CAR-T plus pembrolizumab ‘promising’ for malignant pleural mesothelioma
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Chimeric antigen receptor T-cell therapy followed by pembrolizumab appeared safe and feasible for patients with malignant pleural mesothelioma, phase 1 trial results published in Cancer Discovery showed.
Eighty-three percent of patients who received the regimen remained alive 1 year after CAR-T infusion. Researchers reported no cases of high-grade cytokine release syndrome or neurotoxicity.
The first-in-human, single-center, dose-escalation study used autologous, gene-edited CAR T cells that target the mesothelin protein on the surface of cancer cells. The fully humanized CAR-T — developed by Memorial Sloan Kettering Cancer Center — is engineered to express an iCaspase-9 gene that serves as a “safety switch” to halt the activity of the modified T cells.
Mesothelin-expressing tumors tend to be very aggressive. Median survival is approximately 18 months, according to Prasad S. Adusumilli, MD, FACS, FCCP, head of solid tumors cell therapy for the Cellular Therapeutics Center and director of the mesothelioma program at Memorial Sloan Kettering Cancer Center.
“Previous research has indicated that the [mesothelin] antigen imparts aggressiveness to the cancer and its expression on normal tissue is very low, so we selected mesothelin as our target,” he told Healio.
The researchers chose a locoregional CAR-T dosing strategy because this type of cancer typically does not metastasize outside the chest cavity, Adusumilli added.
“We thought, why not introduce the CAR T cells directly into the chest cavity where the tumor is?” he said. “We know from the published literature and our own research that if we administer CAR T cells intravenously, they get stuck in the lungs for about 4 to 5 days and, by the time they reach the tumor, they cannot enter it with sufficient numbers.”
Adusumilli and colleagues reported results from a cohort of 18 patients (median age, 70 years; range, 53–77; 83% male) with previously treated and histologically confirmed pleural cavity malignancies, including malignant pleural mesothelioma, metastatic lung cancer or metastatic breast cancer.
Study participants received at least one intrapleural infusion of mesothelin-directed CAR T cells followed by pembrolizumab (Keytruda, Merck), an anti-PD-1 therapy.
All patients had received at least one previous line of therapy before study enrollment and had confirmed mesothelin expression of greater than 10% on tumor cells.
Study patients underwent lymphodepletion with cyclophosphamide (1500 mg/m2) followed by CAR-T infusion at a dose level ranging from 3 × 105 to 6.5 × 107 cells/kg. Patients received at least three doses of pembrolizumab and had at least 3 months of follow-up after the third dose.
Four patients who had clinically beneficial responses to therapy and no significant treatment-related adverse events received a second infusion of CAR T cells after disease progression.
Safety, dosing requirements and CAR T-cell targeting efficiency served as the study’s primary objectives. CAR T-cell persistence in peripheral blood served as a secondary assessment.
Median follow-up was 20.3 months (interquartile range, 19.2-26.1) at data cutoff in June 2020.
Results showed no dose-limiting toxicities or grade 5 adverse events related to treatment.
No cases of grade 3 or greater cytokine release syndrome or neurotoxicity occurred. Six patients experienced other grade 3 treatment-related adverse events — two had constipation and one each developed dysphagia, dyspnea after reinfusion, thromboembolism or febrile neutropenia.
All grade 4 treatment-related adverse events were hematologic in nature and attributed to the preconditioning lymphodepletion therapy, according to investigators.
Median OS after CAR T-cell infusion was 23.9 months (95%CI, 14.7-not estimable), with a 1-year OS rate of 83%.
Sixteen patients had measurable disease per RECIST criteria. Two patients (13%) achieved a metabolic complete response to therapy
Nine patients (56%) had stable disease, eight of whom maintained stable disease status for 6 months or longer after therapy.
Thirty-nine percent of patients had CAR T cells detectable in peripheral blood more than 100 days after infusion.
Adusumilli called the results “promising,” especially because no major treatment-related adverse events occurred. He cautioned that study participants were carefully selected based on their ability to wait for the manufacturing of CAR T cells.
“For patients with unresectable mesothelioma, the typical median survival is 18 months,” he told Healio. “Compared with that, these results are very encouraging, but we need to wait to see the results of larger studies.”
A phase 2 study using a fixed dose of mesothelin-directed CAR T cells followed by pembrolizumab is underway. Four patients have been treated so far, Adusumilli said.
“With this approach of using antigen-directed CAR T cells, we are promoting T-cell infiltration into the tumor, and then we are keeping them activated with checkpoint blockade,” he said. “I think that’s what was making these kinds of ‘cold’ tumors go ‘hot.’”
For more information:
Prasad S. Adusumilli, MD, FACS, FCCP, can be reached at Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065; email: adusumip@mskcc.org.
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