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

Andrew R. Haas; Janos L. Tanyi; Mark H. O'Hara; Whitney L. Gladney; Simon F. Lacey; Drew A. Torigian; Michael C. Soulen; Lifeng Tian; Maureen McGarvey; Anne Marie Nelson; Caitlin S. Farabaugh; Edmund Moon; Bruce L. Levine; J. Joseph Melenhorst; Gabriela Plesa; Carl H. June; Steven M. Albelda; Gregory L. Beatty

doi:10.1016/j.ymthe.2019.07.015

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

Andrew R. Haas, Janos L. Tanyi, Mark H. O'Hara, Whitney L. Gladney, Simon F. Lacey, Drew A. Torigian, Michael C. Soulen, Lifeng Tian, Maureen McGarvey, Anne Marie Nelson, Caitlin S. Farabaugh, Edmund Moon, Bruce L. Levine, J. Joseph Melenhorst, Gabriela Plesa, Carl H. June, Steven M. Albelda, Gregory L. Beatty

Department of Obstetrics and Gynecology

Research output: Contribution to journal › Article › peer-review

261 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1919-1929
Number of pages	11
Journal	Molecular Therapy
Volume	27
Issue number	11
DOIs	https://doi.org/10.1016/j.ymthe.2019.07.015
State	Published - Nov 6 2019

All Science Journal Classification (ASJC) codes

Molecular Medicine
Molecular Biology
Genetics
Pharmacology
Drug Discovery

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ymthe.2019.07.015

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Haas, A. R., Tanyi, J. L., O'Hara, M. H., Gladney, W. L., Lacey, S. F., Torigian, D. A., Soulen, M. C., Tian, L., McGarvey, M., Nelson, A. M., Farabaugh, C. S., Moon, E., Levine, B. L., Melenhorst, J. J., Plesa, G., June, C. H., Albelda, S. M., & Beatty, G. L. (2019). Phase I Study of Lentiviral-Transduced Chimeric Antigen Receptor-Modified T Cells Recognizing Mesothelin in Advanced Solid Cancers. Molecular Therapy, 27(11), 1919-1929. https://doi.org/10.1016/j.ymthe.2019.07.015

@article{254a9030a56b476fa6e1d88fa62a4225,

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

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.",

author = "Haas, {Andrew R.} and Tanyi, {Janos L.} and O'Hara, {Mark H.} and Gladney, {Whitney L.} and Lacey, {Simon F.} and Torigian, {Drew A.} and Soulen, {Michael C.} and Lifeng Tian and Maureen McGarvey and Nelson, {Anne Marie} and Farabaugh, {Caitlin S.} and Edmund Moon and Levine, {Bruce L.} and Melenhorst, {J. Joseph} and Gabriela Plesa and June, {Carl H.} and Albelda, {Steven M.} and Beatty, {Gregory L.}",

note = "Publisher Copyright: {\textcopyright} 2019 The American Society of Gene and Cell Therapy",

year = "2019",

month = nov,

day = "6",

doi = "10.1016/j.ymthe.2019.07.015",

language = "English (US)",

volume = "27",

pages = "1919--1929",

journal = "Molecular Therapy",

issn = "1525-0016",

publisher = "Cell Press",

number = "11",

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Haas, AR, Tanyi, JL, O'Hara, MH, Gladney, WL, Lacey, SF, Torigian, DA, Soulen, MC, Tian, L, McGarvey, M, Nelson, AM, Farabaugh, CS, Moon, E, Levine, BL, Melenhorst, JJ, Plesa, G, June, CH, Albelda, SM & Beatty, GL 2019, 'Phase I Study of Lentiviral-Transduced Chimeric Antigen Receptor-Modified T Cells Recognizing Mesothelin in Advanced Solid Cancers', Molecular Therapy, vol. 27, no. 11, pp. 1919-1929. https://doi.org/10.1016/j.ymthe.2019.07.015

TY - JOUR

T1 - Phase I Study of Lentiviral-Transduced Chimeric Antigen Receptor-Modified T Cells Recognizing Mesothelin in Advanced Solid Cancers

AU - Haas, Andrew R.

AU - Tanyi, Janos L.

AU - O'Hara, Mark H.

AU - Gladney, Whitney L.

AU - Lacey, Simon F.

AU - Torigian, Drew A.

AU - Soulen, Michael C.

AU - Tian, Lifeng

AU - McGarvey, Maureen

AU - Nelson, Anne Marie

AU - Farabaugh, Caitlin S.

AU - Moon, Edmund

AU - Levine, Bruce L.

AU - Melenhorst, J. Joseph

AU - Plesa, Gabriela

AU - June, Carl H.

AU - Albelda, Steven M.

AU - Beatty, Gregory L.

PY - 2019/11/6

Y1 - 2019/11/6

N2 - 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.

AB - 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.

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SN - 1525-0016

VL - 27

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JO - Molecular Therapy

JF - Molecular Therapy

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ER -

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

Abstract

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