Gregory L. Beatty, MD, PhD
Although chimeric antigen receptor (CAR) T-cell therapy has not yet proved effective against solid tumors, a novel CAR that targets mesothelin proteins expressed in pancreatic cancer is showing early signs of activity, according to Gregory L. Beatty, MD, PhD.
At Penn, Beatty’s laboratory developed a CAR specific for mesothelin, a protein that is overexpressed by pancreatic ductal adenocarcinoma cells. It incorporates the mouse monoclonal antibody SS1 and contains the costimulatory CD137 domain to enhance proliferation and survival and a CD3ζ signaling domain to induce T-cell activation.3
In vitro, CAR T cells engineered to express mesothelin “will react and kill tumor cells that are mesothelin positive but not those that are negative,” he said. Even in autologous T cells, the CAR T cells were effective in recognizing mesothelin-positive tumor cells.
Table. Ongoing CAR T-Cell Therapy Trials in Pancreatic Cancer1
One strategy to engineer CAR T cells uses an RNA platform and electroporation to transiently express the CAR in T cells. An alternative strategy involves using a lentiviral platform and transduction to permanently express the CAR. “Although permanent transduction leads to superior activity,” Beatty said, both exhibited antitumor activity in a mesothelioma human tumor model; however, the transient expression of CAR elicited through the RNA platform might appeal to safety.
Early Phase Activity and Safety
The safety, feasibility, and activity of RNA mesothelin-specific CARTmeso therapy was explored in a phase I study in 6 patients with chemotherapy- refractory metastatic pancreatic ductal adenocarcinoma.4
All patients had received 2 or more prior lines of therapy. The RNA CAR T cells were infused 3 times weekly for a total of 9 doses. “We observed no dose-limiting toxicities, and we found no evidence of cytokine release syndrome,” Beatty said. The most common adverse events included fatigue and abdominal pain, possibly a result of the pancreatic cancer itself. The best overall response was stable disease in 2 patients who experienced a progression-free survival time of 3.8 months and 5.4 months.
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