Researchers are devising a technique, called CAR T-cell (chimeric antigen receptors) therapy in which patient’s T cells are reprogrammed to specifically attack the cancerous cells.
The main objective of this research is to target mesothelin (MSLN), which is a cell surface protein and is highly expressed in the 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. Initial clinical evaluation of the study was presented on 31st March at the American Association for Cancer Research meetings in Atlanta.
The study was 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 3 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 anti-PD1 drug showed a significant presence of infusion in the blood for several weeks, depicting eradication of cancerous cells for a longer time period.
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 major 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 are then 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 natural 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) which is present on the surface of some normal cells. The function of this protein in the normal cells is not yet confirmed.
In cancer patients higher than normal expression of mesothelin protein is observed. Overexpression of mesothelin was assessed through several studies in pancreatic cancer, ovarian cancer, mesotheliomas and other tumors (hepatomas, renal cell carcinoma, melanomas, thyroid cancer, etc.).
Higher expression of mesothelin is also linked to the poor survival 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 overexpression of mesothelin in most of the solid tumors, and comparatively very low expression in normal 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 fair 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 further validate the results. Selection of the patients as per the research criterion and then the production of T-cells for the analysis takes about 2 months, so these trials are time taking.
These T-cells are taken before or during the treatment of the patient through chemotherapy, without interrupting the treatment.
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 effect on the resistant tumors.
The research being 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 normal 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.