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

339 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

UN SDGs

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

SDG 3 Good Health and Well-being

All Science Journal Classification (ASJC) codes

Molecular Medicine
Molecular Biology
Genetics
Pharmacology
Drug Discovery

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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",

}

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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UR - https://www.scopus.com/pages/publications/85070512319#tab=citedBy

U2 - 10.1016/j.ymthe.2019.07.015

DO - 10.1016/j.ymthe.2019.07.015

M3 - Article

C2 - 31420241

AN - SCOPUS:85070512319

SN - 1525-0016

VL - 27

SP - 1919

EP - 1929

JO - Molecular Therapy

JF - Molecular Therapy

IS - 11

ER -

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

Abstract

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