Early Signs of Efficacy Seen With Mesothelin CAR T-Cell Therapy

Prasad S. Adusumilli, MD

Mesothelin-targeted chimeric antigen receptor (CAR) T-cell therapy has shown early evidence of efficacy in a phase I trial of patients with malignant pleural disease and mesothelioma, non—small cell lung cancer, or breast cancer (NCT02414269). Additionally, significant responses were seen in patients who went on to receive subsequent PD-1 checkpoint inhibition treatment. Preliminary results from the ongoing study were presented at the 2018 American Society of Gene and Cell Therapy (ASGCT) Annual Meeting.¹

“We provide the first clinical evidence that combination immunotherapy with CAR T cells followed by anti—PD-1 agents can elicit responses in patients with hard-to-treat, therapy-refractory solid tumors,” said principal investigator Prasad S. Adusumilli, MD, when presenting the current findings at the ASGCT meeting.

Mesothelin is a cell-surface tumor-differentiation antigen that is frequently highly expressed in several cancers, including mesothelioma, lung, pancreas, breast, and ovarian. The mesothelin protein has been found to be expressed in 85% to 90% of mesotheliomas, 80% to 85% of pancreatic cancers, and 60% to 65% of lung cancers, ovarian cancers, and cholangiocarcinomas.²On the other hand, mesothelin is not commonly expressed on normal mesothelial cells, making it an attractive therapeutic target.

In preclinical studies, administration of mesothelin-targeted M28z CAR T cells showed the potential to induce long-term complete remissions, especially through early antigen activation of CD4-positive CAR T cells, which allows for greater T-cell accumulation than concurrent activation.³

Adusumilli, deputy chief of the Thoracic Service, director of the Mesothelioma Program, and head of solid tumors cell therapy for the Cellular Therapeutics Center at Memorial Sloan Kettering Cancer Center in New York, New York, also noted that intrapleural administration compared with intravenous administration potentiated greater efficacy for the CAR T-cell therapy. The median overall survival was not reached with intrapleural administration in tumor-bearing mice compared with 27 days with the 1 x 105 dose and 86 days with the 3 x 106 dose with intravenous administration.

The results of this preclinical trial led to the opening of the phase I study looking at patients with primary or secondary pleural malignancies.

As of data cutoff, 13 patients of a planned 36 participants have been treated in the phase I trial with infusions of the mesothelin-targeted iCasM28z CAR T-cell therapy, which contains a CD28 costimulatory domain and an iCaspase 9 safety gene. Patients were treated with single doses of the CAR T-cell therapy at doses varying from 3 x 105 cells/kg to 1 x 107 cells/kg across 6 cohorts. Patients in cohorts 2 through 6 also received preconditioning with 1.5 g/m2 intravenous cyclophosphamide.

Overall, 11 of the 13 patients are still alive at data cutoff. Of 10 evaluable patients who also received cyclophosphamide preconditioning, 1 patient achieved a complete metabolic response and 1 partial response was also achieved; 3 additional patients had stable disease. CAR T cells were detected in the peripheral blood in 8 of the 10 patients.

“Regional administration of mesothelin-targeted CAR T cells is safe to date, and dose escalation is ongoing,” Adusumilli commented.

No on-target, off-tumor toxicity has yet been seen in the trial, and no adverse events (AEs) above grade 2 related to treatment with CAR T-cell therapy have been observed; however, 1 patient did experience cyclophosphamide-induced grade 3 febrile neutropenia. Clinical AEs observed included pleuritis, pericarditis, and peritonitis.

Based on preclinical studies suggesting that PD-1/PD-L1 checkpoint blockade could improve the efficacy of CAR T-cell therapy, 6 patients went on to receive anti—PD-1 therapy, all of whom were still alive as of data cutoff. “Following the establishment of CAR T cells’ safety in patients, and based on successful modeling of combination therapy in mice, we are now testing combination therapy in patients,” Adusumilli said.

One of the 6 patients experienced a complete metabolic response, 2 had partial responses, 1 achieved stable disease, and 2 had progressive disease. Five of these patients have not yet received any subsequent therapies (range, 25-52 weeks). Persistence of CAR T cells was detected in the peripheral blood (range, 1-38 weeks) in all 5 patients. Additionally, no AEs above grade 2 as a result of anti—PD-1 therapy were observed.

Adusumilli pointed out a 73-year-old patient with mesothelioma who received iCasM28z CAR T-cell therapy at 3 x 105 cells/kg and cyclophosphamide followed by pembrolizumab (Keytruda). The patient achieved a complete metabolic response, and CAR T cells were detected in the peripheral blood and tissue at 32 weeks. Approximately a year after treatment with the CAR T-cell therapy, this patient has not received any additional treatments.

Adusumilli also referenced another ongoing phase I trial that is looking at mesothelin-targeted CAR T-cell therapy in patients with metastatic HER2-negative breast cancer that expresses mesothelin (NCT02792114).

References:

1. Adusumilli PS, Zauderer M, Rusch V, et al. A phase I clinical trial of malignant pleural disease treated with regionally delivered autologous mesothelin-targeted CART cells: safety and efficacy - a preliminary report. Presented at: 2018 ASGCT Annual Meeting; May 16-19, 2018; Chicago, IL. Abstract 342.
2. Morello A, Sadelain M, Adusumilli PS. Mesothelin-targeted CARs: driving T cells to solid tumors. Cancer Discov. 2016;6(2):133-146. doi: 10.1158/2159-8290.CD-15-0583.
3. Adusumilli PS, Cherkassky L, Villena-Vargas J, et al. Regional delivery of mesothelin-targeted CAR T cell therapy generates potent and long-lasting CD4-dependent tumor immunity. Sci Transl Med. 2014;6(261):261ra151. doi: 10.1126/scitranslmed.3010162.