A Phase I Trial of Regional Mesothelin-Targeted CAR T-cell Therapy in Patients with Malignant Pleural Disease, in Combination with the Anti-PD-1 Agent Pembrolizumab.
Prasad S AdusumilliMarjorie G ZaudererIsabelle RivièreStephen B SolomonValerie W RuschRoisin E O'CearbhaillAmy ZhuWaseem CheemaNavin K ChintalaElizabeth HaltonJohn PinedaRocio Perez-JohnstonKay See TanBobby DalyJose A Araujo FilhoDaniel NgaiErin McGeeAlain VincentClaudia DiamonteJennifer L SauterShanu ModiDevanjan SikderBrigitte SenechalXiuyan WangWilliam D TravisMithat GönenCharles M RudinRenier J BrentjensDavid R JonesMichel SadelainPublished in: Cancer discovery (2021)
Malignant pleural diseases, comprising metastatic lung and breast cancers and malignant pleural mesothelioma (MPM), are aggressive solid tumors with poor therapeutic response. We developed and conducted a first-in-human, phase I study of regionally delivered, autologous, mesothelin-targeted chimeric antigen receptor (CAR) T-cell therapy. Intrapleural administration of 0.3M to 60M CAR T cells/kg in 27 patients (25 with MPM) was safe and well tolerated. CAR T cells were detected in peripheral blood for >100 days in 39% of patients. Following our demonstration that PD-1 blockade enhances CAR T-cell function in mice, 18 patients with MPM also received pembrolizumab safely. Among those patients, median overall survival from CAR T-cell infusion was 23.9 months (1-year overall survival, 83%). Stable disease was sustained for ≥6 months in 8 patients; 2 exhibited complete metabolic response on PET scan. Combination immunotherapy with CAR T cells and PD-1 blockade agents should be further evaluated in patients with solid tumors. SIGNIFICANCE: Regional delivery of mesothelin-targeted CAR T-cell therapy followed by pembrolizumab administration is feasible, safe, and demonstrates evidence of antitumor efficacy in patients with malignant pleural diseases. Our data support the investigation of combination immunotherapy with CAR T cells and PD-1 blockade agents in solid tumors.See related commentary by Aldea et al., p. 2674.This article is highlighted in the In This Issue feature, p. 2659.
Keyphrases
- cell therapy
- end stage renal disease
- ejection fraction
- newly diagnosed
- stem cells
- chronic kidney disease
- mesenchymal stem cells
- squamous cell carcinoma
- bone marrow
- prognostic factors
- computed tomography
- small cell lung cancer
- clinical trial
- magnetic resonance imaging
- patient reported outcomes
- type diabetes
- randomized controlled trial
- advanced non small cell lung cancer
- metabolic syndrome
- cancer therapy
- adipose tissue
- study protocol
- skeletal muscle
- epidermal growth factor receptor
- pet ct
- tyrosine kinase