Development of a Novel Anti-CD19 Chimeric Antigen Receptor: A Paradigm for an Affordable CAR T Cell Production at Academic Institutions

被引：86

作者：

Castella, Maria ^{[1
,3
]}

Boronat, Anna ^{[2
,3
]}

Martin-Ibanez, Raquel ^{[4
]}

Rodriguez, Vanina ^{[3
,5
]}

Sune, Guillermo ^{[1
,3
]}

Caballero, Miguel ^{[2
,6
]}

Marzal, Berta ^{[2
]}

Perez-Amill, Lorena ^{[1
,3
]}

Martin-Antonio, Beatriz ^{[1
,3
]}

Castano, Julio ^{[7
]}

Bueno, Clara ^{[7
]}

Balague, Olga ^{[8
]}

Azucena Gonzalez-Navarro, Europa ^{[2
]}

Serra-Pages, Carles ^{[2
,9
]}

Engel, Pablo ^{[2
,3
,14
]}

Vilella, Ramon ^{[2
]}

Benitez-Ribas, Daniel ^{[2
,3
]}

Ortiz-Maldonado, Valentin ^{[1
]}

Cid, Joan ^{[3
,10
]}

Tabera, Jaime ^{[11
]}

Canals, Josep M. ^{[3
,9
]}

Lozano, Miquel ^{[3
,10
]}

Baumann, Tycho ^{[1
]}

Vilarrodona, Anna ^{[11
]}

Trias, Esteve ^{[11
]}

Campo, Elias ^{[3
,5
,9
,12
]}

Menendez, Pablo ^{[7
,12
,13
]}

Urbano-Ispizua, Alvaro ^{[1
,3
,7
,9
]}

Yague, Jordi ^{[2
,3
,9
]}

Perez-Galan, Patricia ^{[3
,5
,12
]}

Rives, Susana ^{[6
]}

Delgado, Julio ^{[1
,3
,9
,12
]}

Juan, Manel ^{[2
,3
,6
,9
]}

机构：

[1] Hosp Clin Barcelona, ICMHO, Dept Hematol, Villarroel 170, E-08036 Barcelona, Spain

[2] Hosp Clin Barcelona, CDB, Dept Immunol, Villarroel 170, E-08036 Barcelona, Spain

[3] Inst Invest Biomed August Pi & Sunyer IDIBAPS, Rossello 153, Barcelona 08036, Spain

[4] Univ Barcelona, Stem Cells & Regenerat Med Lab, Prod & Validat Ctr Adv Therapies Creatio, Dept Biomed Sci, Casanova 143, E-08036 Barcelona, Spain

[5] IDIBAPS, Physiopathol & Mol Bases Hematol Grp, Rossello 153, Barcelona 08036, Spain

[6] Univ Barcelona, Hosp St Joan de Deu, Inst Recerca Pediat, Passeig St Joan de Deu 2, Barcelona 08950, Spain

[7] Univ Barcelona, Sch Med, Dept Biomed, Josep Carreras Leukemia Res Inst, Casanova 143, E-08036 Barcelona, Spain

[8] IDIBAPS, Hosp Clin, Dept Pathol, Villarroel 170, Barcelona 08036, Spain

[9] Univ Barcelona, Casanova 143, E-08036 Barcelona, Spain

[10] Hosp Clin Barcelona, ICMHO, Dept Hemotherapy & Hemostasis, Villarroel 170, E-08036 Barcelona, Spain

[11] Hosp Clin Barcelona, Blood & Tissue Bank BST, Unit Adv Therapies, Passeig Taulat 106, Barcelona 08005, Spain

[12] Ctr Invest Biomed Red Canc ISCIII CIBERONC, Barcelona, Spain

[13] ICREA, Barcelona, Spain

[14] Univ Barcelona, Dept Biomed Sci, Immunol Unit, Casanova 143, E-08036 Barcelona, Spain

来源：

MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT | 2019年 / 12卷

基金：

欧洲研究理事会;

关键词：

LENTIVIRUS VECTOR; CD19; THERAPY;

D O I：

10.1016/j.omtm.2018.11.010

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

Genetically modifying autologous T cells to express an anti-CD19 chimeric antigen receptor (CAR) has shown impressive response rates for the treatment of CD19+ B cell malignancies in several clinical trials (CTs). Making this treatment available to our patients prompted us to develop a novel CART19 based on our own anti-CD19 antibody (A3B1), followed by CD8 hinge and transmembrane region, 4-1BB- and CD3z-signaling domains. We show that A3B1 CAR T cells are highly cytotoxic and specific against CD19+ cells in vitro, inducing secretion of pro-inflammatory cytokines and CAR T cell proliferation. In vivo, A3B1 CAR T cells are able to fully control disease progression in an NOD. Cg-Prkdc(scid) Il2rd(tm1Wjl)/SzJ (NSG) xenograph B-ALL mouse model. Based on the pre-clinical data, we conclude that our CART19 is clearly functional against CD19+ cells, to a level similar to other CAR19s currently being used in the clinic. Concurrently, we describe the implementation of our CAR T cell production system, using lentiviral vector and CliniMACS Prodigy, within a medium-sized academic institution. The results of the validation phase show our system is robust and reproducible, while maintaining a low cost that is affordable for academic institutions. Our model can serve as a paradigm for similar institutions, and it may help to make CAR T cell treatment available to all patients.

引用

页码：134 / 144

页数：11

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