Researchers are devising a technique, called CAR T-cell (chimeric antigen receptors) therapy in which patient's T cells are reprogrammed by doctors to attack the cancerous cells specifically.
The main objective of this research is to target mesothelin (MSLN), which is a cell surface protein seen in malignant mesothelioma patients. Initial clinical results of this research have shown encouraging results with the evidence of a decrease in the tumor.
A team of researchers at the Memorial Sloan Kettering Cancer Center, New York, led by Dr. Prasad S. Adusumilli is working on developing a customized technique in which CAR T-cell therapy is combined with PD-1 (programmed cell death protein- 1) targeting the most prominent protein, mesothelin, in the patients of MPM, and other malignancies.
PD-1 is a cell surface protein that downregulates the cancer patient's immune system and inhibits the immune system to attack cancer cells. Using a drug to turn off the expression of this protein and targeting the overexpressed protein can protein in the cancerous cells can treat malignant cancers.
"In this phase, I clinical trial, intrapleurally administered MSLN-targeted CAR T cells have been well-tolerated, with no evidence of on-target, off-tumor or therapy-related toxicity and with evidence of CAR T-cell antitumor activity. MSLN-targeted CAR T-cell therapy combined with anti-PD1 agents shows encouraging clinical outcome."
Optimistic Results for Mesothelioma Patients
Adusumilli started phase I clinical trials in 2015 in which the team developed genetically engineered T cells to formulate a treatment for pleural mesothelioma patients. Doctors presented the initial clinical evaluation of the study was on 31st March at the American Association for Cancer Research meetings in Atlanta.
The study started with 12 patients, all of which received a different combination of therapies alongside CART T-cell therapy.
A cohort of patients received cyclophosphamide preconditioning chemotherapy, some patients received PD-1 blocking drug, and three patients received CAR T-cell therapy. Screening of the patients showed the presence of CAR T-cells in the bloodstream of the patients, "and evidence of tumor regression on imaging studies."
One MPM patient who was administered CAR T cells and an anti-PD1 drug showed a significant presence of infusion in the blood for several weeks, depicting the eradication of cancerous cells for a more extended time.
As the lead author has written in his preliminary research report,
"this patient remains clinically well 8 months after CAR T-cell infusion, with evidence of CAR T-cell persistence in peripheral blood and tissue at 31 weeks."
How CAR T-cell Therapy Works
T cells are the type of white blood cells that play a significant role in the immune system of the human body. In this technique, T cells are genetically modified and are armored with chimeric antigen receptors (CAR) on their surface. These receptors help T- cells to recognize and target specific proteins or antigens and attack.
For treating malignant cancers, this immunotherapy is used by administering genetically modified T-cells (CAR- T-cells) to target the mesothelin. In this procedure, millions of these biologically engineered CAR T-cells are grown inside the lab and administered to the selected patients through an infusion.
CAR T-cells, infused in the bloodstream of the patient, be there and continue multiplying. There, the attached antigens on the surface of the engineered T-cells start performing its essential task, which is to attack the cancerous cells that are rich in mesothelin content. These biologically engineered T-cells can remain there for months and kill the cancerous cells. Clinical trials of this therapy are still underway on the mesothelioma patients.
Expression of Mesothelin in Mesothelioma and Other Malignancies
Mesothelin is a cell surface protein (antigen) that is present on the surface of some healthy cells. The function of this protein in the normal cells is not yet confirmed.
In cancer patients higher than the regular expression of mesothelin protein is observed. Researchers assessed the overexpression of mesothelin through several studies in pancreatic cancer, ovarian cancer, mesotheliomas, and other tumors (hepatomas, renal cell carcinoma, melanomas, thyroid cancer, etc.).
Doctors have linked the higher expression of mesothelin to the reduced survival rate of malignant pleural mesothelioma patients.
The researchers in Dr. Prasad S. Adusumilli's team studied several antigens to use as a target of their technique. Observing the overexpression of mesothelin in most of the solid tumors, and comparatively deficient expression in healthy cells convinced the researchers to target this protein.
Regarding this, the American Association for Cancer Research quoted the lead researcher in the team on March 31, 2019 tweeting,
"Adusumilli: Our CAR T cells target mesothelin, which is present on the most cancer cells, and they are delivered directly to the tumor site using regional delivery techniques."
And fortunately, the initial results have proved it to be the right choice. As the researchers explained,
“We are encouraged by these results. With the increasing understanding of mesothelioma tumor immunology, we hope to advance the benefits of immunotherapy to mesothelioma patients,”
The study is still recruiting patients to analyze a bigger group of samples to validate the results further. Selection of the patients as per the research criterion and then the production of T-cells for the analysis takes about two months, so these trials are time taking.
Doctors take these T-cells before or during the treatment of the patient through chemotherapy, without interrupting the procedure.
CAR T-cell therapy has been provided encouraging antitumor effects in initial clinical trials in patients dealing with advanced cancers. Further research with a higher number of patients is needed to know its impact on resistant tumors.
The scientific research done by Dr. Prasad S. Adusumilli and his co-workers will take more 6- 9 months to complete, and the results will show the impact of customized CAR T-cell therapy combined with PD-1 in eradicating MPM without damaging healthy cells.
Dr. Prasad S. Adusumilli works as the Deputy Chief of thoracic service at Memorial Sloan Kettering Cancer Center, Head of Solid Tumors Cell Therapy, Cellular Therapeutics Center, and Co-Director of mesothelioma program.