CAR T cells targeting mesothelin show strong early signal in advanced solid cancers

CAR T cells targeting tumors expressing mesothelin have been shown to be safe and effective in a preliminary clinical evaluation in patients with malignant pleural disease.

The results showed that 13 out of 21 patients had persistent T cell CAR T cells in the peripheral blood from day 1 to 38 weeks, which was badociated with a greater than 50% reduction in the mesothelin-badociated peptide and a regression of the tumor by imaging. Objective responses were observed in eight of the eleven patients treated with cyclophosphamide, CAR T cells and at least three doses of an anti-PD-1 agent.

CAR single-dose T-cell therapy produced no tumor / target toxicity, no evidence of immunogenicity, and no serious toxicity, as reported at the annual meeting. AACR of 2019.¹

"We have not observed any evidence of immunogenicity or significant toxicity," said Prasad S. Adusumilli, MD, of the Memorial Sloan Kettering (MSK) Cancer Center in New York. "The regional distribution of CAR targeting mesothelin in combination with an anti-PD-1 agent provides lasting responses. This study strongly supports the continuation of T – cell – based therapy with anti – PD – 1 strategies in solid tumors. "

At MSK, Andusumulli is Deputy Chief of the Department of Thoracic Surgery, Co-Director of the Mesothelioma Program and Head of Cell Therapy for Solid Tumors at the Cell Therapy Center.

CAR T cell therapy has been remarkably successful in recurrent / refractory hematologic malignancies. However, replicating the success achieved in solid tumors has proved difficult.

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

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

Adusumilli and colleagues have previously demonstrated that mesothelin, a cell surface antigen, is strongly expressed in malignant pleural conditions and is badociated with aggressive clinical course and poor survival.² Normal tissues have only weak expression of mesothelin.

The researchers developed a completely human-centered CAR that incorporates the caspase-9 inducible safety switch that can be activated to neutralize CAR T cells in the event of unexpected toxicity. In preclinical studies, intrapleural administration of CAR T cells has demonstrated antitumor activity. Studies have also shown that CAR T cells can be functionally depleted in the presence of significant tumor burden, but administration of an anti-PD-1 agent may restore CAR T cell function.^3.4

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

The safety badysis showed a single case of neutropenia badociated with grade 3 cyclophosphamide. CAR T-cell therapy was not badociated with neurotoxicity greater than 2 nor with cytokine release syndrome. or toxicity to the target or out of the tumor.

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

Then, in 2020, a clinical trial involving a dominant dominant PD1 negative receptor intrinsic to CAR T cells, a decoy receptor, should begin.

Adusumilli did not want to comment on the SSP among the test participants, noting that the preliminary nature of the study would make the results of any badysis hypothetical. He also declined to comment on the characteristics of patients who did not respond to treatment, but said the researchers compared the results to some of the preclinical data.

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

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