Inducible Caspase-9 Selectively Modulates the Toxicities of CD19-Specific Chimeric Antigen Receptor-Modified T Cells

被引:201
作者
Diaconu, Iulia [1 ,2 ]
Ballard, Brandon [1 ,2 ]
Zhang, Ming [1 ,2 ]
Chen, Yuhui [7 ]
West, John [6 ]
Dotti, Gianpietro [1 ,2 ,3 ,4 ,6 ]
Savoldols, Barbara [1 ,2 ,5 ,7 ]
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] Methodist Hosp, Baylor Coll Med, Dept Med, Houston, TX 77030 USA
[4] Methodist Hosp, Baylor Coll Med, Dept Immunol, Houston, TX 77030 USA
[5] Methodist Hosp, Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA
[6] Univ N Carolina, Lineberger Comprehens Canc Ctr, Dept Microbiol & Immunol, Chapel Hill, NC 27599 USA
[7] Univ N Carolina, Lineberger Comprehens Canc Ctr, Dept Pediat, Chapel Hill, NC 27599 USA
关键词
ENGINEERED DONOR LYMPHOCYTES; SUICIDE-GENE; IN-VIVO; SAFETY SWITCH; EXPANSION; CYTOKINE; INFUSION; LEUKEMIA; ENHANCE;
D O I
10.1016/j.ymthe.2017.01.011
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
Immunotherapy with T cells expressing the chimeric antigen receptor (CAR) specific for the CD19 antigen (CD19.CAR-Ts) is a very effective treatment in B cell lymphoid malignancies. However, B cell aplasia and cytokine release syndrome (CRS) secondary to the infusion of CD19.CAR-Ts remain significant drawbacks. The inclusion of safety switches into the vector encoding the CAR is seen as the safest method to terminate the effects of CD19.CAR-Ts in case of severe toxicities or after achieving long-term sustained remissions. By contrast, the complete elimination of CD19.CAR-Ts when CRS occurs may jeopardize clinical responses as CRS and antitumor activity seem to concur. We have demonstrated, in a humanized mouse model, that the inducible caspase-9 (iC9) safety switch can eliminate CD19.CAR-Ts in a dose-dependent manner, allowing either a selective containment of CD19.CAR-T expansion in case of CRS or complete deletion on demand granting normal B cell reconstitution.
引用
收藏
页码:580 / 592
页数:13
相关论文
共 41 条
[1]   The immunogenicity of virus-derived 2A sequences in immunocompetent individuals [J].
Arber, C. ;
Abhyankar, H. ;
Heslop, H. E. ;
Brenner, M. K. ;
Liu, H. ;
Dotti, G. ;
Savoldo, B. .
GENE THERAPY, 2013, 20 (09) :958-962
[2]   Safety of retroviral gene marking with a truncated NGF receptor [J].
Bonini, C ;
Grez, M ;
Traversari, C ;
Ciceri, F ;
Marktel, S ;
Ferrari, G ;
Dinauer, M ;
Sadat, M ;
Aiuti, A ;
Deola, S ;
Radrizzani, M ;
Hagenbeek, A ;
Apperley, J ;
Ebeling, S ;
Martens, A ;
Kolb, HJ ;
Weber, M ;
Lotti, F ;
Grande, A ;
Weissinger, E ;
Bueren, JA ;
Lamana, M ;
Falkenburg, JHF ;
Heemskerk, MHM ;
Austin, T ;
Kornblau, S ;
Marini, F ;
Benati, C ;
Magnani, Z ;
Cazzaniga, S ;
Toma, S ;
Gallo-Stampino, C ;
Introna, M ;
Slavin, S ;
Greenberg, PD ;
Bregni, M ;
Mavilio, F ;
Bordignon, C .
NATURE MEDICINE, 2003, 9 (04) :367-369
[3]   HSV-TK gene transfer into donor lymphocytes for control of allogeneic graft-versus-leukemia [J].
Bonini, C ;
Ferrari, G ;
Verzeletti, S ;
Servida, P ;
Zappone, E ;
Ruggieri, L ;
Ponzoni, M ;
Rossini, S ;
Mavilio, F ;
Traversari, C ;
Bordignon, C .
SCIENCE, 1997, 276 (5319) :1719-1724
[4]   CD19-Targeted T Cells Rapidly Induce Molecular Remissions in Adults with Chemotherapy-Refractory Acute Lymphoblastic Leukemia [J].
Brentjens, Renier J. ;
Davila, Marco L. ;
Riviere, Isabelle ;
Park, Jae ;
Wang, Xiuyan ;
Cowell, Lindsay G. ;
Bartido, Shirley ;
Stefanski, Jolanta ;
Taylor, Clare ;
Olszewska, Malgorzata ;
Borquez-Ojeda, Oriana ;
Qu, Jinrong ;
Wasielewska, Teresa ;
He, Qing ;
Bernal, Yvette ;
Rijo, Ivelise V. ;
Hedvat, Cyrus ;
Kobos, Rachel ;
Curran, Kevin ;
Steinherz, Peter ;
Jurcic, Joseph ;
Rosenblat, Todd ;
Maslak, Peter ;
Frattini, Mark ;
Sadelain, Michel .
SCIENCE TRANSLATIONAL MEDICINE, 2013, 5 (177)
[5]   Overcoming the toxicity hurdles of genetically targeted T cells [J].
Casucci, Monica ;
Hawkins, Robert E. ;
Dotti, Gianpietro ;
Bondanza, Attilio .
CANCER IMMUNOLOGY IMMUNOTHERAPY, 2015, 64 (01) :123-130
[6]   CD44v6-targeted T cells mediate potent antitumor effects against acute myeloid leukemia and multiple myeloma [J].
Casucci, Monica ;
di Robilant, Benedetta Nicolis ;
Falcone, Laura ;
Camisa, Barbara ;
Norelli, Margherita ;
Genovese, Pietro ;
Gentner, Bernhard ;
Gullotta, Fabiana ;
Ponzoni, Maurilio ;
Bernardi, Massimo ;
Marcatti, Magda ;
Saudemont, Aurore ;
Bordignon, Claudio ;
Savoldo, Barbara ;
Ciceri, Fabio ;
Naldini, Luigi ;
Dotti, Gianpietro ;
Bonini, Chiara ;
Bondanza, Attilio .
BLOOD, 2013, 122 (20) :3461-3472
[7]   Clonal Dynamics In Vivo of Virus Integration Sites of T Cells Expressing a Safety Switch [J].
Chang, Edmund C. ;
Liu, Hao ;
West, John A. ;
Zhou, Xiaoou ;
Dakhova, Olga ;
Wheeler, David A. ;
Heslop, Helen E. ;
Brenner, Malcolm K. ;
Dotti, Gianpietro .
MOLECULAR THERAPY, 2016, 24 (04) :736-745
[8]   Antitumor effects of HSV-TK-engineered donor lymphocytes after allogeneic stem-cell transplantation [J].
Ciceri, Fabio ;
Bonini, Chiara ;
Marktel, Sarah ;
Zappone, Elisabetta ;
Servida, Paolo ;
Bernardi, Massimo ;
Pescarollo, Alessandra ;
Bondanza, Attilio ;
Peccatori, Jacopo ;
Rossini, Silvano ;
Magnani, Zulma ;
Salomoni, Monica ;
Benati, Claudia ;
Ponzoni, Maurilio ;
Callegaro, Luciano ;
Corradini, Paolo ;
Bregni, Marco ;
Traversari, Catia ;
Bordignon, Claudio .
BLOOD, 2007, 109 (11) :4698-4707
[9]   Infusion of suicide-gene-engineered donor lymphocytes after family haploidentical haemopoietic stem-cell transplantation for leukaemia (the TK007 trial): a non-randomised phase I-II study [J].
Ciceri, Fabio ;
Bonini, Chiara ;
Stanghellini, Maria Teresa Lupo ;
Bondanza, Attilio ;
Traversari, Catia ;
Salomoni, Monica ;
Turchetto, Lucia ;
Colombi, Scialini ;
Bernardi, Massimo ;
Peccatori, Jacopo ;
Pescarollo, Alessandra ;
Servida, Paolo ;
Magnani, Zulma ;
Perna, Serena K. ;
Valtolina, Veronica ;
Crippa, Fulvio ;
Callegaro, Luciano ;
Spoldi, Elena ;
Crocchiolo, Roberto ;
Fleischhauer, Katharina ;
Ponzoni, Maurilio ;
Vago, Luca ;
Rossini, Silvano ;
Santoro, Armando ;
Todisco, Elisabetta ;
Apperley, Jane ;
Olavarria, Eduardo ;
Slavin, Shimon ;
Weissinger, Eva M. ;
Ganser, Arnold ;
Stadler, Michael ;
Yannaki, Evangelia ;
Fassas, Athanasios ;
Anagnostopoulos, Achilles ;
Bregni, Marco ;
Stampino, Corrado Gallo ;
Bruzzi, Paolo ;
Bordignon, Claudio .
LANCET ONCOLOGY, 2009, 10 (05) :489-500
[10]   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)