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

Gastroenterology. 2018 Jul;155(1):29-32. doi: 10.1053/j.gastro.2018.03.029. Epub 2018 Mar 20.

Abstract

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.

Keywords: Antitumor Immunity; Immune Response Heterogeneity; Immune Therapy; Pancreatic Cancer Treatment.

Publication types

  • Clinical Trial, Phase I
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Carcinoma, Pancreatic Ductal / drug therapy*
  • Carcinoma, Pancreatic Ductal / secondary
  • Disease-Free Survival
  • Female
  • Fluorodeoxyglucose F18
  • GPI-Linked Proteins / immunology*
  • Humans
  • Immunotherapy, Adoptive / methods*
  • Male
  • Middle Aged
  • Neoplasm Metastasis
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / pathology
  • Positron Emission Tomography Computed Tomography
  • RNA, Messenger / genetics*
  • Radiopharmaceuticals
  • Receptors, Antigen, T-Cell / genetics*
  • Survival Rate
  • T-Lymphocytes / immunology
  • T-Lymphocytes / transplantation*
  • Transplantation, Autologous

Substances

  • GPI-Linked Proteins
  • RNA, Messenger
  • Radiopharmaceuticals
  • Receptors, Antigen, T-Cell
  • Fluorodeoxyglucose F18
  • mesothelin