Scientists at the University of Pennsylvania’s Perelman School of Medicine report that engineered CARTmeso cells, which are designed to direct antitumor immune responses toward tumors that carry mesothelin, showed antitumor activity in two patients with advanced cancers that had not responded to prior treatments. They published their study (“Mesothelin-Specific Chimeric Antigen Receptor mRNA-Engineered T Cells Induce Antitumor Activity in Solid Malignancies”) in Cancer Immunology Research.
Chimeric antigen receptor T cells (CAR T cells) are a form of personalized cell therapy that uses T cells from patients. After T cells are harvested, they are engineered to bear a molecule that allows them to attach to a specific protein carried by the patient's cancer cells and to be triggered to kill the cancer cells when they do so. CAR T cells have shown early promising results for patients with some types of leukemia and lymphoma. However, they have not been successful for solid cancers, one of the major issues being toxicity. Because normal cells express the CAR T cell target protein, albeit at lower levels than cancer cells, the engineered T cells recognize and attack the normal cells as well the cancer cells, causing off-target toxicity.
Up to now, scientists have been modifying T cells by using a number of techniques, including using viruses, according to Carl H. June, M.D., a professor of pathology and laboratory medicine in the Perelman School of Medicine at the University of Pennsylvania and director of translational research in the university's Abramson Cancer Center.
“We present two case reports from ongoing trials indicating that adoptive transfer of mRNA CAR T cells that target mesothelin is feasible and safe without overt evidence of off-tumor on-target toxicity against normal tissues,” wrote the investigators. “CARTmeso cells persisted transiently within the peripheral blood after intravenous administration and migrated to primary and metastatic tumor sites. Clinical and laboratory evidence of antitumor activity was shown in both patients, and the CARTmeso cells elicited an antitumor immune response revealed by the development of novel antiself antibodies.”
“We engineered T cells to express a CAR for about three days, after which the mRNA is metabolized rapidly by the system, so the T cells basically revert to what they were before in the patient,” explained Dr. June.
He and his colleagues recruited two patients, ages 75 and 81 years, to a Phase I clinical trial. One patient had advanced mesothelioma, and the other patient had metastatic pancreatic cancer that progressed after failing first-line therapy. The objective of this trial was to evaluate the manufacturing feasibility and safety of the mRNA-based CARTmeso cells. The researchers isolated T cells from the patients, reproduced them in large numbers in the laboratory, and engineered them to recognize mesothelin on tumor cells, using a biological material called mRNA. After ensuring viability and specificity of the engineered cells, the researchers infused the patients' modified T cells back into their bodies.
After receiving three infusions of CARTmeso cells, the patient with mesothelioma showed stable disease, as evaluated by imaging. The patient with pancreatic cancer received eight infusions of CARTmeso cells, and fluid collected from his abdomen showed a 40% decrease in the number of tumor cells that expressed mesothelin. The researchers evaluated additional tumor markers and confirmed antitumor activity.
“We found that these CARTmeso cells not only have antitumor activity, but also act like a vaccine, and trigger a response against the patient's own tumor,” said Dr. June. “This new form of CAR therapy provides a new tool to evaluate CAR therapies for solid cancers.”