Prasad S. Adusumilli, MD
In the findings presented during the annual AACR meeting in 2019, safety and efficacy were observed in CARs T cells targeting tumors expressing mesothelin in a preliminary clinical evaluation in patients with malignant pleural disease.
According to the results, of 21 patients, 13 had persistent CAR T cells in peripheral blood from day 1 to 38 weeks, which was associated with> 50% reduction in peptide related to mesothelin and evidence of tumor regression in the image. Objective responses were seen in 8 of 11 patients who received a combination of conditioning therapy with cyclophosphamide, CAR T cells and at least 3 doses of an anti-PD-1 agent.
In addition, single dose CAR T-cell therapy did not produce target / tumor toxicity, no evidence of immunogenicity, and no serious toxicity, as reported at the AACR Annual Meeting of 2019.1
"We found no evidence of immunogenicity and no significant toxicity," said Prasad S. Adusumilli, MD, deputy chief of the Thoracic Service, co-director of the Mesothelioma Program, and head of Solid Tumor Therapy at the Cell Therapy Center in Memorial Sloan Kettering Cancer Center. "The regional supply of mesothelin targeted CARs in combination with an anti-PD-1 agent shows durable responses. This study strongly supports the pursuit of CAR T-cell therapy combined with anti-PD-1 strategies in solid tumors. "
CAR T-cell therapy has had remarkable success in relapsing / refractory haematological neoplasms. However, the replication of success in solid tumors has been challenging.
Malignant pleural mesothelioma is an aggressive solid tumor arising as a primary tumor or as a 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 inhibition of the immunological checkpoint, which is associated with 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 the second-line treatment of malignant pleural mesothelioma.
Adusumilli and colleagues have previously shown 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 a low level expression of mesothelin.
The researchers developed fully targeted CARs for human mesothelin by incorporating the inducible caspase-9 safety switch that can be activated to neutralize CAR T cells in case of unexpected toxicity. In preclinical studies, intrapleural administration of CAR T cells demonstrated antitumor activity. Studies have also shown that CAR T cells may become functionally depleted in the presence of a large tumor burden, but administration of an anti-PD-1 agent may revive the function of CAR T cells.3,4
Adusumilli reported results of a phase I study 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 CAR T cells, preceded by preconditioning cyclophosphamide in all but three cases.
Safety analysis showed a single case of neutropenia associated with grade 3 cyclophosphamide. T-cell therapy was not associated with neurotoxicity greater than grade 2, cytokine release syndrome or toxicity at the target or out of the tumor.
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, CAR T-cell therapy and at least 3 doses of an anti-PD-1 agent and were followed for at least 3 months. A combination clinical trial is expected to begin in the second quarter of 2019.
Then, in 2020, a clinical trial with a dominant negative PD1 receptor intrinsic T-cell CAR, a decoy receptor, is set to begin.
Adusumilli did not comment on PFS among study participants, noting that the preliminary nature of the study would make the results of any speculative analysis. He also declined to comment on the characteristics of patients who did not respond to the treatment, but said the researchers are comparing the results with some data from preclinical studies.
The therapeutic potential for mesothelin-targeted CARs could go beyond malignant pleural disease. Adusumilli cited data indicating an estimated annual incidence of solid tumors expressing mesothelin in the United States of 371,977 and annual prevalence of more than 2.1 million tumors. The numbers included most gastric tumors, cholangiocarcinomas, pancreatic cancer, lung cancer and ovarian cancer.
- Andusumilli PS. Phase I clinical trial of malignant pleural disease treated with autologous CAR T cells directed to mesothelin and delivered regionally: Safety and efficacy. Presented at: 2019 AACR Annual Meeting: March 29 to April 3, 2019; Atlanta, GA.
- CAR from Morello A, Sadelain M, Adusumilli PS.Mesothelin-targeted: T-cell conduction to solid tumors. Cancer discov. 2016; 6 (2): 133-146. doi: 10.1158 / 2159-8290.CD-15-0583.
- Adusumilli PS, Cherkassky L, Villena-Vargas, et al. Regional delivery of mesothelin CAR T-cell therapy generates potent and long-lasting CD4 dependent tumor immunity. J Sci Transl Med. 2014; 6 (261): 261-151. doi: 10.1126 / scitranslmed.3010162.
- Cherkassky L, Morello A, Villena-Vargas J, et al. Intrinsic cellular PD-1 checkpoint-blocking CAR cell T cells resist tumor-mediated inhibition. J Clin Invest. August 1, 2016; 126 (8): 3130-3144. doi: 10.1172 / JCI83092.