Advertisement

Chimeric antigen receptor T-cells for B-cell malignancies

  • Eben I. Lichtman
    Correspondence
    Reprint requests: Eben I. Lichtman, Division of Hematology/Oncology, Department of Medicine, University of North Carolina, 170 Manning Drive, CB#7305, Chapel Hill, NC, 27599
    Affiliations
    Department of Medicine, University of North Carolina, Chapel Hill, NC

    Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC
    Search for articles by this author
  • Gianpietro Dotti
    Affiliations
    Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC

    Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC
    Search for articles by this author
      The adoptive transfer of T-lymphocytes modified to express chimeric antigen receptors (CAR-Ts) has produced impressive clinical responses among patients with B-cell malignancies. This has led to a rapid expansion in the number of clinical trials over the past several years. Although CD19-specific CAR-Ts are the most extensively evaluated, CAR-Ts specific for other B-cell–associated targets have also shown promise. However, despite this success, toxicities associated with CAR-T administration remain a significant concern. There continues to be substantial heterogeneity among CAR-T products, and differences in both CAR designs and CAR-T production strategies can substantially affect clinical outcomes. Ongoing clinical studies will further elucidate these differences and many other innovative approaches are being evaluated at the preclinical level. In this review, we will discuss the background and rationale for the use of CAR-Ts, provide an overview of advances in the field, and examine the application of CAR-Ts to the treatment of B-cell malignancies, including a summary of clinical trials published to date.

      Abbreviations:

      ALL (acute lymphoblastic leukemia), B-ALL (B-cell acute lymphoblastic leukemia), CAR-T (chimeric antigen receptor T-cell), CAR (chimeric antigen receptor), CD (cluster of differentiation), CHOP (Children's Hospital of Philadelphia), CLL (chronic lymphocytic leukemia), CR (complete remission or complete response), CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats CRISPR-associated protein 9), CRS (cytokine release syndrome), CTLA-4 (cytotoxic T-lymphocyte–associated protein 4), DLBCL (diffuse large B-cell lymphoma), DNA (deoxyribonucleic acid), FHCRC (Fred Hutchinson Cancer Research Center), FL (follicular lymphoma), HIV (human immunodeficiency virus), iC9 (inducible caspase-9), IFNγ (interferon gamma), IL (interleukin), ITAM (immunoreceptor tyrosine-based activation motif), JAK/STAT (Janus kinase/signal transducers and activators of transcription), MCL (mantle cell lymphoma), MHC (major histocompatibility complex), MRD (minimal residual disease), mRNA (messenger ribonucleic acid), MSKCC (Memorial Sloan Kettering Cancer Center), NCI (National Cancer Institute), NHL (non-Hodgkin lymphoma), ORR (overall response rate), PBMCs (peripheral blood mononuclear cells), PD-1 (programmed cell death protein 1), PR (partial remission or partial response), scFv (single-chain variable fragment), TALEN (transcription activator-like effector), TBI (total body irradiation), TCR (T-cell receptor), TM (transmembrane), ZFN (zinc-finger nuclease)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Translational Research
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Sun C.
        • Dotti G.
        • Savoldo B.
        Utilizing cell-based therapeutics to overcome immune evasion in hematologic malignancies.
        Blood. 2016; 127: 3350-3359
        • Schreiber R.D.
        • Old L.J.
        • Smyth M.J.
        Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion.
        Science. 2011; 331: 1565-1570
        • Gaillard H.
        • Garcia-Muse T.
        • Aguilera A.
        Replication stress and cancer.
        Nat Rev Cancer. 2015; 15: 276-289
        • Billingham R.E.
        • Brent L.
        • Medawar P.B.
        Quantitative studies on tissue transplantation immunity. II. The origin, strength and duration of actively and adoptively acquired immunity.
        Proc R Soc Lond B Biol Sci. 1954; 143: 58-80
        • Gross G.
        • Waks T.
        • Eshhar Z.
        Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity.
        Proc Natl Acad Sci U S A. 1989; 86: 10024-10028
        • Kuwana Y.
        • Asakura Y.
        • Utsunomiya N.
        • et al.
        Expression of chimeric receptor composed of immunoglobulin-derived V regions and T-cell receptor-derived C regions.
        Biochem Biophys Res Commun. 1987; 149: 960-968
        • Gill S.
        • Maus M.V.
        • Porter D.L.
        Chimeric antigen receptor T cell therapy: 25years in the making.
        Blood Rev. 2016; 30: 157-167
        • Chen L.
        • Ashe S.
        • Brady W.A.
        • et al.
        Costimulation of antitumor immunity by the B7 counterreceptor for the T lymphocyte molecules CD28 and CTLA-4.
        Cell. 1992; 71: 1093-1102
        • Chen L.
        • Flies D.B.
        Molecular mechanisms of T cell co-stimulation and co-inhibition.
        Nat Rev Immunol. 2013; 13: 227-242
        • Gimmi C.D.
        • Freeman G.J.
        • Gribben J.G.
        • Gray G.
        • Nadler L.M.
        Human T-cell clonal anergy is induced by antigen presentation in the absence of B7 costimulation.
        Proc Natl Acad Sci U S A. 1993; 90: 6586-6590
        • Eshhar Z.
        • Waks T.
        • Gross G.
        • Schindler D.G.
        Specific activation and targeting of cytotoxic lymphocytes through chimeric single chains consisting of antibody-binding domains and the gamma or zeta subunits of the immunoglobulin and T-cell receptors.
        Proc Natl Acad Sci U S A. 1993; 90: 720-724
        • Deeks S.G.
        • Wagner B.
        • Anton P.A.
        • et al.
        A phase II randomized study of HIV-specific T-cell gene therapy in subjects with undetectable plasma viremia on combination antiretroviral therapy.
        Mol Ther. 2002; 5: 788-797
        • Pule M.A.
        • Savoldo B.
        • Myers G.D.
        • et al.
        Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastoma.
        Nat Med. 2008; 14: 1264-1270
        • Louis C.U.
        • Savoldo B.
        • Dotti G.
        • et al.
        Antitumor activity and long-term fate of chimeric antigen receptor-positive T cells in patients with neuroblastoma.
        Blood. 2011; 118: 6050-6056
        • Lamers C.H.
        • Sleijfer S.
        • van Steenbergen S.
        • et al.
        Treatment of metastatic renal cell carcinoma with CAIX CAR-engineered T cells: clinical evaluation and management of on-target toxicity.
        Mol Ther. 2013; 21: 904-912
        • Park J.R.
        • Digiusto D.L.
        • Slovak M.
        • et al.
        Adoptive transfer of chimeric antigen receptor re-directed cytolytic T lymphocyte clones in patients with neuroblastoma.
        Mol Ther. 2007; 15: 825-833
        • Kershaw M.H.
        • Westwood J.A.
        • Parker L.L.
        • et al.
        A phase I study on adoptive immunotherapy using gene-modified T cells for ovarian cancer.
        Clin Cancer Res. 2006; 12: 6106-6115
        • Till B.G.
        • Jensen M.C.
        • Wang J.
        • et al.
        Adoptive immunotherapy for indolent non-Hodgkin lymphoma and mantle cell lymphoma using genetically modified autologous CD20-specific T cells.
        Blood. 2008; 112: 2261-2271
        • Jensen M.C.
        • Popplewell L.
        • Cooper L.J.
        • et al.
        Antitransgene rejection responses contribute to attenuated persistence of adoptively transferred CD20/CD19-specific chimeric antigen receptor redirected T cells in humans.
        Biol Blood Marrow Transplant. 2010; 16: 1245-1256
        • Dotti G.
        • Gottschalk S.
        • Savoldo B.
        • Brenner M.K.
        Design and development of therapies using chimeric antigen receptor-expressing T cells.
        Immunol Rev. 2014; 257: 107-126
        • Hacein-Bey-Abina S.
        • Garrigue A.
        • Wang G.P.
        • et al.
        Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1.
        J Clin Invest. 2008; 118: 3132-3142
        • von Kalle C.
        • Deichmann A.
        • Schmidt M.
        Vector integration and tumorigenesis.
        Hum Gene Ther. 2014; 25: 475-481
        • Scholler J.
        • Brady T.L.
        • Binder-Scholl G.
        • et al.
        Decade-long safety and function of retroviral-modified chimeric antigen receptor T cells.
        Sci Transl Med. 2012; 4: 132ra153
        • Finney H.M.
        • Lawson A.D.
        • Bebbington C.R.
        • Weir A.N.
        Chimeric receptors providing both primary and costimulatory signaling in T cells from a single gene product.
        J Immunol. 1998; 161: 2791-2797
        • Savoldo B.
        • Ramos C.A.
        • Liu E.
        • et al.
        CD28 costimulation improves expansion and persistence of chimeric antigen receptor-modified T cells in lymphoma patients.
        J Clin Invest. 2011; 121: 1822-1826
        • Imai C.
        • Mihara K.
        • Andreansky M.
        • et al.
        Chimeric receptors with 4-1BB signaling capacity provoke potent cytotoxicity against acute lymphoblastic leukemia.
        Leukemia. 2004; 18: 676-684
        • Carpenito C.
        • Milone M.C.
        • Hassan R.
        • et al.
        Control of large, established tumor xenografts with genetically retargeted human T cells containing CD28 and CD137 domains.
        Proc Natl Acad Sci U S A. 2009; 106: 3360-3365
        • Zhong X.S.
        • Matsushita M.
        • Plotkin J.
        • Riviere I.
        • Sadelain M.
        Chimeric antigen receptors combining 4-1BB and CD28 signaling domains augment PI3kinase/AKT/Bcl-XL activation and CD8+ T cell-mediated tumor eradication.
        Mol Ther. 2010; 18: 413-420
        • Gomes da Silva D.
        • Mukherjee M.
        • Srinivasan M.
        • et al.
        Direct comparison of in vivo fate of second and third-generation CD19-specific chimeric antigen receptor (CAR)-T cells in patients with B-Cell lymphoma: Reversal of toxicity from tonic signaling.
        Blood. 2016; 128: 1851
        • Geldres C.
        • Savoldo B.
        • Dotti G.
        Chimeric antigen receptor-redirected T cells return to the bench.
        Semin Immunol. 2016; 28: 3-9
        • Sharifzadeh Z.
        • Rahbarizadeh F.
        • Shokrgozar M.A.
        • et al.
        Genetically engineered T cells bearing chimeric nanoconstructed receptors harboring TAG-72-specific camelid single domain antibodies as targeting agents.
        Cancer Lett. 2013; 334: 237-244
        • Zhang A.H.
        • Yoon J.H.
        • Kim Y.C.
        • Scott D.W.
        Targeting FVIII-specific B cells using BAR-transduced regulatory T cells.
        Blood. 2016; 128: 329
        • Cruz C.R.
        • Micklethwaite K.P.
        • Savoldo B.
        • et al.
        Infusion of donor-derived CD19-redirected virus-specific T cells for B-cell malignancies relapsed after allogeneic stem cell transplant: a phase 1 study.
        Blood. 2013; 122: 2965-2973
        • Brudno J.N.
        • Somerville R.P.
        • Shi V.
        • et al.
        Allogeneic T cells that express an anti-CD19 chimeric antigen receptor induce remissions of B-Cell malignancies that progress after allogeneic hematopoietic stem-cell transplantation without causing graft-versus-host disease.
        J Clin Oncol. 2016; 34: 1112-1121
        • Kebriaei P.
        • Singh H.
        • Huls M.H.
        • et al.
        Phase I trials using Sleeping Beauty to generate CD19-specific CAR T cells.
        J Clin Invest. 2016; 126: 3363-3376
        • Kochenderfer J.N.
        • Wilson W.H.
        • Janik J.E.
        • et al.
        Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19.
        Blood. 2010; 116: 4099-4102
        • Qasim W.
        • Zhan H.
        • Samarasinghe S.
        • et al.
        Molecular remission of infant B-ALL after infusion of universal TALEN gene-edited CAR T cells.
        Sci Transl Med. 2017; 9
        • Qasim W.
        • Amrolia P.J.
        • Samarasinghe S.
        • et al.
        First clinical application of Talen engineered universal CAR19 T cells in B-ALL.
        Blood. 2015; 126: 2046
        • Montini E.
        • Cesana D.
        • Schmidt M.
        • et al.
        Hematopoietic stem cell gene transfer in a tumor-prone mouse model uncovers low genotoxicity of lentiviral vector integration.
        Nat Biotechnol. 2006; 24: 687-696
        • Kebriaei P.
        • Huls H.
        • Jena B.
        • et al.
        Infusing CD19-directed T cells to augment disease control in patients undergoing autologous hematopoietic stem-cell transplantation for advanced B-lymphoid malignancies.
        Hum Gene Ther. 2012; 23: 444-450
        • Manuri P.V.
        • Wilson M.H.
        • Maiti S.N.
        • et al.
        piggyBac transposon/transposase system to generate CD19-specific T cells for the treatment of B-lineage malignancies.
        Hum Gene Ther. 2010; 21: 427-437
        • Till B.G.
        • Jensen M.C.
        • Wang J.
        • et al.
        CD20-specific adoptive immunotherapy for lymphoma using a chimeric antigen receptor with both CD28 and 4-1BB domains: pilot clinical trial results.
        Blood. 2012; 119: 3940-3950
        • Ellis J.
        Silencing and variegation of gammaretrovirus and lentivirus vectors.
        Hum Gene Ther. 2005; 16: 1241-1246
        • Eyquem J.
        • Mansilla-Soto J.
        • Giavridis T.
        • et al.
        Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection.
        Nature. 2017; 543: 113-117
        • Schumann K.
        • Lin S.
        • Boyer E.
        • et al.
        Generation of knock-in primary human T cells using Cas9 ribonucleoproteins.
        Proc Natl Acad Sci U S A. 2015; 112: 10437-10442
        • MacLeod D.T.
        • Antony J.
        • Martin A.J.
        • et al.
        Integration of a CD19 CAR into the TCR Alpha Chain Locus Streamlines Production of Allogeneic Gene-Edited CAR T Cells.
        Mol Ther. 2017; 25: 949-961
        • Gattinoni L.
        • Lugli E.
        • Ji Y.
        • et al.
        A human memory T cell subset with stem cell-like properties.
        Nat Med. 2011; 17: 1290-1297
        • Berger C.
        • Jensen M.C.
        • Lansdorp P.M.
        • Gough M.
        • Elliott C.
        • Riddell S.R.
        Adoptive transfer of effector CD8+ T cells derived from central memory cells establishes persistent T cell memory in primates.
        J Clin Invest. 2008; 118: 294-305
        • Hinrichs C.S.
        • Borman Z.A.
        • Cassard L.
        • et al.
        Adoptively transferred effector cells derived from naive rather than central memory CD8+ T cells mediate superior antitumor immunity.
        Proc Natl Acad Sci U S A. 2009; 106: 17469-17474
        • Gattinoni L.
        • Klebanoff C.A.
        • Palmer D.C.
        • et al.
        Acquisition of full effector function in vitro paradoxically impairs the in vivo antitumor efficacy of adoptively transferred CD8+ T cells.
        J Clin Invest. 2005; 115: 1616-1626
        • Xu Y.
        • Zhang M.
        • Ramos C.A.
        • et al.
        Closely related T-memory stem cells correlate with in vivo expansion of CAR.CD19-T cells and are preserved by IL-7 and IL-15.
        Blood. 2014; 123: 3750-3759
        • Cieri N.
        • Camisa B.
        • Cocchiarella F.
        • et al.
        IL-7 and IL-15 instruct the generation of human memory stem T cells from naive precursors.
        Blood. 2013; 121: 573-584
        • Gardner R.
        • Finney O.
        • Smithers H.
        • et al.
        CD19CAR T cell products of defined CD4:CD8 composition and transgene expression show prolonged persistence and durable MRD-negative remission in pediatric and young adult B-Cell all.
        Blood. 2016; 128: 219
        • Turtle C.J.
        • Hanafi L.A.
        • Berger C.
        • et al.
        Rate of durable complete response in ALL, NHL, and CLL after immunotherapy with optimized lymphodepletion and defined composition CD19 CAR-T cells.
        J Clin Oncol. 2016; 34 (suppl; abstr 102)
        • Turtle C.J.
        • Hanafi L.A.
        • Berger C.
        • et al.
        CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients.
        J Clin Invest. 2016; 126: 2123-2138
        • Dudley M.E.
        • Yang J.C.
        • Sherry R.
        • et al.
        Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens.
        J Clin Oncol. 2008; 26: 5233-5239
        • Dai H.
        • Zhang W.
        • Li X.
        • et al.
        Tolerance and efficacy of autologous or donor-derived T cells expressing CD19 chimeric antigen receptors in adult B-ALL with extramedullary leukemia.
        Oncoimmunology. 2015; 4: e1027469
        • Turtle C.J.
        • Hanafi L.A.
        • Berger C.
        • et al.
        Addition of fludarabine to cyclophosphamide lymphodepletion improves in vivo expansion of CD19 chimeric antigen receptor-modified T cells and clinical outcome in adults with B cell acute lymphoblastic leukemia.
        Blood. 2015; 126: 3773
        • Lee D.W.
        • Stetler-Stevenson M.
        • Yuan C.M.
        • et al.
        Long-term outcomes following CD19 CAR T cell therapy for B-ALL are superior in patients receiving a fludarabine/cyclophosphamide preparative regimen and post-CAR hematopoietic stem cell transplantation.
        Blood. 2016; 128: 218
        • Brudno J.N.
        • Kochenderfer J.N.
        Toxicities of chimeric antigen receptor T cells: recognition and management.
        Blood. 2016; 127: 3321-3330
        • Lee D.W.
        • Gardner R.
        • Porter D.L.
        • et al.
        Current concepts in the diagnosis and management of cytokine release syndrome.
        Blood. 2014; 124: 188-195
        • Porter D.L.
        • Hwang W.T.
        • Frey N.V.
        • et al.
        Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia.
        Sci Transl Med. 2015; 7: 303ra139
        • Davila M.L.
        • Riviere I.
        • Wang X.
        • et al.
        Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia.
        Sci Transl Med. 2014; 6: 224ra225
      1. Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03. US Department of Health and Human Services, Bethesda, MD, 2010
        • Bedoya F.
        • Frigault M.J.
        • Maus M.V.
        The flipside of the power of engineered T cells: observed and potential toxicities of genetically modified T cells as therapy.
        Mol Ther. 2017; 25: 314-320
        • Kenderian S.S.
        • Ruella M.
        • Shestova O.
        • et al.
        Ruxolitinib prevents cytokine release syndrome after CART cell therapy without impairing the anti-tumor effect in a xenograft model.
        Blood. 2016; 128: 652
        • Ruella M.
        • Kenderian S.S.
        • Shestova O.
        • et al.
        Kinase inhibitor ibrutinib prevents cytokine-release syndrome after anti-CD19 chimeric antigen receptor T cells (CART) for B cell neoplasms.
        Blood. 2016; 128: 2159
        • Frey N.
        • Shaw P.A.
        • Hexner E.O.
        • et al.
        Optimizing chimeric antigen receptor (CAR) T cell therapy for adult patients with relapsed or refractory (r/r) acute lymphoblastic leukemia (ALL).
        J Clin Oncol. 2016; 34 (suppl; abstr 7002)
        • Juno Therapeutics, Inc
        Study Evaluating the Efficacy and Safety of JCAR015 in Adult B-cell Acute Lymphoblastic Leukemia (B-ALL) (ROCKET).
        in: ClinicalTrials.gov [Internet]. National Library of Medicine (US), Bethesda (MD)2000 (Available at:) (Accessed March 17, 2017. NLM Identifier: NCT02535364)
        • Juno Therapeutics Inc
        Juno Therapeutics Reports Fourth Quarter and 2016 Financial Results.
        2017 (Available at:) (Accessed March 6, 2017)
        • Fitzgerald J.C.
        • Weiss S.L.
        • Maude S.L.
        • et al.
        Cytokine release syndrome after chimeric antigen receptor T cell therapy for acute lymphoblastic leukemia.
        Crit Care Med. 2017; 45: e124-e131
        • Teachey D.T.
        • Lacey S.F.
        • Shaw P.A.
        • et al.
        Identification of predictive biomarkers for cytokine release syndrome after chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia.
        Cancer Discov. 2016; 6: 664-679
        • Morgan R.A.
        • Yang J.C.
        • Kitano M.
        • Dudley M.E.
        • Laurencot C.M.
        • Rosenberg S.A.
        Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2.
        Mol Ther. 2010; 18: 843-851
        • Ramos C.A.
        • Savoldo B.
        • Torrano V.
        • et al.
        Clinical responses with T lymphocytes targeting malignancy-associated kappa light chains.
        J Clin Invest. 2016; 126: 2588-2596
        • Holzinger A.
        • Barden M.
        • Abken H.
        The growing world of CAR T cell trials: a systematic review.
        Cancer Immunol Immunother. 2016; 65: 1433-1450
        • Bonini C.
        • Ferrari G.
        • Verzeletti S.
        • et al.
        HSV-TK gene transfer into donor lymphocytes for control of allogeneic graft-versus-leukemia.
        Science. 1997; 276: 1719-1724
        • Ciceri F.
        • Bonini C.
        • Stanghellini M.T.
        • et al.
        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.
        Lancet Oncol. 2009; 10: 489-500
        • Berger C.
        • Flowers M.E.
        • Warren E.H.
        • Riddell S.R.
        Analysis of transgene-specific immune responses that limit the in vivo persistence of adoptively transferred HSV-TK-modified donor T cells after allogeneic hematopoietic cell transplantation.
        Blood. 2006; 107: 2294-2302
        • Diaconu I.
        • Ballard B.
        • Zhang M.
        • et al.
        Inducible Caspase-9 selectively modulates the toxicities of CD19-specific chimeric antigen receptor-modified T cells.
        Mol Ther. 2017; 25: 580-592
        • Di Stasi A.
        • Tey S.K.
        • Dotti G.
        • et al.
        Inducible apoptosis as a safety switch for adoptive cell therapy.
        N Engl J Med. 2011; 365: 1673-1683
        • Baylor College of Medicine
        3rd Generation GD-2 Chimeric Antigen Receptor and iCaspase Suicide Safety Switch, Neuroblastoma, GRAIN (GRAIN).
        in: ClinicalTrials.gov [Internet]. National Library of Medicine (US), Bethesda (MD)2000 (Available at:) (Accessed March 7, 2017. NLM Identifier: NCT01822652)
        • National Cancer Institute (NCI)
        A Phase I Trial of T Cells Expressing an Anti-GD2 Chimeric Antigen Receptor in Children and Young Adults With GD2+ Solid Tumors.
        in: ClinicalTrials.gov [Internet]. National Library of Medicine (US), Bethesda (MD)2000 (Available at:) (Accessed March 17, 2017. NLM Identifier: NCT02107963)
        • Memorial Sloan Kettering Cancer Center
        Malignant Pleural Disease Treated With Autologous T Cells Genetically Engineered to Target the Cancer-Cell Surface Antigen Mesothelin.
        in: ClinicalTrials.gov [Internet]. National Library of Medicine (US), Bethesda (MD)2000 (Available at:) (Accessed March 17, 2017. NLM Identifier: NCT02414269)
        • Peking University
        Evaluation of 4th Generation Safety-designed CAR T Cells Targeting High-risk and Refractory B Cell Lymphomas (4SCAR19273).
        in: ClinicalTrials.gov [Internet]. National Library of Medicine (US), Bethesda (MD)2000 (Available at:) (Accessed March 7, 2017. NLM Identifier: NCT02247609)
        • Shenzhen Geno-Immune Medical Institute
        A Phase I/II Multiple Center Trial of 4SCAR19 Cells in the Treatment of Relapsed and Refractory B Cell Malignancies.
        in: ClinicalTrials.gov [Internet]. National Library of Medicine (US), Bethesda (MD)2000 (Available at:) (Accessed March 7, 2017. NLM Identifier: NCT03050190)
        • UNC Lineberger Comprehensive Cancer Center
        Administration of Autologous CAR-T CD19 Antigen With Inducible Safety Switch in Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia.
        in: ClinicalTrials.gov [Internet]. National Library of Medicine (US), Bethesda (MD)2000 (Available at:) (Accessed March 7, 2017. NLM Identifier: NCT03016377)
        • Wang X.
        • Chang W.C.
        • Wong C.W.
        • et al.
        A transgene-encoded cell surface polypeptide for selection, in vivo tracking, and ablation of engineered cells.
        Blood. 2011; 118: 1255-1263
        • Brentjens R.
        • Riviere I.
        • Hollyman D.
        • et al.
        401. Unexpected toxicity of cyclophosphamide followed by adoptively transferred CD19-targeted T cells in a patient with Bulky CLL.
        Mol Ther. 2009; 17: S157
        • Porter D.L.
        • Levine B.L.
        • Kalos M.
        • Bagg A.
        • June C.H.
        Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia.
        N Engl J Med. 2011; 365: 725-733
        • Kalos M.
        • Levine B.L.
        • Porter D.L.
        • et al.
        T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia.
        Sci Transl Med. 2011; 3: 95ra73
        • Lee D.W.
        • Kochenderfer J.N.
        • Stetler-Stevenson M.
        • et al.
        T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial.
        Lancet. 2015; 385: 517-528
        • Maude S.L.
        • Frey N.
        • Shaw P.A.
        • et al.
        Chimeric antigen receptor T cells for sustained remissions in leukemia.
        N Engl J Med. 2014; 371: 1507-1517
        • Kochenderfer J.N.
        • Dudley M.E.
        • Kassim S.H.
        • et al.
        Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor.
        J Clin Oncol. 2015; 33: 540-549
        • Maude S.L.
        • Teachey D.T.
        • Rheingold S.R.
        • et al.
        Sustained remissions with CD19-specific chimeric antigen receptor (CAR)-modified T cells in children with relapsed/refractory ALL.
        J Clin Oncol. 2016; 34 (suppl; abstr 3011)
        • Grupp S.A.
        • Maude S.L.
        • Shaw P.A.
        • et al.
        Durable remissions in children with relapsed/refractory ALL treated with T Cells engineered with a CD19-targeted chimeric antigen receptor (CTL019).
        Blood. 2015; 126: 681
        • Grupp S.A.
        • Kalos M.
        • Barrett D.
        • et al.
        Chimeric antigen receptor-modified T cells for acute lymphoid leukemia.
        N Engl J Med. 2013; 368: 1509-1518
        • Grupp S.A.
        • Laetsch T.W.
        • Buechner J.
        • et al.
        Analysis of a global registration trial of the efficacy and safety of CTL019 in pediatric and young adults with relapsed/refractory acute lymphoblastic leukemia (all).
        Blood. 2016; 128: 221
        • Maude S.L.
        • Pulsipher M.A.
        • Boyer M.W.
        • et al.
        Efficacy and safety of CTL019 in the first us phase II multicenter trial in pediatric relapsed/refractory acute lymphoblastic leukemia: results of an interim analysis.
        Blood. 2016; 128: 2801
        • Maude S.L.
        • Barrett D.M.
        • Rheingold S.R.
        • et al.
        Efficacy of humanized CD19-targeted chimeric antigen receptor (CAR)-modified T cells in children with relapsed ALL.
        J Clin Oncol. 2016; 34 (suppl; abstr 3007)
        • Maude S.L.
        • Barrett D.M.
        • Rheingold S.R.
        • et al.
        Efficacy of humanized CD19-targeted chimeric antigen receptor (CAR)-modified T cells in children and young adults with relapsed/refractory acute lymphoblastic leukemia.
        Blood. 2016; 128: 217
        • Chang L.J.
        • Dong L.
        • Liu Y.C.
        • et al.
        Safety and efficacy evaluation of 4SCAR19 chimeric antigen receptor-modified T cells targeting B cell acute lymphoblastic leukemia–three-year follow-up of a multicenter phase I/II study.
        Blood. 2016; 128: 587
        • Deng B.
        • Chang A.H.
        • Yang J.
        • et al.
        Safety and efficacy of low dose CD19 targeted chimeric antigen receptor T (CAR-T) cell immunotherapy in 47 cases with relapsed refractory B-cell acute lymphoblastic leukemia (B-ALL).
        Blood. 2016; 128: 649
        • Park J.H.
        • Riviere I.
        • Wang X.
        • Purdon T.
        • Sadelain M.
        • Brentjens R.J.
        Impact of disease burden on long-term outcome of 19-28z CAR modified T cells in adult patients with relapsed B-ALL.
        J Clin Oncol. 2016; 34 (suppl; abstr 7003)
        • Park J.H.
        • Riviere I.
        • Wang X.
        • et al.
        Implications of minimal residual disease negative complete remission (MRD-CR) and allogeneic stem cell transplant on safety and clinical outcome of CD19-targeted 19-28z CAR modified T cells in adult patients with relapsed, refractory B-Cell ALL.
        Blood. 2015; 126: 682
        • Brentjens R.J.
        • Davila M.L.
        • Riviere I.
        • et al.
        CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia.
        Sci Transl Med. 2013; 5: 177ra138
        • Brentjens R.J.
        • Riviere I.
        • Park J.H.
        • et al.
        Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias.
        Blood. 2011; 118: 4817-4828
        • Dyer O.
        FDA lifts hold on cancer immunotherapy trial placed after patients died.
        BMJ. 2016; 354
        • Shah B.
        • Huynh V.
        • Sender L.S.
        • et al.
        High rates of minimal residual disease-negative (MRD−) complete responses (CR) in adult and pediatric and patients with relapsed/refractory acute lymphoblastic leukemia (R/R all) treated with KTE-C19 (Anti-CD19 chimeric antigen receptor [CAR] T cells): preliminary results of the ZUMA-3 and ZUMA-4 trials.
        Blood. 2016; 128: 2803
        • Shah N.N.
        • Stetler-Stevenson M.
        • Yuan C.M.
        • et al.
        Minimal residual disease negative complete remissions following anti-CD22 chimeric antigen receptor (CAR) in children and young adults with relapsed/refractory acute lymphoblastic leukemia (ALL).
        Blood. 2016; 128: 650
        • Kochenderfer J.N.
        • Dudley M.E.
        • Feldman S.A.
        • et al.
        B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor-transduced T cells.
        Blood. 2012; 119: 2709-2720
        • Sauter C.S.
        • Riviere I.
        • Bernal Y.
        • et al.
        Phase I trial of 19-28z chimeric antigen receptor modified T cells (19-28z CAR-T) post-high dose therapy and autologous stem cell transplant (HDT-ASCT) for relapsed and refractory (rel/ref) aggressive B-cell non-Hodgkin lymphoma (B-NHL).
        J Clin Oncol. 2015; 33 (suppl; abstr 8515)
        • Zhang W.
        • Wang Y.
        • Guo Y.
        • et al.
        Treatment of CD20-directed chimeric antigen receptor-modified T cells in patients with relapsed or refractory B-cell non-Hodgkin lymphoma: an early phase IIa trial report.
        Signal Transduct Target Ther. 2016; 1: 1
        • Wang Y.
        • Zhang W.Y.
        • Han Q.W.
        • et al.
        Effective response and delayed toxicities of refractory advanced diffuse large B-cell lymphoma treated by CD20-directed chimeric antigen receptor-modified T cells.
        Clin Immunol. 2014; 155: 160-175
        • Turtle C.J.
        • Hanafi L.-A.
        • Li D.
        • et al.
        CD19 CAR-T cells are highly effective in ibrutinib-refractory chronic lymphocytic leukemia.
        Blood. 2016; 128: 56
        • Turtle C.J.
        • Hanafi L.A.
        • Berger C.
        • et al.
        Immunotherapy of non-Hodgkin's lymphoma with a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen receptor-modified T cells.
        Sci Transl Med. 2016; 8: 355ra116
        • Turtle C.J.
        • Berger C.
        • Sommermeyer D.
        • et al.
        Anti-CD19 chimeric antigen receptor-modified T cell Therapy for B Cell non-Hodgkin lymphoma and chronic lymphocytic leukemia: fludarabine and cyclophosphamide lymphodepletion improves in vivo expansion and persistence of CAR-T cells and clinical outcomes.
        Blood. 2015; 126: 184
        • Geyer M.B.
        • Park J.H.
        • Riviere I.
        • et al.
        Implications of concurrent ibrutinib therapy on CAR T-cell manufacturing and phenotype and on clinical outcomes following CD19-targeted CAR T-cell administration in adults with relapsed/refractory CLL.
        Blood. 2016; 128: 58
        • Neelapu S.S.
        • Locke F.L.
        • Bartlett N.L.
        • et al.
        A phase 2 multicenter trial of KTE-C19 (anti-CD19 CAR T cells) in patients with chemorefractory primary mediastinal B-Cell lymphoma (PMBCL) and transformed follicular lymphoma (TFL): interim results from ZUMA-1.
        Blood. 2016; 128: 998
        • Abramson J.S.
        • Palomba L.
        • Gordon L.I.
        • et al.
        Transcend NHL 001: immunotherapy with the CD19-directed CAR T-cell product JCAR017 results in high complete response rates in relapsed or refractory B-Cell non-Hodgkin lymphoma.
        Blood. 2016; 128: 4192
        • Kochenderfer J.N.
        • Somerville R.P.
        • Lu T.
        • et al.
        Anti-CD19 chimeric antigen receptor T cells preceded by low-dose chemotherapy to induce remissions of advanced lymphoma.
        J Clin Oncol. 2016; 34 (suppl; abstr LBA3010)
        • Brudno J.N.
        • Shi V.
        • Stroncek D.
        • et al.
        T cells expressing a novel fully-human anti-CD19 chimeric antigen receptor induce remissions of advanced lymphoma in a first-in-humans clinical trial.
        Blood. 2016; 128: 999
        • Porter D.L.
        • Frey N.V.
        • Melenhorst J.J.
        • et al.
        Randomized, phase II dose optimization study of chimeric antigen receptor modified T cells directed against CD19 (CTL019) in patients with relapsed, refractory CLL.
        Blood. 2014; 124: 1982
        • Porter D.L.
        • Frey N.
        • Melenhorst J.J.
        • et al.
        Randomized, phase II dose optimization study of chimeric antigen receptor (CAR) modified T cells directed against CD19 in patients (pts) with relapsed, refractory (R/R) CLL.
        J Clin Oncol. 2016; 34 (suppl; abstr 3009)
        • Schuster S.J.
        • Svoboda J.
        • Nasta S.
        • et al.
        Phase IIa trial of chimeric antigen receptor modified T cells directed against CD19 (CTL019) in patients with relapsed or refractory CD19+ lymphomas.
        J Clin Oncol. 2015; 33 (suppl; abstr 8516)
        • Schuster S.J.
        • Svoboda J.
        • Nasta S.D.
        • et al.
        Treatment with chimeric antigen receptor modified T cells directed against CD19 (CTL019) results in durable remissions in patients with relapsed or refractory diffuse large B cell lymphomas of germinal center and non-germinal center origin, “Double Hit” diffuse large B cell lymphomas, and transformed follicular to diffuse large B cell lymphomas.
        Blood. 2016; 128: 3026
        • Chong E.A.
        • Svoboda J.
        • Nasta S.D.
        • et al.
        Chimeric antigen receptor modified T cells directed against CD19 (CTL019) in patients with poor prognosis, relapsed or refractory CD19+ follicular lymphoma: prolonged remissions relative to antecedent therapy.
        Blood. 2016; 128: 1100
        • Schuster S.J.
        • Svoboda J.
        • Dwivedy Nasta S.
        • et al.
        Phase IIa trial of chimeric antigen receptor modified T cells directed against CD19 (CTL019) in patients with relapsed or refractory CD19+ lymphomas.
        Blood. 2014; 124: 3087
        • Locke F.L.
        • Neelapu S.S.
        • Bartlett N.L.
        • et al.
        Phase 1 results of ZUMA-1: a multicenter study of KTE-C19 anti-CD19 CAR T cell therapy in refractory aggressive lymphoma.
        Mol Ther. 2017; 25: 285-295
        • Locke F.L.
        • Neelapu S.S.
        • Bartlett N.L.
        • et al.
        Phase 1 clinical results of the ZUMA-1 (KTE-C19-101) study: a phase 1-2 multi-center study evaluating the safety and efficacy of anti-CD19 CAR T cells (KTE-C19) in subjects with refractory aggressive non-Hodgkin lymphoma (NHL).
        Blood. 2015; 126: 3991
        • Gardner R.
        • Wu D.
        • Cherian S.
        • et al.
        Acquisition of a CD19-negative myeloid phenotype allows immune escape of MLL-rearranged B-ALL from CD19 CAR-T-cell therapy.
        Blood. 2016; 127: 2406-2410
        • Deniger D.C.
        • Yu J.
        • Huls M.H.
        • et al.
        Sleeping beauty transposition of chimeric antigen receptors targeting receptor tyrosine kinase-like orphan Receptor-1 (ROR1) into diverse memory T-cell populations.
        PLoS One. 2015; 10: e0128151
        • Fred Hutchinson Cancer Research Center
        Genetically Modified T-Cell Therapy in Treating Patients With Advanced ROR1+ Malignancies.
        in: ClinicalTrials.gov [Internet]. National Library of Medicine (US), Bethesda (MD)2000 (Available at:) (Accessed March 7, 2017. NLM Identifier: NCT02706392)
        • M.D. Anderson Cancer Center
        Autologous ROR1R-CAR-T Cells for Chronic Lymphocytic Leukemia (CLL).
        in: ClinicalTrials.gov [Internet]. National Library of Medicine (US), Bethesda (MD)2000 (Available at:) (Accessed March 7, 2017. NLM Identifier: NCT02194374)
        • Jackson H.J.
        • Rafiq S.
        • Brentjens R.J.
        Driving CAR T-cells forward.
        Nat Rev Clin Oncol. 2016; 13: 370-383
        • Fesnak A.D.
        • June C.H.
        • Levine B.L.
        Engineered T cells: the promise and challenges of cancer immunotherapy.
        Nat Rev Cancer. 2016; 16: 566-581
        • Wilkie S.
        • van Schalkwyk M.C.
        • Hobbs S.
        • et al.
        Dual targeting of ErbB2 and MUC1 in breast cancer using chimeric antigen receptors engineered to provide complementary signaling.
        J Clin Immunol. 2012; 32: 1059-1070
        • Fedorov V.D.
        • Themeli M.
        • Sadelain M.
        PD-1- and CTLA-4-based inhibitory chimeric antigen receptors (iCARs) divert off-target immunotherapy responses.
        Sci Transl Med. 2013; 5: 215ra172
        • Roybal K.T.
        • Rupp L.J.
        • Morsut L.
        • et al.
        Precision tumor Recognition by T Cells with combinatorial antigen-sensing circuits.
        Cell. 2016; 164: 770-779
        • Kloss C.C.
        • Condomines M.
        • Cartellieri M.
        • Bachmann M.
        • Sadelain M.
        Combinatorial antigen recognition with balanced signaling promotes selective tumor eradication by engineered T cells.
        Nat Biotechnol. 2013; 31: 71-75
        • Ruella M.
        • Maus M.V.
        Catch me if you can: leukemia escape after CD19-directed T cell immunotherapies.
        Comput Struct Biotechnol J. 2016; 14: 357-362
        • Poirot L.
        • Philip B.
        • Schiffer-Mannioui C.
        • et al.
        Multiplex genome-edited T-cell manufacturing platform for “Off-the-Shelf” adoptive T-cell immunotherapies.
        Cancer Res. 2015; 75: 3853-3864
        • Torikai H.
        • Reik A.
        • Liu P.Q.
        • et al.
        A foundation for universal T-cell based immunotherapy: T cells engineered to express a CD19-specific chimeric-antigen-receptor and eliminate expression of endogenous TCR.
        Blood. 2012; 119: 5697-5705
        • Valton J.
        • Guyot V.
        • Marechal A.
        • et al.
        A multidrug-resistant engineered CAR T cell for allogeneic combination immunotherapy.
        Mol Ther. 2015; 23: 1507-1518
        • Osborn M.J.
        • Webber B.R.
        • Knipping F.
        • et al.
        Evaluation of TCR gene editing achieved by TALENs, CRISPR/Cas9, and megaTAL nucleases.
        Mol Ther. 2016; 24: 570-581
        • Institut de Recherches Internationales Servier
        Study of UCART19 in Pediatric Patients With Relapsed/Refractory B Acute Lymphoblastic Leukemia (PALL).
        in: ClinicalTrials.gov [Internet]. National Library of Medicine (US), Bethesda (MD)2000 (Available at:) (Accessed March 17, 2017. NLM Identifier: NCT02808442)
        • Servier
        Dose Escalation Study to Evaluate the Safety, Tolerability and Biological Activity of a Single Dose of UCART19 in Patients With Relapsed/Refractory (R/R) B-cell Acute Lymphoblastic Leukaemia (ALL) and Chronic Lymphocytic Leukaemia (CLL) (CALM).
        in: ClinicalTrials.gov [Internet]. National Library of Medicine (US), Bethesda (MD)2000 (Available at:) (Accessed March 17, 2017. NLM Identifier: NCT02746952)
        • Khalil D.N.
        • Smith E.L.
        • Brentjens R.J.
        • Wolchok J.D.
        The future of cancer treatment: immunomodulation, CARs and combination immunotherapy.
        Nat Rev Clin Oncol. 2016; 13: 273-290