Engineering CD19-specific T lymphocytes with interleukin-15 and a suicide gene to enhance their anti-lymphoma/leukemia effects and safety

被引：455

作者：

Hoyos, V. ^{[1
,2
]}

Savoldo, B. ^{[1
,2
,3
]}

Quintarelli, C. ^{[1
,2
]}

Mahendravada, A. ^{[1
,2
]}

Zhang, M. ^{[1
,2
]}

Vera, J. ^{[1
,2
]}

Heslop, H. E. ^{[1
,2
,3
,4
]}

Rooney, C. M. ^{[1
,2
,3
,4
,5
,6
]}

Brenner, M. K. ^{[1
,2
,3
,4
]}

Dotti, G. ^{[1
,2
,4
,5
]}

机构：

[1] Methodist Hosp, Baylor Coll Med, Ctr Cell & Gene Therapy, Houston, TX 77030 USA

[2] Texas Childrens Hosp, Houston, TX 77030 USA

[3] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA

[4] Baylor Coll Med, Dept Med, Houston, TX 77030 USA

[5] Baylor Coll Med, Dept Immunol, Houston, TX 77030 USA

[6] Baylor Coll Med, Dept Mol Virol & Microbiol, Houston, TX 77030 USA

来源：

LEUKEMIA | 2010年 / 24卷 / 06期

关键词：

chimeric antigen receptor; IL-15; suicide gene; ADOPTIVE-CELL-TRANSFER; CHIMERIC RECEPTORS; ANTITUMOR-ACTIVITY; CLONAL EXPANSION; TRANSFER THERAPY; PD-1; EXPRESSION; PHASE-I; IMMUNOTHERAPY; IL-15; CYTOKINE;

D O I：

10.1038/leu.2010.75

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

T lymphocytes expressing a chimeric antigen receptor (CAR) targeting the CD19 antigen (CAR. 19) may be of value for the therapy of B-cell malignancies. Because the in vivo survival, expansion and anti-lymphoma activity of CAR.19(+) T cells remain suboptimal even when the CAR contains a CD28 costimulatory endodomain, we generated a novel construct that also incorporates the interleukin-15 (IL-15) gene and an inducible caspase-9-based suicide gene (iC9/CAR.19/IL-15). We found that compared with CAR.19(+) T cells, iC9/CAR.19/IL-15(+) T cells had: (1) greater numeric expansion upon antigen stimulation (10-fold greater expansion in vitro, and 3- to 15-fold greater expansion in vivo) and reduced cell death rate (Annexin-V+/7-AAD(+) cells 10 +/- 6% for iC9/CAR.19/IL-15(+) T cells and 32 +/- 19% for CAR.19(+) T cells); (2) reduced expression of the programmed death 1 (PD-1) receptor upon antigen stimulation (PD-1(+) cells <15% for iC9/CAR.19/IL-15(+) T cells versus >40% for CAR.19(+) T cells); and (3) improved antitumor effects in vivo (from 4.7- to 5.4-fold reduced tumor growth). In addition, iC9/CAR.19/IL-15(+) T cells were efficiently eliminated upon pharmacologic activation of the suicide gene. In summary, this strategy safely increases the anti-lymphoma/leukemia effects of CAR.19-redirected T lymphocytes and may be a useful approach for treatment of patients with B-cell malignancies. Leukemia (2010) 24, 1160-1170; doi:10.1038/leu.2010.75; published online 29 April 2010

引用

页码：1160 / 1170

页数：11

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[1] Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired [J].

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Wunderlich, John R. ;

Dudley, Mark E. ;

White, Donald E. ;

Rosenberg, Steven A. .

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[2] IL-15 Renders Conventional Lymphocytes Resistant to Suppressive Functions of Regulatory T Cells through Activation of the Phosphatidylinositol 3-Kinase Pathway [J].

Ahmed, Melika Ben ;

Hmida, Nadia Belhadj ;

Moes, Nicolette ;

Buyse, Sophie ;

Abdeladhim, Maha ;

Louzir, Hechmi ;

Cerf-Bensussan, Nadine .

JOURNAL OF IMMUNOLOGY, 2009, 182 (11) :6763-6770

[3] Safety and immunologic effects of IL-15 administration in nonhuman primates [J].

Berger, Carolina ;

Berger, Michael ;

Hackman, Robert C. ;

Gough, Michael ;

Elliott, Carole ;

Jensen, Michael C. ;

Riddell, Stanley R. .

BLOOD, 2009, 114 (12) :2417-2426

[4] Treatment of Chronic Lymphocytic Leukemia With Genetically Targeted Autologous T Cells: Case Report of an Unforeseen Adverse Event in a Phase I Clinical Trial [J].

Brentjens, Renier ;

Yeh, Raymond ;

Bernal, Yvette ;

Riviere, Isabelle ;

Sadelain, Michel .

MOLECULAR THERAPY, 2010, 18 (04) :666-668

[5] Eradication of systemic B-cell tumors by genetically targeted human T lymphocytes co-stimulated by CD80 and interleukin-15 [J].

Brentjens, RJ ;

Latouche, JB ;

Santos, E ;

Marti, F ;

Gong, MC ;

Lyddane, C ;

King, PD ;

Larson, S ;

Weiss, M ;

Rivière, I ;

Sadelain, M .

NATURE MEDICINE, 2003, 9 (03) :279-286

[6] Control of large, established tumor xenografts with genetically retargeted human T cells containing CD28 and CD137 domains [J].

Carpenito, Carmine ;

Milone, Michael C. ;

Hassan, Raffit ;

Simonet, Jacqueline C. ;

Lakhal, Mehdi ;

Suhoski, Megan M. ;

Varela-Rohena, Angel ;

Haines, Kathleen M. ;

Heitjan, Daniel F. ;

Albelda, Steven M. ;

Carroll, Richard G. ;

Riley, James L. ;

Pastan, Ira ;

June, Carl H. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2009, 106 (09) :3360-3365

[7] T-cell clones can be rendered specific for CD19: toward the selective augmentation of the graft-versus-B-lineage leukemia effect [J].

Cooper, LJN ;

Topp, MS ;

Serrano, LM ;

Gonzalez, S ;

Chang, WC ;

Naranjo, A ;

Wright, C ;

Popplewell, L ;

Raubitschek, A ;

Forman, SJ ;

Jensen, MC .

BLOOD, 2003, 101 (04) :1637-1644

[8] Blockade of B7-H1 improves myeloid dendritic cell-mediated antitumor immunity [J].

Curiel, TJ ;

Wei, S ;

Dong, HD ;

Alvarez, X ;

Cheng, P ;

Mottram, P ;

Krzysiek, R ;

Knutson, KL ;

Daniel, B ;

Zimmermann, MC ;

David, O ;

Burow, M ;

Gordon, A ;

Dhurandhar, N ;

Myers, L ;

Berggren, R ;

Hemminki, A ;

Alvarez, RD ;

Emilie, D ;

Curiel, DT ;

Chen, LP ;

Zou, WP .

NATURE MEDICINE, 2003, 9 (05) :562-567

[9] PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression [J].

Day, Cheryl L. ;

Kaufmann, Daniel E. ;

Kiepiela, Photini ;

Brown, Julia A. ;

Moodley, Eshia S. ;

Reddy, Sharon ;

Mackey, Elizabeth W. ;

Miller, Joseph D. ;

Leslie, Alasdair J. ;

DePierres, Chantal ;

Mncube, Zenele ;

Duraiswamy, Jaikumar ;

Zhu, Baogong ;

Eichbaum, Quentin ;

Altfeld, Marcus ;

Wherry, E. John ;

Coovadia, Hoosen M. ;

Goulder, Philip J. R. ;

Klenerman, Paul ;

Ahmed, Rafi ;

Freeman, Gordon J. ;

Walker, Bruce D. .

NATURE, 2006, 443 (7109) :350-354

[10] T lymphocytes coexpressing CCR4 and a chimeric antigen receptor targeting CD30 have improved homing and antitumor activity in a Hodgkin tumor model [J].

Di Stasi, Antonio ;

De Angelis, Biagio ;

Rooney, Cliona M. ;

Zhang, Lan ;

Mahendravada, Aruna ;

Foster, Aaron E. ;

Heslop, Helen E. ;

Brenner, Malcolm K. ;

Dotti, Gianpietro ;

Savoldo, Barbara .

BLOOD, 2009, 113 (25) :6392-6402

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