FLAG-tagged CD19-specific CAR-T cells eliminate CD19-bearing solid tumor cells in vitro and in vivo

被引：17

作者：

Berahovich, Robert ^{[1
]}

Xu, Shirley ^{[1
]}

Zhou, Hua ^{[1
]}

Harto, Hizkia ^{[1
]}

Xu, Qumiao ^{[1
]}

Garcia, Andres ^{[1
]}

Liu, Fenyong ^{[2
]}

Golubovskaya, Vita ^{[1
]}

Wu, Lijun ^{[1
]}

机构：

[1] ProMab Biotechnol, 2600 Hilltop Dr, Richmond, CA 94806 USA

[2] Univ Calif Berkeley, Dept Infect Dis, Berkeley, CA 94720 USA

来源：

FRONTIERS IN BIOSCIENCE-LANDMARK | 2017年 / 22卷

关键词：

Chimeric antigen receptor; immunotherapy; cancer; cytokine; cell; ANTITUMOR-ACTIVITY; RECEPTORS; TOXICITY;

D O I：

10.2741/4563

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Autologous T cells expressing chimeric antigen receptors (CARs) specific for CD19 have demonstrated remarkable efficacy as therapeutics for B cell malignancies. In the present study, we generated FLAG-tagged CD19-specific CAR-T cells (CD19-FLAG) and compared them to their non-tagged counterparts for their effects on solid and hematological cancer cells in vitro and in vivo. For solid tumors, we used HeLa cervical carcinoma cells engineered to overexpress CD19 (HeLa-CD19), and for hematological cancer we used Raji Burkitt's lymphoma cells, which endogenously express CD19. Like non-tagged CD19 CAR-T cells, CD19-FLAG CAR-T cells expanded in culture >100-fold and exhibited potent cytolytic activity against both HeLa-CD19 and Raji cells in vitro. CD19-FLAG CAR-T cells also secreted significantly more IFN-gamma and IL-2 than the control T cells. In vivo, CD19-FLAG CAR-T cells significantly blocked the growth of HeLa-CD19 solid tumors, increased tumor cleaved caspase-3 levels, and expanded systemically. CD19-FLAG CAR-T cells also significantly reduced Raji tumor burden and extended mouse survival. These results demonstrate the strong efficacy of FLAG-tagged CD19 CAR-T cells in solid and hematological cancer models.

引用

页码：1644 / 1654

页数：11

共 23 条

[1] Toxicity and management in CAR T-cell therapy [J].

Bonifant, Challice L. ;

Jackson, Hollie J. ;

Brentjens, Renier J. ;

Curran, Kevin J. .

MOLECULAR THERAPY-ONCOLYTICS, 2016, 3 :16011

[2] Efficacy and Toxicity Management of 19-28z CAR T Cell Therapy in B Cell Acute Lymphoblastic Leukemia [J].

Davila, Marco L. ;

Riviere, Isabelle ;

Wang, Xiuyan ;

Bartido, Shirley ;

Park, Jae ;

Curran, Kevin ;

Chung, Stephen S. ;

Stefanski, Jolanta ;

Borquez-Ojeda, Oriana ;

Olszewska, Malgorzata ;

Qu, Jinrong ;

Wasielewska, Teresa ;

He, Qing ;

Fink, Mitsu ;

Shinglot, Himaly ;

Youssif, Maher ;

Satter, Mark ;

Wang, Yongzeng ;

Hosey, James ;

Quintanilla, Hilda ;

Halton, Elizabeth ;

Bernal, Yvette ;

Bouhassira, Diana C. G. ;

Arcila, Maria E. ;

Gonen, Mithat ;

Roboz, Gail J. ;

Maslak, Peter ;

Douer, Dan ;

Frattini, Mark G. ;

Giralt, Sergio ;

Sadelain, Michel ;

Brentjens, Renier .

SCIENCE TRANSLATIONAL MEDICINE, 2014, 6 (224)

[3]

Eshhar Z, 1990, Br J Cancer Suppl, V10, P27

[4] The Emergence of T-Bodies/CAR T Cells [J].

Eshhar, Zelig ;

Waks, Tova ;

Gross, Gideon .

CANCER JOURNAL, 2014, 20 (02) :123-126

[5] CAR-T Cell Therapies From the Transfusion Medicine Perspective [J].

Fesnak, Andrew ;

Lin, ChieYu ;

Siegel, Don L. ;

Maus, Marcela V. .

TRANSFUSION MEDICINE REVIEWS, 2016, 30 (03) :139-145

[6] EXPRESSION OF IMMUNOGLOBULIN-T-CELL RECEPTOR CHIMERIC MOLECULES AS FUNCTIONAL RECEPTORS WITH ANTIBODY-TYPE SPECIFICITY [J].

GROSS, G ;

WAKS, T ;

ESHHAR, Z .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1989, 86 (24) :10024-10028

[7] Chimeric Antigen Receptor-Modified T Cells for Acute Lymphoid Leukemia [J].

Grupp, Stephan A. ;

Kalos, Michael ;

Barrett, David ;

Aplenc, Richard ;

Porter, David L. ;

Rheingold, Susan R. ;

Teachey, David T. ;

Chew, Anne ;

Hauck, Bernd ;

Wright, J. Fraser ;

Milone, Michael C. ;

Levine, Bruce L. ;

June, Carl H. .

NEW ENGLAND JOURNAL OF MEDICINE, 2013, 368 (16) :1509-1518

[8] Chimeric Antigen Receptor (CAR)-Specific Monoclonal Antibody to Detect CD19-Specific T Cells in Clinical Trials [J].

Jena, Bipulendu ;

Maiti, Sourindra ;

Huls, Helen ;

Singh, Harjeet ;

Lee, Dean A. ;

Champlin, Richard E. ;

Cooper, Laurence J. N. .

PLOS ONE, 2013, 8 (03)

[9] Blockade of PD-1 immunosuppression boosts CAR T-cell therapy [J].

John, Liza B. ;

Kershaw, Michael H. ;

Darcy, Phillip K. .

ONCOIMMUNOLOGY, 2013, 2 (10)

[10] Anti-PD-1 Antibody Therapy Potently Enhances the Eradication of Established Tumors By Gene-Modified T Cells [J].

John, Liza B. ;

Devaud, Christel ;

Duong, Connie P. M. ;

Yong, Carmen S. ;

Beavis, Paul A. ;

Haynes, Nicole M. ;

Chow, Melvyn T. ;

Smyth, Mark J. ;

Kershaw, Michael H. ;

Darcy, Phillip K. .

CLINICAL CANCER RESEARCH, 2013, 19 (20) :5636-5646

← 1 2 3 →