Skip to main content

Chimeric Antigen Receptor Therapy in Acute Lymphoblastic Leukemia Clinical Practice

Current Hematologic Malignancy Reports volume 12, pages 370–379 (2017)Cite this article

Abstract

Over half of patients diagnosed with B-cell acute lymphoblastic leukemia (ALL) develop relapsed or refractory disease. Traditional chemotherapy salvage is inadequate, and new therapies are needed. Chimeric antigen receptor (CAR) T cell therapy is a novel, immunologic approach where T cells are genetically engineered to express a CAR conferring specificity against a target cell surface antigen, most commonly the pan-B-cell marker CD19. After infusion, CAR T cells expand and persist, allowing ongoing tumor surveillance. Several anti-CD19 CAR T cell constructs have induced high response rates in heavily pre-treated populations, although durability of response varied. Severe toxicity (cytokine release syndrome and neurotoxicity) is the primary constraint to broad implementation of CAR T cell therapy. Here, we review the experience of CAR T cell therapy for ALL and ongoing efforts to modify existing technology to improve efficacy and decrease toxicity. As an anti-CD19 CAR T cell construct may be FDA approved soon, we focus on issues relevant to practicing clinicians.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Fielding AK, Rowe JM, Buck G, et al. UKALLXII/ECOG2993: addition of imatinib to a standard treatment regimen enhances long-term outcomes in Philadelphia positive acute lymphoblastic leukemia. Blood. 2014;123:843–50.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. Ravandi F, O’Brien S, Thomas D, et al. First report of phase 2 study of dasatinib with hyper-CVAD for the frontline treatment of patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia. Blood. 2010;116:2070–7.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. Foa R, Vitale A, Vignetti M, et al. Dasatinib as first-line treatment for adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood. 2011;118:6521–8.

    CAS  Article  PubMed  Google Scholar 

  4. DeAngelo DJ, Stevenson KE, Dahlberg SE, et al. Long-term outcome of a pediatric-inspired regimen used for adults aged 18–50 years with newly diagnosed acute lymphoblastic leukemia. Leukemia. 2014;29:526–34.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Stock W, La M, Sanford B, et al. What determines the outcomes for adolescents and young adults with acute lymphoblastic leukemia treated on cooperative group protocols? A comparison of Children’s Cancer Group and Cancer and Leukemia Group B studies. Blood. 2008;112:1646–54.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. Huguet F, Leguay T, Raffoux E, et al. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol. 2009;27:911–8.

    CAS  Article  PubMed  Google Scholar 

  7. Goldstone AH, Richards SM, Lazarus HM, et al. In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood. 2008;111:1827–33.

    CAS  Article  PubMed  Google Scholar 

  8. Cornelissen JJ, van der Holt B, Verhoef GE, et al. Myeloablative allogeneic versus autologous stem cell transplantation in adult patients with acute lymphoblastic leukemia in first remission: a prospective sibling donor versus no-donor comparison. Blood. 2009;113:1375–82.

    CAS  Article  PubMed  Google Scholar 

  9. Gupta V, Richards S, Rowe J, Acute Leukemia Stem Cell Transplantation Trialists’ Collaborative G. Allogeneic, but not autologous, hematopoietic cell transplantation improves survival only among younger adults with acute lymphoblastic leukemia in first remission: an individual patient data meta-analysis. Blood. 2013;121:339–50.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. Fielding AK, Richards SM, Chopra R, et al. Outcome of 609 adults after relapse of acute lymphoblastic leukemia (ALL); an MRC UKALL12/ECOG 2993 study. Blood. 2007;109:944–50.

    CAS  Article  PubMed  Google Scholar 

  11. Kantarjian H, Thomas D, O’Brien S, et al. Long-term follow-up results of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper-CVAD), a dose-intensive regimen, in adult acute lymphocytic leukemia. Cancer. 2004;101:2788–801.

    CAS  Article  PubMed  Google Scholar 

  12. Pui CH, Relling MV, Downing JR. Acute lymphoblastic leukemia. N Engl J Med. 2004;350:1535–48.

    CAS  Article  PubMed  Google Scholar 

  13. Rosen PJ, Rankin C, Head DR, et al. A phase II study of high dose ARA-C and mitoxantrone for treatment of relapsed or refractory adult acute lymphoblastic leukemia. Leuk Res. 2000;24:183–7.

    CAS  Article  PubMed  Google Scholar 

  14. Kantarjian H, Gandhi V, Cortes J, et al. Phase 2 clinical and pharmacologic study of clofarabine in patients with refractory or relapsed acute leukemia. Blood. 2003;102:2379–86.

    CAS  Article  PubMed  Google Scholar 

  15. O’Brien S, Schiller G, Lister J, et al. High-dose vincristine sulfate liposome injection for advanced, relapsed, and refractory adult Philadelphia chromosome-negative acute lymphoblastic leukemia. J Clin Oncol. 2013;31:676–83.

    Article  PubMed  Google Scholar 

  16. DeAngelo DJ, Yu D, Johnson JL, et al. Nelarabine induces complete remissions in adults with relapsed or refractory T-lineage acute lymphoblastic leukemia or lymphoblastic lymphoma: Cancer and Leukemia Group B study 19801. Blood. 2007;109:5136–42.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. Gokbuget N, Stanze D, Beck J, et al. Outcome of relapsed adult lymphoblastic leukemia depends on response to salvage chemotherapy, prognostic factors, and performance of stem cell transplantation. Blood. 2012;120:2032–41.

    Article  PubMed  Google Scholar 

  18. Oriol A, Vives S, Hernandez-Rivas JM, et al. Outcome after relapse of acute lymphoblastic leukemia in adult patients included in four consecutive risk-adapted trials by the PETHEMA Study Group. Haematologica. 2010;95:589–96.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Thomas DA, Kantarjian H, Smith TL, et al. Primary refractory and relapsed adult acute lymphoblastic leukemia: characteristics, treatment results, and prognosis with salvage therapy. Cancer. 1999;86:1216–30.

    CAS  Article  PubMed  Google Scholar 

  20. DeAngelo DJ. The use of novel monoclonal antibodies in the treatment of acute lymphoblastic leukemia. Hematology Am Soc Hematol Educ Program. 2015;2015:400–5.

    PubMed  Google Scholar 

  21. Topp MS, Gokbuget N, Stein AS, et al. Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study. Lancet Oncol. 2015;16:57–66.

    CAS  Article  PubMed  Google Scholar 

  22. Kantarjian HM, DeAngelo DJ, Stelljes M, et al. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med. 2016;375:740–53.

    CAS  Article  PubMed  Google Scholar 

  23. Kantarjian HM, Stein A, Gokbuget N, et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med. 2017;376:836–47.

    CAS  Article  PubMed  Google Scholar 

  24. Maus MV, Grupp SA, Porter DL, June CH. Antibody-modified T cells: CARs take the front seat for hematologic malignancies. Blood. 2014;123:2625–35.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. Milone MC, Fish JD, Carpenito C, et al. Chimeric receptors containing CD137 signal transduction domains mediate enhanced survival of T cells and increased antileukemic efficacy in vivo. Mol Ther. 2009;17:1453–64.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. Maher J, Brentjens RJ, Gunset G, Riviere I, Sadelain M. Human T-lymphocyte cytotoxicity and proliferation directed by a single chimeric TCRzeta /CD28 receptor. Nat Biotechnol. 2002;20:70–5.

    CAS  Article  PubMed  Google Scholar 

  27. Campana D, Schwarz H, Imai C. 4-1BB chimeric antigen receptors. Cancer J. 2014;20:134–40.

    CAS  Article  PubMed  Google Scholar 

  28. Savoldo B, Ramos CA, Liu E, et al. CD28 costimulation improves expansion and persistence of chimeric antigen receptor-modified T cells in lymphoma patients. J Clin Invest. 2011;121:1822–6.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. 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;86:10024–8.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. Brentjens RJ, Riviere I, Park JH, 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;118:4817–28.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. Porter DL, Levine BL, Kalos M, Bagg A, June CH. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med. 2011;365:725–33.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. Park JH, Geyer MB, Brentjens RJ. CD19-targeted CAR T-cell therapeutics for hematologic malignancies: interpreting clinical outcomes to date. Blood. 2016;127:3312–20.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. •• Davila ML, 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;6:224ra25. Important initial clinical report from MSK reporting efficacy and toxicity of their CAR T-cell construct (with CD28 co-stimulatory domain) for adults with ALL.

    Article  PubMed  PubMed Central  Google Scholar 

  34. •• Lee DW, Kochenderfer JN, 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;385:517–28. Important initial clinical report from NCI reporting efficacy and toxicity of their CAR T-cell construct (with CD28 co-stimulatory domain) for children and young adults with ALL.

    CAS  Article  PubMed  Google Scholar 

  35. •• Maude SL, Frey N, Shaw PA, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371:1507–17. Important initial clinical report from CHOP/UPENN reporting efficacy and toxicity of their CAR T-cell construct (with 4-1BB co-stimulatory domain) for children and young adults with ALL.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. Grupp S, Maude, SL, Shaw PA. Durable remissions in children with relapsed/refractory ALL treated with T cells engineered with a CD19-targeted chimeric antigen receptor (CTL019) [abstract]. Blood 2015;126:Abstract 681

  37. Park JH RI, Wang X. 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 [abstract]. Blood 2015;126:Abstract 682.

  38. • Porter DL, Hwang WT, Frey NV, et al. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med. 2015;7:303ra139. Important report highlighting the persistence of the CHOP/UPENN CAR T-cell construct in patients with CLL (persistence beyond 4 years documented).

    Article  PubMed  Google Scholar 

  39. Levine BL, June CH. Perspective: assembly line immunotherapy. Nature. 2013;498:S17.

    CAS  Article  PubMed  Google Scholar 

  40. Torikai H, Reik A, Liu PQ, 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;119:5697–705.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. Torikai H, Reik A, Soldner F, et al. Toward eliminating HLA class I expression to generate universal cells from allogeneic donors. Blood. 2013;122:1341–9.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. Zakrzewski JL, Suh D, Markley JC, et al. Tumor immunotherapy across MHC barriers using allogeneic T-cell precursors. Nat Biotechnol. 2008;26:453–61.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  43. Themeli M, Kloss CC, Ciriello G, et al. Generation of tumor-targeted human T lymphocytes from induced pluripotent stem cells for cancer therapy. Nat Biotechnol. 2013;31:928–33.

    CAS  Article  PubMed  Google Scholar 

  44. • Grupp SA, Waetsch WT, 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 [abstract]. Blood 2016;128:Abstract 221 Important initial report of the phase II registration trial of the CHOP/UPENN construct demonstrating feasibility of global distribution of a CAR T-cell construct.

  45. Frey NV, Porter DL. Cytokine release syndrome with novel therapeutics for acute lymphoblastic leukemia. Hematology Am Soc Hematol Educ Program. 2016;2016:567–72.

    PubMed  Google Scholar 

  46. Lee DW, Gardner R, Porter DL, et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood. 2014;124:188–95.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. Gardner R, Leger KJ, Annesley CE, et al. Decreased rates of severe CRS seen with early intervention strategies for CD19 CAR-T cell toxicity management [abstract]. Blood 2016: 128: Abstract 612.

  48. • Teachey DT, Lacey SF, Shaw PA, et al. Identification of predictive biomarkers for cytokine release syndrome after chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. Cancer Discov. 2016;6:664–79. Important report highlighting predictive biomarkers for cytokine release syndrome which may help focus pre-emptive therapy.

  49. Garde D and Keshavan M. Juno halts its immunotherapy trial for cancer after three patient deaths. July 7, 2016. Stat News www.statnews.com/2016/07/07/juno-cancer-immunotherapy-deaths/

  50. Jackson HJ, Rafiq S, Brentjens RJ. Driving CAR T-cells forward. Nat Rev Clin Oncol. 2016;13:370–83.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  51. • Turtle CJ, Hanafi LA, Berger C, et al. CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients. J Clin Invest. 2016;126:2123–38. Important report highlighting the feasibility of controlling T-cell subset composition in a CAR T-cell product.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Sommermeyer D, Hudecek M, Kosasih PL, et al. Chimeric antigen receptor-modified T cells derived from defined CD8+ and CD4+ subsets confer superior antitumor reactivity in vivo. Leukemia. 2016;30:492–500.

    CAS  PubMed  Google Scholar 

  53. Ruella M, June CH. Chimeric antigen receptor T cells for B cell neoplasms: choose the right CAR for you. Curr Hematol Malign Rep. 2016;11:368–84.

    Article  Google Scholar 

  54. Yang S, Ji Y, Gattinoni L, et al. Modulating the differentiation status of ex vivo-cultured anti-tumor T cells using cytokine cocktails. Cancer Immunol Immunother. 2013;62:727–36.

    CAS  Article  PubMed  Google Scholar 

  55. Maude SL, Barett DM, Rheingold SR, et al. Efficacy of humanized CD19-targeted chimeric antigen receptor (CAR)-modified T cells in children and young adults with relapsed/refractory ALL [abstract]. Blood 2016;122:Abstract 614.

  56. Carpenito C, Milone MC, 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;106:3360–5.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  57. Zhong XS, 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;18:413–20.

    CAS  Article  PubMed  Google Scholar 

  58. Yeku OO, Brentjens RJ. Armored CAR T-cells: utilizing cytokines and pro-inflammatory ligands to enhance CAR T-cell anti-tumour efficacy. Biochem Soc Trans. 2016;44:412–8.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  59. • Pegram HJ, Lee JC, Hayman EG, et al. Tumor-targeted T cells modified to secrete IL-12 eradicate systemic tumors without need for prior conditioning. Blood. 2012;119:4133–41. Important pre-clinical study demonstrating the efficacy of “armored” CAR T-cell therapy (T-cells engineered to express IL-12).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  60. Curran KJ, Seinstra BA, Nikhamin Y, et al. Enhancing antitumor efficacy of chimeric antigen receptor T cells through constitutive CD40L expression. Mol Ther. 2015;23:769–78.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  61. Stephan MT, Ponomarev V, Brentjens RJ, et al. T cell-encoded CD80 and 4-1BBL induce auto- and transcostimulation, resulting in potent tumor rejection. Nat Med. 2007;13:1440–9.

    CAS  Article  PubMed  Google Scholar 

  62. • John LB, Devaud C, Duong CP, et al. Anti-PD-1 antibody therapy potently enhances the eradication of established tumors by gene-modified T cells. Clin Cancer Res. 2013;19:5636–46. Important pre-clinical study demonstrating that checkpoint blockade (PD-1 immunosuppression with a PD-1 blocking antibody) can enhance CAR T-cell therapy.

    CAS  Article  PubMed  Google Scholar 

  63. June CH. Remote controlled CARs: towards a safer therapy for leukemia. Cancer Immunol Res. 2016;4:643.

    CAS  Article  PubMed  Google Scholar 

  64. • Sakemura R, Terakura S, Watanabe K, et al. A Tet-On inducible system for controlling CD19-chimeric antigen receptor expression upon drug administration. Cancer Immunol Res. 2016;4:658–68. Important pre-clinical study demonstrating the feasibility of an inducible CAR T-cell therapy.

    CAS  Article  PubMed  Google Scholar 

  65. Shah NN, Stevenson MS, Yuan CM, et al. Characterization of CD22 expression in acute lymphoblastic leukemia. Pediatr Blood Cancer. 2015;62:964–9.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  66. Haso W, Lee DW, Shah NN, et al. Anti-CD22-chimeric antigen receptors targeting B-cell precursor acute lymphoblastic leukemia. Blood. 2013;121:1165–74.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  67. Long AH, Haso WM, Orentas RJ. Lessons learned from a highly-active CD22-specific chimeric antigen receptor. Oncoimmunology. 2013;2:e23621.

    Article  PubMed  PubMed Central  Google Scholar 

  68. • Shah NN, Stetler-Stevenson M, Yuan CM, 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) [abstract]. Blood 2016;128:Abstract 650. Important preliminary clinical study demonstrating the safety and efficacy of anti-CD22 CAR T-cell construct.

  69. Quin H, Haso W, Nguyen SM, and Fry TJ. Preclinical development of bispecific chimeric antigen receptor targeting both CD19 and CD22 [abstract]. Blood 2015;126: Abstract 4427.

  70. Walker A, Johnson R. Commercialization of cellular immunotherapies for cancer. Biochem Soc Trans. 2016;44:329–32.

    CAS  Article  PubMed  Google Scholar 

  71. Shah B, Huynh, V, Sender LS, 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 Trial [abstract]. Blood 2016;128:Abstract 2803.

  72. Gardner R, Finney O, Smithers H, et al. CD19 CAR 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 [abstract]. Blood 2016;128:Abstract 219.

Download references

Author information

Affiliations

  1. Harvard Medical School, Boston, MA, USA

    Marlise R. Luskin & Daniel J. DeAngelo

  2. Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA, 02215, USA

    Marlise R. Luskin & Daniel J. DeAngelo

Authors
  1. Marlise R. Luskin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daniel J. DeAngelo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Marlise R. Luskin.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflicts of interest.

Human and Animal Rights and Informed Consent

This article contains no studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Acute Lymphocytic Leukemias

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Luskin, M.R., DeAngelo, D.J. Chimeric Antigen Receptor Therapy in Acute Lymphoblastic Leukemia Clinical Practice. Curr Hematol Malig Rep 12, 370–379 (2017). https://doi.org/10.1007/s11899-017-0394-x

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11899-017-0394-x

Keywords

  • Acute lymphoblastic leukemia
  • Immunotherapy
  • Chimeric antigen receptor T cells
  • CART
  • Adoptive cell therapy