciting-new-car-t-cell-therapy-trial-opens-msk. Accessed September 4, 2018.
  4. Astor, L. (2018). "Early Signs of Efficacy Seen With Mesothelin CAR T-Cell Therapy." Targeted Oncology. Retrieved from: https://www.targetedonc.com/publications/targeted-therapy-news/2018/August-2018/early-signs-of-efficacy-seen-with-mesothelin-car-tcell-therapy. Accessed September 4, 2018.
  5. Hassan, R., & Ho, M. (2008). Mesothelin targeted cancer immunotherapy. European Journal of Cancer (Oxford, England : 1990), 44(1), 46–53. Retrieved from: http://doi.org/10.1016/j.ejca.2007.08.028. Accessed September 4, 2018.
  6. National Cancer Institute. "Mesothelin." Retrieved from: https://www.cancer.gov/publications/dictionaries/cancer-terms/def/mesothelin. Accessed September 4, 2018.
  7. National Multiple Sclerosis Society. "T-Cells." Retrieved from: https://www.nationalmssociety.org/What-is-MS/Definition-of-MS/T-cells. Accessed September 7, 2018.

Last modified: October 9, 2018