1. Phase I Study of Lentiviral-Transduced Chimeric Antigen Receptor-Modified T Cells Recognizing Mesothelin in Advanced Solid Cancers
- Author
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Lifeng Tian, Andrew R. Haas, Janos L. Tanyi, Whitney L. Gladney, Drew A. Torigian, Steven M. Albelda, Edmund K. Moon, Mark H. O'Hara, Bruce L. Levine, Gabriela Plesa, J. Joseph Melenhorst, Caitlin S. Farabaugh, Anne Marie Nelson, Maureen McGarvey, Carl H. June, Michael C. Soulen, Gregory L. Beatty, and Simon F. Lacey
- Subjects
Male ,T-Lymphocytes ,medicine.medical_treatment ,Cell ,Immunotherapy, Adoptive ,0302 clinical medicine ,Neoplasms ,Drug Discovery ,polycyclic compounds ,0303 health sciences ,Receptors, Chimeric Antigen ,biology ,virus diseases ,Middle Aged ,medicine.anatomical_structure ,Mesothelin ,030220 oncology & carcinogenesis ,Molecular Medicine ,Female ,Original Article ,Antibody ,medicine.drug ,Cyclophosphamide ,Genetic Vectors ,Receptors, Antigen, T-Cell ,GPI-Linked Proteins ,03 medical and health sciences ,Genetics ,medicine ,Humans ,Molecular Biology ,Aged ,Neoplasm Staging ,030304 developmental biology ,Pharmacology ,business.industry ,Lentivirus ,fungi ,Cancer ,Genetic Therapy ,Immunotherapy ,medicine.disease ,Chimeric antigen receptor ,carbohydrates (lipids) ,biology.protein ,Cancer research ,Tomography, X-Ray Computed ,Ovarian cancer ,business ,Biomarkers - 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 × 10(7) or 1–3 × 10(8) CART-meso cells/m(2) with or without 1.5 g/m(2) cyclophosphamide. Lentiviral-transduced CART-meso cells were well tolerated; one dose-limiting toxicity (grade 4, sepsis) occurred at 1–3 × 10(7)/m(2) 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.
- Published
- 2019
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