Novel Engineering of Immune Cells Holds Promise for Mesothelioma Patients

Patients with advanced malignant pleural mesothelioma and metastatic pancreatic cancer received surprisingly positive results during a small, recent Phase
I clinical trial involving a novel engineering of immune cells.

The trial was done at the Abramson Cancer Center in Philadelphia, and the
results were published in Cancer Immunology Research.

It accentuated the growing belief that the next big step in combating mesothelioma will come from immunotherapy, which uses a patient’s own immune system to fight deadly diseases.

“These results, albeit preliminary, are very promising,” said Carl H. June, M.D., professor of pathology and laboratory medicine at the University of
Pennsylvania and director of translational research at Abramson.

The trial involved elderly patients with advanced cancers that had not responded to prior treatments.

Using a Patient’s Own Immune System

Researchers harvested a patient’s own immune cells, then clinically engineering them with a molecule that attaches to a mesothelin protein that is common
in cancer cells. It helps the immune cells to recognize and destroy the cancer cells more effectively.

The engineered cells are known as chimeric antigen receptor T cells (CARTmeso cells) and considered a form of personalized therapy currently conducted at
leading research laboratories.

These types of CART cells previously have shown promising results in some types of leukemia and lymphoma, but have not been successful with solid tumors in
the past because of off-target toxicity that causes serious problems for surrounding healthy cells.

The latest trial involved a different modification that allows the T cells to express the chimeric antigen receptor (CAR) for just three days, instead of
the permanent transformation that causes much of the off-target problem.

Strategy Eliminates the Toxicity

The new method allows the T cells to revert to what they were before the modification. The new strategy involves multiple infusions of the CARTmeso cells,
which would allow doctors to quickly change course with therapy, and eliminates much of the
toxicity.

The mesothelioma patient in the study, whose condition had been worsening, received three infusions of
the CARTmeso cells, and his disease stabilized. The patient with pancreatic cancer received eight infusions of CARTmeso cells, and he showed a 40 percent
decrease in tumor cells.

“We found that the temporary CARs we engineered were safe, with no significant off-target, off-tumor toxicity,” June told Science Codex. “We have evidence
of antitumor effects in two patients whose advanced tumors failed previous therapies.”

The trial originally was designed to evaluate the safety of the CARTmeso cells, the novel engineering process, and the manufacturing feasibility. The researchers, after harvesting the immune cells, reproduced them in large numbers, which
allowed the multiple infusions. The engineered cells were reintroduced to the patient’s body.

“We found that these CARTmeso cells not only have antitumor activity, but they also act like a vaccine, and trigger a response against the patient’s own
tumor,” June said. “This new form of CAR therapy provides a new tool to evaluate therapies for solid cancers.”