Phase I Study of Lentiviral-Transduced Chimeric Antigen Receptor-Modified T Cells Recognizing Mesothelin in Advanced Solid Cancers

Mol Ther. 2019 Nov 6;27(11):1919-1929. doi: 10.1016/j.ymthe.2019.07.015. Epub 2019 Jul 30.

Abstract

This phase I study investigated the safety and activity of lentiviral-transduced chimeric antigen receptor (CAR)-modified autologous T cells redirected against mesothelin (CART-meso) in patients with malignant pleural mesothelioma, ovarian carcinoma, and pancreatic ductal adenocarcinoma. Fifteen patients with chemotherapy-refractory cancer (n = 5 per indication) were treated with a single CART-meso cell infusion. CART-meso cells were engineered by lentiviral transduction with a construct composed of the anti-mesothelin single-chain variable fragment derived from the mouse monoclonal antibody SS1 fused to intracellular signaling domains of 4-1BB and CD3zeta. Patients received 1-3 × 107 or 1-3 × 108 CART-meso cells/m2 with or without 1.5 g/m2 cyclophosphamide. Lentiviral-transduced CART-meso cells were well tolerated; one dose-limiting toxicity (grade 4, sepsis) occurred at 1-3 × 107/m2 CART-meso without cyclophosphamide. The best overall response was stable disease (11/15 patients). CART-meso cells expanded in the blood and reached peak levels by days 6-14 but persisted transiently. Cyclophosphamide pre-treatment enhanced CART-meso expansion but did not improve persistence beyond 28 days. CART-meso DNA was detected in 7/10 tumor biopsies. Human anti-chimeric antibodies (HACA) were detected in the blood of 8/14 patients. CART-meso cells were well tolerated and expanded in the blood of all patients but showed limited clinical activity. Studies evaluating a fully human anti-mesothelin CAR are ongoing.

Keywords: CAR; adoptive cell therapy; chimeric antigen receptor T cell; immunotherapy; mesothelin; mesothelioma; ovarian cancer; pancreatic ductal adenocarcinoma.

Publication types

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

MeSH terms

  • Aged
  • Biomarkers
  • Female
  • GPI-Linked Proteins / antagonists & inhibitors
  • GPI-Linked Proteins / immunology*
  • Genetic Therapy
  • Genetic Vectors / genetics
  • Humans
  • Immunotherapy, Adoptive* / adverse effects
  • Immunotherapy, Adoptive* / methods
  • Lentivirus / genetics
  • Male
  • Mesothelin
  • Middle Aged
  • Neoplasm Staging
  • Neoplasms / diagnosis
  • Neoplasms / immunology*
  • Neoplasms / therapy*
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / metabolism*
  • Receptors, Chimeric Antigen / genetics
  • Receptors, Chimeric Antigen / metabolism*
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism*
  • Tomography, X-Ray Computed

Substances

  • Biomarkers
  • GPI-Linked Proteins
  • Msln protein, mouse
  • Receptors, Antigen, T-Cell
  • Receptors, Chimeric Antigen
  • Mesothelin