Regional Delivery of Mesothelin-Targeted CAR T-Cell Therapy Creates a Win for Solid Tumors

In patients with malignant pleural disease, autologous mesothelin-targeted chimeric antigen receptor (CAR) T-cell therapy demonstrated clinical benefit with no significant toxicity, outcomes that may be due to the regional delivery of the CAR T cells to the intrapleural cavity rather than conventional systemic delivery. The phase I trial (ClinicalTrials.gov identifier: NCT02414269) results were presented at the 2019 American Association for Cancer Research (AACR) Annual Meeting, held March 29–April 3 in Atlanta, Georgia (abstract CT036).

“We estimated that more than 2 million patients in the United States will be eligible for this therapy because they express mesothelin on the solid tumor,” said study presenter Prasad S. Adusumilli, MD, deputy chief of thoracic surgery at Memorial Sloan Kettering Cancer Center, during a press conference. “Most importantly, we have studied in our lab over 2,000 human tumors and observed that mesothelin expression makes this cancer aggressive; thereby, it’s unlikely cancer cells will shed this antigen and develop immune escape.”

The phase I trial included 21 patients, of whom 19 had malignant pleural mesothelioma, 1 had metastatic lung cancer, and 1 had metastatic breast cancer. Following preconditioning with cyclophosphamide, all patients received a second-generation CD28-costimulated fully human mesothelin CAR with the Icaspase-9 safety gene (IcasM28z), which was administered intrapleurally via either a pleural catheter or an interventional radiology procedure.

For 11 patients, CAR T-cell therapy was followed with at least 3 doses of an anti–programmed cell death 1 (anti–PD-1) agent. “We waited at least 6 to 8 weeks to make sure there was no toxicity from the CAR T cells,” said Adusumilli. “Then we administered the anti–PD-1 agent.”

Among the patients who received CAR T-cell therapy followed by immune checkpoint blockade, 72% (8 of 11 patients) responded, with 2 patients achieving a complete metabolic response and 6 patients achieving partial response.

“Malignant pleural mesothelioma is a very difficult to treat disease, especially once patients have gotten past first-line therapy, and historically response rates to single-agent chemotherapy, which would be considered the standard of care, is on the order of about 10%,” said Liza Villaruz, MD, a medical oncologist/hematologist at UPMC Hillman Cancer Center, during an interview with Cancer Network. “To see such dramatic responses in the setting of CAR T therapy is very impressive. The results are very encouraging, and it’d be interesting to see how this pans out in larger patient populations.”

Villaruz applauded the intrapleural delivery, describing it as “novel” and at the “cutting edge of even CAR T therapy.” She said the method makes sense because “all the disease is there within the cavity.”

As for toxicity, Adusumilli said, “We had no evidence of CAR T-cell related toxicity more than grade 2. Most importantly, the neurotoxicity, severe cytokine release syndrome, and on-target/off-tumor toxicity that has been seen with other CAR T cell trials, we did not notice in our trial.”

“It seemed to be very well tolerated,” said Villaruz. She noted that systemic administration of CAR T-cell therapy is “typically” associated with “more significant” toxicity. “It would suggest that, at least potentially, the intrapleural delivery of this drug might bear some of the toxicity we typically think about with CAR T therapy.”

A clinical trial is being planned for later this year that will assess the combination of mesothelin-targeted CAR T-cell therapy followed by immune checkpoint blockade in this population of patients.