Autologous Mesothelin-Targeted T-Cells Induce Responses in Pleural Solid Tumors
Chicago, IL—A mesothelin-targeted chimeric antigen receptor (CAR) T-cell immunotherapy demonstrated encouraging antitumor activity in combination with pembrolizumab in patients with mesothelin-associated malignant pleural solid tumors, primarily mesothelioma, who had disease progression after platinum-containing chemotherapy, according to results presented at ASCO 2019.
This phase 1 clinical trial included a subset of 16 patients who also received lymphodepleting chemotherapy and at least 3 doses of pembrolizumab (Keytruda). With a minimum follow-up of 3 months after receiving the final dose of PD-1 therapy, the 12-month overall survival (OS) rate was 80% and the best overall response rate was 63% in patients with malignant pleural mesothelioma who received a single dose of intrapleural mesothelin-diluted CAR T-cells. Prasad S. Adusumilli, MD, FACS, FCCP, Head, Solid Tumors Cell Therapy, Cellular Therapeutics Center, Memorial Sloan Kettering Cancer Center, New York, reported the results.
“About 150,000 patients in the United States develop pleural cancers, either from primary malignant mesothelioma or metastatic pleural cancer from the lung and breast,” said Dr Adusumilli. “Among these, pleural mesothelioma is an aggressive solid tumor. Even with combined chemotherapy and radiation and surgical therapy, the median survival in the best case scenario is 9 to 17 months,” he added.
The most recent treatment approved by the FDA for mesothelioma was in 2003 for a platinum-based combination chemotherapy.
Checkpoint inhibitors have been investigated in large cohorts of patients with mesothelioma that resulted in no complete responses, approximately 20% to 30% partial responses, and progression-free survival ranging from 4 to 6 months.
“Perhaps this is not surprising, realizing that among many solid tumors, mesothelioma has a very low mutational burden and a low PD-L1 expression,” Dr Adusumilli said.
Approximately 2 million patients in the United States have mesothelin expression in their solid tumors, making it an attractive target for therapy, according to Dr Adusumilli. Mesothelin expression imparts aggressiveness in these tumors.
In this dose-escalation trial, second-generation CD28 costimulated mesothelin-targeted autologous CAR T-cells were administered to 27 patients with mesothelin expression in at least 10% of the tumor. Of these, 25 patients had malignant pleural mesothelioma. In addition, 1 patient had metastatic lung cancer, and 1 patient had metastatic breast cancer. Patients received a median of 3 previous treatment regimens.
The first cohort of patients did not receive preconditioning; cohorts 2 through 8 received cyclophosphamide preconditioning, with increasing doses of CAR T-cells administered intrapleurally. Of the 27 patients, 22 subsequently received treatment with pembrolizumab, which served to rescue functionally exhausted CAR T-cells.
No off-target tumor toxicity was detected, and none of the patients had cytokine release syndrome. One patient had a grade 3 febrile neutropenia related to cyclophosphamide. After pembrolizumab administration, 1 patient had grade 3 shortness of breath.
Of the subset of 16 patients who received lymphodepleting chemotherapy and at least 3 doses of pembrolizumab, there were 10 (63%) responses, consisting of 3 complete responses and 7 partial responses.
With a median follow-up of 8.4 months since the CAR T-cell infusion in 23 patients, the 6-month OS rate was 90.3% and the 1-year OS rate was 74.1%. In the subcohort of 16 patients who received lymphodepleting chemotherapy, which had a median follow-up of 11.8 months, the 6-month OS rate was 100% and the 1-year OS rate was 80.2%.
A total of 11 of the 16 patients in the subcohort had PD-L1–negative disease after treatment, with 6 of the 10 total responses observed in these patients.
These data strongly support that mesothelin-targeted CAR T-cells are “transforming the cold solid tumors…to make them hot and to keep them functionally active by the addition of anti–PD-1 antibody strategies,” said Dr Adusumilli.