Gastroenterology

Gastroenterology

Volume 155, Issue 1, July 2018, Pages 29-32
Gastroenterology

Original Research
Brief Report
Activity of Mesothelin-Specific Chimeric Antigen Receptor T Cells Against Pancreatic Carcinoma Metastases in a Phase 1 Trial

https://doi.org/10.1053/j.gastro.2018.03.029Get rights and content

Pancreatic ductal adenocarcinoma (PDAC) is resistant to T-cell–mediated immunotherapy. We engineered T cells to transiently express a messenger RNA encoding a chimeric antigen receptor (CAR) specific for mesothelin, a protein that is overexpressed by PDAC cells. We performed a phase I study to evaluate the safety and efficacy of adoptive cell therapy with autologous mesothelin-specific CAR T cells (CARTmeso cells) in 6 patients with chemotherapy-refractory metastatic PDAC. Patients were given intravenous CARTmeso cells 3 times weekly for 3 weeks. None of the patients developed cytokine release syndrome or neurologic symptoms and there were no dose-limiting toxicities. Disease stabilized in 2 patients, with progression-free survival times of 3.8 and 5.4 months. We used 18F-2-fluoro-2-deoxy-D-glucose (FDG)-positron emission tomography/computed tomography imaging to monitor the metabolic active volume (MAV) of individual tumor lesions. The total MAV remained stable in 3 patients and decreased by 69.2% in 1 patient with biopsy-proven mesothelin expression; in this patient, all liver lesions had a complete reduction in FDG uptake at 1 month compared with baseline, although there was no effect on the primary PDAC. Transient CAR expression was detected in patients’ blood after infusion and led to expansion of new immunoglobulin G proteins. Our results provide evidence for the potential antitumor activity of messenger RNA CARTmeso cells, as well as PDAC resistance to the immune response.

Section snippets

Acknowledgments

The authors thank the nurses of the Clinical Trials Research Center, Don Siegel Director of Transfusion Medicine and Therapeutic Pathology, and the staff of the Apheresis Unit at the Hospital of the University of Pennsylvania for their outstanding and dedicated patient care and careful data collection. We also acknowledge Natalka Kengle for cytokine luminex assays, Jeffrey Finklestein and Minnal Gupta for sample processing, Vanessa Gonzalez for data management and quality control, and Andrea

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Conflicts of interest The authors disclose the following: Bruce L. Levine, Carl H. June, Gregory L. Beatty, Gabriela Plesa, Simon F. Lacey, and J. Joseph Melenhorst are inventors of intellectual property related to chimeric antigen receptor T cells that is licensed by the University of Pennsylvania to Novartis. The remaining authors disclose no conflicts.

Funding This work was supported by a research grant funded by the Lustgarten Foundation and Cancer Research Institute. Additional support was provided in part by a Doris Duke Charitable Foundation Clinical Investigator Award (to G.L. Beatty) and by grant number K08 CA138907 (to G.L. Beatty) and 5R01 CA120409 (to Carl H. June).

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