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

被引：275

作者：

Haas, Andrew R. ^{[1
,2
]}

Tanyi, Janos L. ^{[1
,3
]}

O'Hara, Mark H. ^{[1
,4
]}

Gladney, Whitney L. ^{[1
,5
]}

Lacey, Simon F. ^{[1
,5
,6
]}

Torigian, Drew A. ^{[1
,7
]}

Soulen, Michael C. ^{[1
,7
]}

Tian, Lifeng ^{[1
,5
,6
]}

McGarvey, Maureen ^{[1
]}

Nelson, Anne Marie ^{[1
]}

Farabaugh, Caitlin S. ^{[1
,3
]}

Moon, Edmund ^{[1
]}

Levine, Bruce L. ^{[1
,5
,6
]}

Melenhorst, J. Joseph ^{[1
,5
,6
]}

Plesa, Gabriela ^{[1
,5
]}

June, Carl H. ^{[1
,5
,6
]}

Albelda, Steven M. ^{[1
,2
]}

Beatty, Gregory L. ^{[1
,4
]}

机构：

[1] Univ Penn, Abramson Canc Ctr, South Pavil,Room 8-107,3400 Civ Ctr Blvd,Bldg 421, Philadelphia, PA 19104 USA

[2] Univ Penn, Dept Med, Div Pulm Allergy & Crit Care, Perelman Sch Med, Philadelphia, PA 19104 USA

[3] Univ Penn, Perelman Sch Med, Ovarian Canc Res Ctr, Philadelphia, PA 19104 USA

[4] Univ Penn, Dept Med, Perelman Sch Med, Div Hematol Oncol, Philadelphia, PA 19104 USA

[5] Univ Penn, Ctr Cellular Immunotherapies, Philadelphia, PA 19104 USA

[6] Univ Penn, Dept Pathol & Lab Med, Perelman Sch Med, Philadelphia, PA USA

[7] Univ Penn, Dept Radiol, Perelman Sch Med, Philadelphia, PA 19104 USA

来源：

MOLECULAR THERAPY | 2019年 / 27卷 / 11期

关键词：

ANTITUMOR-ACTIVITY; SUSTAINED REMISSIONS; EFFICACY; IDENTIFICATION; IMMUNOTHERAPY; EXPRESSION; SAFETY; GLIOBLASTOMA; PERSISTENCE; INJECTIONS;

D O I：

10.1016/j.ymthe.2019.07.015

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 ; 0836 ; 090102 ; 100705 ;

摘要：

This phase I study investigated the safety and activity of lentiviral-transduced chimeric antigen receptor (CAR)-modified autologous T cells redirected against mesothelin (CARTmeso) 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 x 10(7) or 1-3 x 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 x 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 antichimeric 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.

引用

页码：1919 / 1929

页数：11

共 48 条

[1] HER2-Specific Chimeric Antigen Receptor-Modified Virus-Specific T Cells for Progressive Glioblastoma A Phase 1 Dose-Escalation Trial [J].

Ahmed, Nabil ;

Brawley, Vita ;

Hegde, Meenakshi ;

Bielamowicz, Kevin ;

Kalra, Mamta ;

Landi, Daniel ;

Robertson, Catherine ;

Gray, Tara L. ;

Diouf, Oumar ;

Wakefield, Amanda ;

Ghazi, Alexia ;

Gerken, Claudia ;

Yi, Zhongzhen ;

Ashoori, Aidin ;

Wu, Meng-Fen ;

Liu, Hao ;

Rooney, Cliona ;

Dotti, Gianpietro ;

Gee, Adrian ;

Su, Jack ;

Kew, Yvonne ;

Baskin, David ;

Zhang, Yi Jonathan ;

New, Pamela ;

Grilley, Bambi ;

Stojakovic, Milica ;

Hicks, John ;

Powell, Suzanne Z. ;

Brenner, Malcolm K. ;

Heslop, Helen E. ;

Grossman, Robert ;

Wels, Winfried S. ;

Gottschalk, Stephen .

JAMA ONCOLOGY, 2017, 3 (08) :1094-1101

[2] Human Epidermal Growth Factor Receptor 2 (HER2) -Specific Chimeric Antigen Receptor-Modified T Cells for the Immunotherapy of HER2-Positive Sarcoma [J].

Ahmed, Nabil ;

Brawley, Vita S. ;

Hegde, Meenakshi ;

Robertson, Catherine ;

Ghazi, Alexia ;

Gerken, Claudia ;

Liu, Enli ;

Dakhova, Olga ;

Ashoori, Aidin ;

Corder, Amanda ;

Gray, Tara ;

Wu, Meng-Fen ;

Liu, Hao ;

Hicks, John ;

Rainusso, Nino ;

Dotti, Gianpietro ;

Mei, Zhuyong ;

Grilley, Bambi ;

Gee, Adrian ;

Rooney, Cliona M. ;

Brenner, Malcolm K. ;

Heslop, Helen E. ;

Wels, Winfried S. ;

Wang, Lisa L. ;

Anderson, Peter ;

Gottschalk, Stephen .

JOURNAL OF CLINICAL ONCOLOGY, 2015, 33 (15) :1688-+

[3]

Argani P, 2001, CLIN CANCER RES, V7, P3862

[4] Activity of Mesothelin-Specific Chimeric Antigen Receptor T Cells Against Pancreatic Carcinoma Metastases in a Phase 1 Trial [J].

Beatty, Gregory L. ;

O'Hara, Mark H. ;

Lacey, Simon F. ;

Torigian, Drew A. ;

Nazimuddin, Farzana ;

Chen, Fang ;

Kulikovskaya, Irina M. ;

Soulen, Michael C. ;

McGarvey, Maureen ;

Nelson, Anne Marie ;

Gladney, Whitney L. ;

Levine, Bruce L. ;

Melenhorst, J. Joseph ;

Plesa, Gabriela ;

June, Carl H. .

GASTROENTEROLOGY, 2018, 155 (01) :29-32

[5] Chimeric antigen receptor-modified T cells for the treatment of solid tumors: Defining the challenges and next steps [J].

Beatty, Gregory L. ;

O'Hara, Mark .

PHARMACOLOGY & THERAPEUTICS, 2016, 166 :30-39

[6] Mesothelin-Specific Chimeric Antigen Receptor mRNA-Engineered T Cells Induce Antitumor Activity in Solid Malignancies [J].

Beatty, Gregory L. ;

Haas, Andrew R. ;

Maus, Marcela V. ;

Torigian, Drew A. ;

Soulen, Michael C. ;

Plesa, Gabriela ;

Chew, Anne ;

Zhao, Yangbing ;

Levine, Bruce L. ;

Albelda, Steven M. ;

Kalos, Michael ;

June, Carl H. .

CANCER IMMUNOLOGY RESEARCH, 2014, 2 (02) :112-120

[7] Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias [J].

Brentjens, Renier J. ;

Riviere, Isabelle ;

Park, Jae H. ;

Davila, Marco L. ;

Wang, Xiuyan ;

Stefanski, Jolanta ;

Taylor, Clare ;

Yeh, Raymond ;

Bartido, Shirley ;

Borquez-Ojeda, Oriana ;

Olszewska, Malgorzata ;

Bernal, Yvette ;

Pegram, Hollie ;

Przybylowski, Mark ;

Hollyman, Daniel ;

Usachenko, Yelena ;

Pirraglia, Domenick ;

Hosey, James ;

Santos, Elmer ;

Halton, Elizabeth ;

Maslak, Peter ;

Scheinberg, David ;

Jurcic, Joseph ;

Heaney, Mark ;

Heller, Glenn ;

Frattini, Mark ;

Sadelain, Michel .

BLOOD, 2011, 118 (18) :4817-4828

[8] Regression of Glioblastoma after Chimeric Antigen Receptor T-Cell Therapy [J].

Brown, Christine E. ;

Alizadeh, Darya ;

Starr, Renate ;

Weng, Lihong ;

Wagner, Jamie R. ;

Naranjo, Araceli ;

Ostberg, Julie R. ;

Blanchard, M. Suzette ;

Kilpatrick, Julie ;

Simpson, Jennifer ;

Kurien, Anita ;

Priceman, Saul J. ;

Wang, Xiuli ;

Harshbarger, Todd L. ;

D'Apuzzo, Massimo ;

Ressler, Julie A. ;

Jensen, Michael C. ;

Barish, Michael E. ;

Chen, Mike ;

Portnow, Jana ;

Forman, Stephen J. ;

Badie, Behnam .

NEW ENGLAND JOURNAL OF MEDICINE, 2016, 375 (26) :2561-2569

[9] Bioactivity and Safety of IL13Rα2-Redirected Chimeric Antigen Receptor CD8+ T Cells in Patients with Recurrent Glioblastoma [J].

Brown, Christine E. ;

Badie, Behnam ;

Barish, Michael E. ;

Weng, Lihong ;

Ostberg, Julie R. ;

Chang, Wen-Chung ;

Naranjo, Araceli ;

Starr, Renate ;

Wagner, Jamie ;

Wright, Christine ;

Zhai, Yubo ;

Bading, James R. ;

Ressler, Julie A. ;

Portnow, Jana ;

D'Apuzzo, Massimo ;

Forman, Stephen J. ;

Jensen, Michael C. .

CLINICAL CANCER RESEARCH, 2015, 21 (18) :4062-4072

[10] Heparanase promotes tumor infiltration and antitumor activity of CAR-redirected T lymphocytes [J].

Caruana, Ignazio ;

Savoldo, Barbara ;

Hoyos, Valentina ;

Weber, Gerrit ;

Liu, Hao ;

Kim, Eugene S. ;

Ittmann, Michael M. ;

Marchetti, Dario ;

Dotti, Gianpietro .

NATURE MEDICINE, 2015, 21 (05) :524-U158

← 1 2 3 4 5 →