CAR T Cells Targeting Mesothelin Show Strong Early Signal in Advanced Solid Cancers

Prasad S. Adusumilli, MD

CAR T cells targeting mesothelin-expressing tumors demonstrated safety and efficacy in a preliminary clinical evaluation in patients with malignant pleural disease.

The results showed that 13 of 21 patients had persistence of CAR T cells in peripheral blood from day 1 to 38 weeks, which was associated with >50% reduction in mesothelin-related peptide and evidence of tumor regression on imaging. Objective responses occurred in eight of 11 patients who received a combination of cyclophosphamide conditioning therapy, the CAR T cells, and at least 3 doses of an anti—PD-1 agent.

The single-dose CAR T-cell therapy produced no on-target/off-tumor toxicity, no evidence of immunogenicity, and no severe toxicity, as reported at the 2019 AACR Annual Meeting.¹

“We observed no evidence of immunogenicity and no significant toxicity,” said Prasad S. Adusumilli, MD, of Memorial Sloan Kettering (MSK) Cancer Center in New York. “Regional delivery of mesothelin-targeted CARs in combination with an anti—PD-1 agent shows durable responses. This study strongly supports pursuing CAR T-cell therapy combined with anti–PD-1 strategies in solid tumors.”

At MSK, Andusumulli is deputy chief of the Thoracic Service, co-director of the Mesothelioma Program, and head of Solid Tumors Cell Therapy in the Cellular Therapeutics Center.

CAR T-cell therapy has had remarkable success in relapsed/refractory hematologic malignancies. However, replicating the success in solid tumors has proved challenging.

Malignant pleural mesothelioma is an aggressive solid tumor that arises either as a primary tumor or as metastatic disease secondary to lung or breast cancer. The disease has a poor prognosis, and the FDA has not approved a new treatment for malignant pleural mesothelioma since 2003, Adusumilli noted.

The disease responds poorly to immune checkpoint inhibition, which is associated with a median progression-free survival (PFS) of 4 to 5.6 months. The National Comprehensive Cancer Network included anti—PD-1 therapy as an option for second-line treatment of malignant pleural mesothelioma.

Adusumilli and colleagues previously demonstrated that mesothelin, a cell-surface antigen, is highly expressed in malignant pleural disease and is associated with an aggressive clinical course and poor survival.² Normal tissues have only low-level expression of mesothelin.

Investigators developed fully human mesothelin-targeted CARs, incorporating the inducible caspase-9 safety switch that can be activated to neutralize CAR T cells in the event of unexpected toxicity. In preclinical studies, intrapleural administration of the CAR T cells demonstrated antitumor activity. The studies also showed that CAR T cells can become functionally exhausted in the presence of a large tumor burden, but administration of an anti—PD-1 agent can revive CAR T-cell function.^3,4

Adusumilli reported findings from a phase I trial involving 21 patients (19 with mesothelioma, 1 with metastatic lung cancer, and 1 with metastatic breast cancer). Each patient received a single intrapleural infusion of the CAR T cells, preceded by cyclophosphamide preconditioning in all but 3 cases.

The safety analysis showed a single case of grade 3 cyclophosphamide-associated neutropenia. The CAR T-cell therapy was not associated with greater than grade 2 neurotoxicity, cytokine release syndrome, or on-target or off-tumor toxicity.

Ten of the 21 patients had objective responses, including 2 complete responses. Two others had stable disease. Objective responses were observed in 8 of 11 patients who received cyclophosphamide, the CAR T-cell therapy, and at least 3 doses of an anti—PD-1 agent and were followed for at least 3 months. A clinical trial of the combination is expected to begin during the second quarter of 2019.

Then, in 2020, a clinical trial with a CAR T-cell intrinsic PD1 dominant negative receptor, a decoy receptor, is set to begin.

Adusumilli would not comment on PFS among the trial participants, noting that the preliminary nature of the study would make results of any analysis speculative. He also declined to comment on characteristics of patients who did not respond to treatment but said investigators are comparing the results with some of the data from preclinical studies.

The therapeutic potential for the mesothelin-targeted CARs could reach well beyond malignant pleural disease. Adusumilli cited data indicating an estimated annual incidence of mesothelin-expressing solid tumors in the United States of 371,977 and annual prevalence of more than 2.1 million tumors. The figures included a majority of gastric tumors, cholangiocarcinomas, pancreatic cancers, lung cancers, and ovarian cancers.

References

1. Andusumilli PS. A phase I clinical trial of malignant pleural disease treated with regionally delivered autologous mesothelin-targeted CAR T cells: Safety and efficacy. Presented at: 2019 AACR Annual Meeting: March 29-April 3, 2019; Atlanta, GA.
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, et al. Regional delivery of mesothelin-targeted CAR T cell therapy generates potent and long-lasting CD4-dependent tumor immunity. J Sci Transl Med. 2014;6(261):261ra151. doi: 10.1126/scitranslmed.3010162.
4. Cherkassky L, Morello A, Villena-Vargas J, et al. Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition. J Clin Invest. 2016 Aug 1;126(8):3130-3144. doi: 10.1172/JCI83092.

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