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

Andrew R Haas1, Janos L Tanyi2, Mark H O'Hara3

  • 1Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA; Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Molecular Therapy : the Journal of the American Society of Gene Therapy
|August 18, 2019
PubMed

Insights

This study found that chimeric antigen receptor T-cells targeting mesothelin (CART-meso) were safe and expanded in patients with difficult cancers. However, clinical activity was limited, suggesting further research is needed.

Area of Science:

  • Oncology
  • Immunotherapy
  • Cell Therapy

Background:

  • Mesothelin is a tumor-associated antigen overexpressed in malignant pleural mesothelioma, ovarian, and pancreatic cancers.
  • Chimeric antigen receptor (CAR) T-cell therapy offers a promising approach for targeting solid tumors.

Purpose of the Study:

  • To investigate the safety and activity of lentiviral-transduced anti-mesothelin CAR T-cells (CART-meso) in patients with advanced solid tumors.
  • To assess CART-meso cell expansion, persistence, and clinical response in chemotherapy-refractory cancers.

Main Methods:

  • Phase I clinical trial involving 15 patients with malignant pleural mesothelioma, ovarian carcinoma, or pancreatic ductal adenocarcinoma.
  • Patients received a single infusion of CART-meso cells engineered with a lentiviral vector encoding an anti-mesothelin CAR.
  • Doses ranged from 1-3 × 10^7 to 1-3 × 10^8 cells/m², with or without cyclophosphamide pre-treatment.

Main Results:

  • CART-meso cells were generally well-tolerated, with one dose-limiting toxicity (sepsis).
  • All patients showed CART-meso cell expansion in blood, peaking by days 6-14, but with transient persistence.
  • Stable disease was the best overall response observed in 11 out of 15 patients; clinical activity was limited.

Conclusions:

  • Lentiviral-transduced CART-meso cells demonstrate acceptable safety and in vivo expansion in patients with mesothelin-expressing cancers.
  • Transient persistence and limited clinical efficacy were observed, highlighting the need for further optimization.
  • Ongoing studies are exploring fully human anti-mesothelin CAR constructs to improve therapeutic outcomes.
Keywords:
CARadoptive cell therapychimeric antigen receptor T cellimmunotherapymesothelinmesotheliomaovarian cancerpancreatic ductal adenocarcinoma

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