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Review: Current clinical applications of chimeric antigen receptor (CAR) modified T cells

  • Mark B. Geyer
    Affiliations
    Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
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  • Renier J. Brentjens
    Correspondence
    Correspondence: Renier J. Brentjens, MD, PhD, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 242, New York, NY, 10021, USA.
    Affiliations
    Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
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Published:August 31, 2016DOI:https://doi.org/10.1016/j.jcyt.2016.07.003

      Abstract

      The past several years have been marked by extraordinary advances in clinical applications of immunotherapy. In particular, adoptive cellular therapy utilizing chimeric antigen receptor (CAR)-modified T cells targeted to CD19 has demonstrated substantial clinical efficacy in children and adults with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL) and durable clinical benefit in a smaller subset of patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or B-cell non-Hodgkin lymphoma (B-NHL). Early-phase clinical trials are currently assessing CAR T-cell safety and efficacy in additional malignancies. Here, we discuss clinical results from the largest series to date investigating CD19-targeted CAR T cells in B-ALL, CLL, and B-NHL, including discussion of differences in CAR T-cell design and production and treatment approach, as well as clinical efficacy, nature of severe cytokine release syndrome and neurologic toxicities, and CAR T-cell expansion and persistence. We additionally review the current and forthcoming use of CAR T cells in multiple myeloma and several solid tumors and highlight challenges and opportunities afforded by the current state of CAR T-cell therapies, including strategies to overcome inhibitory aspects of the tumor microenvironment and enhance antitumor efficacy.

      Key Words

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      References

        • Park J.H.
        • Brentjens R.J.
        Adoptive immunotherapy for B-cell malignancies with autologous chimeric antigen receptor modified tumor targeted T cells.
        Discov Med. 2010; 9: 277-288
        • Till B.G.
        • Jensen M.C.
        • Wang J.
        • Qian X.
        • Gopal A.K.
        • Maloney D.G.
        • 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: 3940-3950https://doi.org/10.1182/blood-2011-10-387969
        • Davenport A.J.
        • Jenkins M.R.
        • Cross R.S.
        • Yong C.S.
        • Prince H.M.
        • Ritchie D.S.
        • et al.
        CAR-T Cells Inflict Sequential Killing of Multiple Tumor Target Cells.
        Cancer Immunol Res. 2015; 3: 483-494https://doi.org/10.1158/2326-6066.CIR-15-0048
        • Kantarjian H.M.
        • Thomas D.
        • Ravandi F.
        • Faderl S.
        • Jabbour E.
        • Garcia-Manero G.
        • et al.
        Defining the course and prognosis of adults with acute lymphocytic leukemia in first salvage after induction failure or short first remission duration.
        Cancer. 2010; 116: 5568-5574https://doi.org/10.1002/cncr.25354
        • Gokbuget N.
        • Stanze D.
        • Beck J.
        • Diedrich H.
        • Horst H.A.
        • Huttmann A.
        • et al.
        Outcome of relapsed adult lymphoblastic leukemia depends on response to salvage chemotherapy, prognostic factors, and performance of stem cell transplantation.
        Blood. 2012; 120: 2032-2041https://doi.org/10.1182/blood-2011-12-399287
        • Brentjens R.J.
        • Davila M.L.
        • Riviere I.
        • Park J.
        • Wang X.
        • Cowell L.G.
        • et al.
        CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia.
        Sci Transl Med. 2013; 5 (177ra138)https://doi.org/10.1126/scitranslmed.3005930
        • Davila M.L.
        • Riviere I.
        • Wang X.
        • Bartido S.
        • Park J.
        • Curran K.
        • 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)https://doi.org/10.1126/scitranslmed.3008226
        • 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 (abstr 7003)
        • Park J.H.
        • Riviere I.
        • Wang X.
        • Bernal Y.
        • Purdon T.
        • Halton E.
        • 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.
        • Yeh R.
        • Bernal Y.
        • Riviere I.
        • Sadelain M.
        Treatment of chronic lymphocytic leukemia with genetically targeted autologous T cells: case report of an unforeseen adverse event in a phase I clinical trial.
        Mol Ther. 2010; 18: 666-668https://doi.org/10.1038/mt.2010.31
        • Turtle C.J.
        • Hanafi L.A.
        • Berger C.
        • Gooley T.A.
        • Cherian S.
        • Hudecek M.
        • et al.
        CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients.
        J Clin Invest. 2016; 126: 2123-2138https://doi.org/10.1172/JCI85309
        • Turtle C.J.
        • Hanafi L.-A.
        • Berger C.
        • Sommermeyer D.
        • Pender B.
        • Robinson E.M.
        • 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
        • Frey N.V.
        • Shaw P.A.
        • Hexner E.O.
        • Gill S.
        • Marcucci K.
        • Luger S.M.
        • 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 (abstr 7002)
        • Nguyen K.
        • Devidas M.
        • Cheng S.C.
        • La M.
        • Raetz E.A.
        • Carroll W.L.
        • et al.
        Factors influencing survival after relapse from acute lymphoblastic leukemia: a Children's Oncology Group study.
        Leukemia. 2008; 22: 2142-2150https://doi.org/10.1038/Leu.2008.251
        • Gaynon P.S.
        Childhood acute lymphoblastic leukaemia and relapse.
        Br J Haematol. 2005; 131 (BJH5773 [pii]): 579-587https://doi.org/10.1111/j.1365-2141.2005.05773.x
        • Reismuller B.
        • Peters C.
        • Dworzak M.N.
        • Potschger U.
        • Urban C.
        • Meister B.
        • et al.
        Outcome of children and adolescents with a second or third relapse of acute lymphoblastic leukemia (ALL): a population-based analysis of the Austrian ALL-BFM (Berlin-Frankfurt-Munster) study group.
        J Pediatr Hematol Oncol. 2013; 35: e200-4https://doi.org/10.1097/MPH.0b013e318290c3d6
        • Grupp S.A.
        • Kalos M.
        • Barrett D.
        • Aplenc R.
        • Porter D.L.
        • Rheingold S.R.
        • et al.
        Chimeric antigen receptor-modified T cells for acute lymphoid leukemia.
        N Engl J Med. 2013; 368: 1509-1518https://doi.org/10.1056/NEJMoa1215134
        • Maude S.L.
        • Frey N.
        • Shaw P.A.
        • Aplenc R.
        • Barrett D.M.
        • Bunin N.J.
        • et al.
        Chimeric antigen receptor T cells for sustained remissions in leukemia.
        N Engl J Med. 2014; 371: 1507-1517https://doi.org/10.1056/NEJMoa1407222
        • Lee D.W.
        • Kochenderfer J.N.
        • Stetler-Stevenson M.
        • Cui Y.K.
        • Delbrook C.
        • Feldman S.A.
        • 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: 517-528https://doi.org/10.1016/S0140-6736(14)61403-3
        • Curran K.J.
        • Riviere I.
        • Silverman L.B.
        • Kobos R.
        • Shukla N.
        • Steinherz P.G.
        • et al.
        Multi-Center Clinical Trial of CAR T Cells in Pediatric/Young Adult Patients with Relapsed B-Cell ALL.
        Blood. 2015; 126: 2533
        • Frey N.V.
        • Levine B.L.
        • Lacey S.F.
        • Grupp S.A.
        • Maude S.L.
        • Schuster S.J.
        • et al.
        Refractory Cytokine Release Syndrome in Recipients of Chimeric Antigen Receptor (CAR) T Cells.
        Blood. 2014; 124: 2296
        • Tam C.S.
        • O'Brien S.
        • Wierda W.
        • Kantarjian H.
        • Wen S.
        • Do K.A.
        • et al.
        Long-term results of the fludarabine, cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic leukemia.
        Blood. 2008; 112: 975-980https://doi.org/10.1182/blood-2008-02-140582
        • Kay N.E.
        • Geyer S.M.
        • Call T.G.
        • Shanafelt T.D.
        • Zent C.S.
        • Jelinek D.F.
        • et al.
        Combination chemoimmunotherapy with pentostatin, cyclophosphamide, and rituximab shows significant clinical activity with low accompanying toxicity in previously untreated B chronic lymphocytic leukemia.
        Blood. 2007; 109: 405-411https://doi.org/10.1182/blood-2006-07-033274
        • Byrd J.C.
        • Furman R.R.
        • Coutre S.E.
        • Flinn I.W.
        • Burger J.A.
        • Blum K.A.
        • et al.
        Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia.
        N Engl J Med. 2013; 369: 32-42https://doi.org/10.1056/NEJMoa1215637
        • Byrd J.C.
        • Furman R.R.
        • Coutre S.E.
        • Burger J.A.
        • Blum K.A.
        • Coleman M.
        • et al.
        Three-year follow-up of treatment-naive and previously treated patients with CLL and SLL receiving single-agent ibrutinib.
        Blood. 2015; 125: 2497-2506https://doi.org/10.1182/blood-2014-10-606038
        • Brentjens R.J.
        • Riviere I.
        • Park J.H.
        • Davila M.L.
        • Wang X.
        • Stefanski J.
        • 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: 4817-4828https://doi.org/10.1182/blood-2011-04-348540
        • Geyer M.B.
        • Park J.H.
        • Riviere I.
        • Wang X.
        • Purdon T.
        • Sadelain M.
        • et al.
        Updated results: phase I trial of autologous CD19-targeted CAR T cells in patients with residual CLL following initial purine analog-based therapy.
        J Clin Oncol. 2016; 34 (abstr 7526)
        • 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: 725-733https://doi.org/10.1056/NEJMoa1103849
        • Kalos M.
        • Levine B.L.
        • Porter D.L.
        • Katz S.
        • Grupp S.A.
        • Bagg A.
        • 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)https://doi.org/10.1126/scitranslmed.3002842
        • Porter D.L.
        • Hwang W.T.
        • Frey N.V.
        • Lacey S.F.
        • Shaw P.A.
        • Loren A.W.
        • et al.
        Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia.
        Sci Transl Med. 2015; 7 (303ra139)https://doi.org/10.1126/scitranslmed.aac5415
        • Porter D.L.
        • Frey N.V.
        • Melenhorst J.J.
        • Hwang W.T.
        • Lacey S.F.
        • Shaw P.A.
        • 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 (abstr 3009)
        • Kochenderfer J.N.
        • Wilson W.H.
        • Janik J.E.
        • Dudley M.E.
        • Stetler-Stevenson M.
        • Feldman S.A.
        • 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: 4099-4102https://doi.org/10.1182/blood-2010-04-281931
        • Kochenderfer J.N.
        • Feldman S.A.
        • Zhao Y.
        • Xu H.
        • Black M.A.
        • Morgan R.A.
        • et al.
        Construction and preclinical evaluation of an anti-CD19 chimeric antigen receptor.
        J Immunother. 2009; 32: 689-702https://doi.org/10.1097/CJI.0b013e3181ac6138
        • Kochenderfer J.N.
        • Dudley M.E.
        • Feldman S.A.
        • Wilson W.H.
        • Spaner D.E.
        • Maric I.
        • 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: 2709-2720https://doi.org/10.1182/blood-2011-10-384388
        • Kochenderfer J.N.
        • Dudley M.E.
        • Kassim S.H.
        • Somerville R.P.
        • Carpenter R.O.
        • Stetler-Stevenson M.
        • 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: 540-549https://doi.org/10.1200/JCO.2014.56.2025
        • Schuster S.J.
        • Svoboda J.
        • Nasta S.D.
        • Porter D.L.
        • Chong E.A.
        • Landsburg D.J.
        • et al.
        Sustained Remissions Following Chimeric Antigen Receptor Modified T Cells Directed Against CD19 (CTL019) in Patients with Relapsed or Refractory CD19+ Lymphomas.
        Blood. 2015; 126: 183
        • Turtle C.J.
        • Berger C.
        • Sommermeyer D.
        • Hanafi L.A.
        • Pender B.
        • Robinson E.M.
        • 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
        • Sauter C.S.
        • Riviere I.
        • Bernal Y.
        • Wang X.
        • Purdon T.
        • Yoo S.
        • 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 (abstr 8515)
        • Garfall A.L.
        • Maus M.V.
        • Hwang W.T.
        • Lacey S.F.
        • Mahnke Y.D.
        • Melenhorst J.J.
        • et al.
        Chimeric Antigen Receptor T Cells against CD19 for Multiple Myeloma.
        N Engl J Med. 2015; 373: 1040-1047https://doi.org/10.1056/NEJMoa1504542
        • Danhof S.
        • Gogishvili T.
        • Koch S.
        • Schreder M.
        • Knop S.
        • Einsele H.
        • et al.
        CAR-Engineered T Cells Specific for the Elotuzumab Target SLAMF7 Eliminate Primary Myeloma Cells and Confer Selective Fratricide of SLAMF7+ Normal Lymphocyte Subsets.
        Blood. 2015; 126: 115
        • Lonial S.
        • Dimopoulos M.
        • Palumbo A.
        • White D.
        • Grosicki S.
        • Spicka I.
        • et al.
        Elotuzumab Therapy for Relapsed or Refractory Multiple Myeloma.
        N Engl J Med. 2015; 373: 621-631https://doi.org/10.1056/NEJMoa1505654
        • Ali S.A.
        • Shi V.
        • Wang M.L.
        • Stroncek D.
        • Maric I.
        • Brudno J.N.
        • et al.
        Remissions of Multiple Myeloma during a First-in-Humans Clinical Trial of T Cells Expressing an Anti-B-Cell Maturation Antigen Chimeric Antigen Receptor.
        in: ASH Annual Meeting: Late-Breaking Abstracts. 2015 (p. LBA-1)
        • Ryan M.C.
        • Hering M.
        • Peckham D.
        • McDonagh C.F.
        • Brown L.
        • Kim K.M.
        • et al.
        Antibody targeting of B-cell maturation antigen on malignant plasma cells.
        Mol Cancer Ther. 2007; 6: 3009-3018https://doi.org/10.1158/1535-7163.MCT-07-0464
        • Ramadoss N.S.
        • Schulman A.D.
        • Choi S.H.
        • Rodgers D.T.
        • Kazane S.A.
        • Kim C.H.
        • et al.
        An anti-B cell maturation antigen bispecific antibody for multiple myeloma.
        J Am Chem Soc. 2015; 137: 5288-5291https://doi.org/10.1021/jacs.5b01876
        • Ahmed N.
        • Brawley V.S.
        • Hegde M.
        • Robertson C.
        • Ghazi A.
        • Gerken C.
        • et al.
        Human Epidermal Growth Factor Receptor 2 (HER2) -Specific Chimeric Antigen Receptor-Modified T Cells for the Immunotherapy of HER2-Positive Sarcoma.
        J Clin Oncol. 2015; 33: 1688-1696https://doi.org/10.1200/JCO.2014.58.0225
        • 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: 843-851https://doi.org/10.1038/mt.2010.24
        • Weiner L.M.
        • Clark J.I.
        • Davey M.
        • Li W.S.
        • Garcia de Palazzo I.
        • Ring D.B.
        • et al.
        Phase I trial of 2B1, a bispecific monoclonal antibody targeting c-erbB-2 and Fc gamma RIII.
        Cancer Res. 1995; 55: 4586-4593
        • Koneru M.
        • O'Cearbhaill R.
        • Pendharkar S.
        • Spriggs D.R.
        • Brentjens R.J.
        A phase I clinical trial of adoptive T cell therapy using IL-12 secreting MUC-16(ecto) directed chimeric antigen receptors for recurrent ovarian cancer.
        J Transl Med. 2015; 13: 102https://doi.org/10.1186/s12967-015-0460-x
        • Hassan R.
        • Bullock S.
        • Premkumar A.
        • Kreitman R.J.
        • Kindler H.
        • Willingham M.C.
        • et al.
        Phase I study of SS1P, a recombinant anti-mesothelin immunotoxin given as a bolus I.V. infusion to patients with mesothelin-expressing mesothelioma, ovarian, and pancreatic cancers.
        Clin Cancer Res. 2007; 13: 5144-5149https://doi.org/10.1158/1078-0432.CCR-07-0869
        • Feng Y.
        • Xiao X.
        • Zhu Z.
        • Streaker E.
        • Ho M.
        • Pastan I.
        • et al.
        A novel human monoclonal antibody that binds with high affinity to mesothelin-expressing cells and kills them by antibody-dependent cell-mediated cytotoxicity.
        Mol Cancer Ther. 2009; 8: 1113-1118https://doi.org/10.1158/1535-7163.MCT-08-0945
        • Cruz C.R.
        • Micklethwaite K.P.
        • Savoldo B.
        • Ramos C.A.
        • Lam S.
        • Ku S.
        • 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: 2965-2973https://doi.org/10.1182/blood-2013-06-506741
        • Brudno J.N.
        • Somerville R.P.
        • Shi V.
        • Rose J.J.
        • Halverson D.C.
        • Fowler D.H.
        • 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: 1112-1121https://doi.org/10.1200/JCO.2015.64.5929
        • Grupp S.A.
        • Maude S.L.
        • Shaw P.A.
        • Aplenc R.
        • Barrett D.
        • Callahan C.
        • 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
        • Sommermeyer D.
        • Hudecek M.
        • Kosasih P.L.
        • Gogishvili T.
        • Maloney D.G.
        • Turtle C.J.
        • et al.
        Chimeric antigen receptor-modified T cells derived from defined CD8(+) and CD4(+) subsets confer superior antitumor reactivity in vivo.
        Leukemia. 2016; 30: 492-500https://doi.org/10.1038/leu.2015.247
        • Minagawa K.
        • Zhou X.
        • Mineishi S.
        • Di Stasi A.
        Seatbelts in CAR therapy: How Safe Are CARS?.
        Pharmaceuticals. 2015; 8: 230-249https://doi.org/10.3390/ph8020230
        • Topp M.S.
        • Gokbuget N.
        • Zugmaier G.
        • Klappers P.
        • Stelljes M.
        • Neumann S.
        • et al.
        Phase II trial of the anti-CD19 bispecific T cell-engager blinatumomab shows hematologic and molecular remissions in patients with relapsed or refractory B-precursor acute lymphoblastic leukemia.
        J Clin Oncol. 2014; 32: 4134-4140https://doi.org/10.1200/JCO.2014.56.3247
        • Park K.H.
        • Riviere I.
        • Wang X.
        • Bernal Y.
        • Purdon T.
        • Halton E.
        • et al.
        Efficacy and safety of CD19-targeted 19-28z CAR modified T cells in adult patients with relapsed or refractory B-ALL.
        J Clin Oncol. 2015; 33 (abstr 7010)
        • Sotillo E.
        • Barrett D.M.
        • Black K.L.
        • Bagashev A.
        • Oldridge D.
        • Wu G.
        • et al.
        Convergence of Acquired Mutations and Alternative Splicing of CD19 Enables Resistance to CART-19 Immunotherapy.
        Cancer Discov. 2015; 5: 1282-1295https://doi.org/10.1158/2159-8290.CD-15-1020
        • Jackson H.J.
        • Brentjens R.J.
        Overcoming Antigen Escape with CAR T-cell Therapy.
        Cancer Discov. 2015; 5: 1238-1240https://doi.org/10.1158/2159-8290.CD-15-1275
        • Reiners K.S.
        • Topolar D.
        • Henke A.
        • Simhadri V.R.
        • Kessler J.
        • Sauer M.
        • et al.
        Soluble ligands for NK cell receptors promote evasion of chronic lymphocytic leukemia cells from NK cell anti-tumor activity.
        Blood. 2013; 121: 3658-3665https://doi.org/10.1182/blood-2013-01-476606
        • Ramsay A.G.
        • Clear A.J.
        • Fatah R.
        • Gribben J.G.
        Multiple inhibitory ligands induce impaired T-cell immunologic synapse function in chronic lymphocytic leukemia that can be blocked with lenalidomide: establishing a reversible immune evasion mechanism in human cancer.
        Blood. 2012; 120: 1412-1421https://doi.org/10.1182/blood-2012-02-411678
        • Gorgun G.
        • Holderried T.A.
        • Zahrieh D.
        • Neuberg D.
        • Gribben J.G.
        Chronic lymphocytic leukemia cells induce changes in gene expression of CD4 and CD8 T cells.
        J Clin Invest. 2005; 115: 1797-1805https://doi.org/10.1172/JCI24176
        • McClanahan F.
        • Hanna B.
        • Miller S.
        • Clear A.J.
        • Lichter P.
        • Gribben J.G.
        • et al.
        PD-L1 checkpoint blockade prevents immune dysfunction and leukemia development in a mouse model of chronic lymphocytic leukemia.
        Blood. 2015; 126: 203-211https://doi.org/10.1182/blood-2015-01-622936
        • Riches J.C.
        • Davies J.K.
        • McClanahan F.
        • Fatah R.
        • Iqbal S.
        • Agrawal S.
        • et al.
        T cells from CLL patients exhibit features of T-cell exhaustion but retain capacity for cytokine production.
        Blood. 2013; 121: 1612-1621https://doi.org/10.1182/blood-2012-09-457531
        • Paggetti J.
        • Haderk F.
        • Seiffert M.
        • Janji B.
        • Distler U.
        • Ammerlaan W.
        • et al.
        Exosomes released by chronic lymphocytic leukemia cells induce the transition of stromal cells into cancer-associated fibroblasts.
        Blood. 2015; https://doi.org/10.1182/blood-2014-12-618025
        • Curran K.J.
        • Seinstra B.A.
        • Nikhamin Y.
        • Yeh R.
        • Usachenko Y.
        • van Leeuwen D.G.
        • et al.
        Enhancing antitumor efficacy of chimeric antigen receptor T cells through constitutive CD40L expression.
        Mol Ther. 2015; 23: 769-778https://doi.org/10.1038/mt.2015.4
        • Pegram H.J.
        • Lee J.C.
        • Hayman E.G.
        • Imperato G.H.
        • Tedder T.F.
        • Sadelain M.
        • et al.
        Tumor-targeted T cells modified to secrete IL-12 eradicate systemic tumors without need for prior conditioning.
        Blood. 2012; 119: 4133-4141https://doi.org/10.1182/blood-2011-12-400044
        • Pegram H.J.
        • Purdon T.J.
        • van Leeuwen D.G.
        • Curran K.J.
        • Giralt S.A.
        • Barker J.N.
        • et al.
        IL-12-secreting CD19-targeted cord blood-derived T cells for the immunotherapy of B-cell acute lymphoblastic leukemia.
        Leukemia. 2015; 29: 415-422https://doi.org/10.1038/leu.2014.215
        • Stephan M.T.
        • Ponomarev V.
        • Brentjens R.J.
        • Chang A.H.
        • Dobrenkov K.V.
        • Heller G.
        • et al.
        T cell-encoded CD80 and 4-1BBL induce auto- and transcostimulation, resulting in potent tumor rejection.
        Nat Med. 2007; 13: 1440-1449https://doi.org/10.1038/nm1676
        • Koneru M.
        • Purdon T.J.
        • Spriggs D.
        • Koneru S.
        • Brentjens R.J.
        IL-12 secreting tumor-targeted chimeric antigen receptor T cells eradicate ovarian tumors.
        Oncoimmunology. 2015; 4: e994446https://doi.org/10.4161/2162402X.2014.994446
        • John L.B.
        • Kershaw M.H.
        • Darcy P.K.
        Blockade of PD-1 immunosuppression boosts CAR T-cell therapy.
        Oncoimmunology. 2013; 2: e26286https://doi.org/10.4161/onci.26286
        • Fraietta J.A.
        • Beckwith K.A.
        • Patel P.R.
        • Ruella M.
        • Zheng Z.
        • Barrett D.M.
        • et al.
        Ibrutinib enhances chimeric antigen receptor T-cell engraftment and efficacy in leukemia.
        Blood. 2016; https://doi.org/10.1182/blood-2015-11-679134
        • 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)https://doi.org/10.1126/scitranslmed.3006597