ENGINEERED T-CELLS EFFECTIVE ALSO AGAINST SOLID TUMORS

New data from Beatty et al of a study of the adoptive transfer of mRNA chimeric antigen receptor (CAR) T cells that target mesothelin (CARTmeso cells) show antitumor activity in two patients with advanced cancers that had not responded to prior treatments. In addition, the therapy was found to be safe and showed no significant evidence of off-tumor, on-target toxicity against normal tissues. The study is published in Cancer Immunology Research.

Toxicity Issues

Although the adoptive transfer of genetically modified T cells engineered to express CAR has produced promising results in the treatment of patients with CD19 hematologic malignancies, it has not been very successful in the treatment of solid tumors, with one of the major issues being toxicity. According to the study, the problem is due in part to the potential of CAR-based therapies to cause on-target, off-tumor toxicity through their recognition of healthy cells that express the target antigen.

“We engineered T cells to express CAR for about 3 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,” said Carl H. June, MD, 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, in a statement.

“These T cells recognize a protein called mesothelin present in many tumors, including mesothelioma and pancreatic cancers, hence we named them CARTmeso cells," he continued. "Our strategy is to give multiple infusions of CARTmeso cells to the patient, and if there is toxicity, we could abort the toxicity just by stopping the infusions, because the mRNA-based CARs rapidly revert to normal cells. We found that the temporary CARs we engineered are safe, with no significant on-target, off-tumor toxicity.”

Study Methodology and Results

Dr. June and colleagues recruited two patients, aged 75 and 81 years, to a phase I clinical trial. One patient had advanced mesothelioma, and the other patient had metastatic pancreatic cancer that had progressed after the failure of first-line therapy. 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 mRNA. The engineered cells were then infused back into the patients.

After receiving three infusions of CARTmeso cells, the patient with mesothelioma was evaluated for tumor response using computed tomographic (CT) imaging and showed stable disease. 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 then evaluated additional tumor markers and confirmed antitumor activity.

Dr. June said, “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. This new form of CAR therapy provides a new tool to evaluate CAR therapies for solid cancers.”

Dr. June and Gregory L. Beatty, MD, PhD, also of the University of Pennsylvania Perelman School of Medicine, are corresponding authors for the Cancer Immunology Research article.

The study was funded by grants from the National Institutes of Health, The Prevor Family Fund for Immunotherapy Cancer Research, and The Lustgarten Foundation. Dr. June and co-investigator Bruce L. Levine, PhD, have received commercial research support and have ownership interest (including patents) from Novartis. Drs. June and Levine and co-investigators Yangbing Zhao, MD, PhD, and Michael Kalos, PhD, have financial interests due to intellectual property and patents in the field of cell and gene therapy.