Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Immunotherapy

CAR T-cells for T-cell malignancies: challenges in distinguishing between therapeutic, normal, and neoplastic T-cells

Leukemia volume 32, pages 2307–2315 (2018)Cite this article

Subjects

Abstract

Chimeric antigen receptor (CAR) T-cells targeting CD19 demonstrated remarkable efficacy for the treatment of B-cell malignancies. The development of CAR T-cells against T-cell malignancies appears more challenging due to the similarities between the therapeutic, normal and malignant T-cells. The obstacles include CAR T-cell fratricide, T-cell aplasia, and contamination of CAR T-cell products with malignant T-cells. Here, we review these challenges and propose solutions to overcome these limitations.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1

Similar content being viewed by others

References

  1. Sadelain M, Brentjens R, Rivière I. The basic principles of chimeric antigen receptor design. Cancer Discov. 2013;3:388–98.

    Article  CAS  Google Scholar 

  2. June CH, O’Connor RS, Kawalekar OU, Ghassemi S, Milone MC. CAR T cell immunotherapy for human cancer. Science. 2018;359:1361–5.

    Article  CAS  Google Scholar 

  3. Brudno JN, Kochenderfer JN. Chimeric antigen receptor T-cell therapies for lymphoma. Nat Rev Clin Oncol. 2018;15:31–46.

    Article  CAS  Google Scholar 

  4. Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018;378:439–48.

    Article  CAS  Google Scholar 

  5. Neelapu SS, Locke FL, Bartlett NL, Lekakis LJ, Miklos DB, Jacobson CA, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377:2531–44.

    Article  Google Scholar 

  6. Salter AI, Pont MJ, Riddell SR. Chimeric antigen receptor modified T cells: CD19 and the road beyond. Blood. 2018;131:2621–29.

    Article  CAS  Google Scholar 

  7. Castellarin M, Watanabe K, June CH, Kloss CC, Posey AD. Driving cars to the clinic for solid tumors. Gene Ther. 2018;25:165–175.

    Article  CAS  Google Scholar 

  8. Weltgesundheitsorganisation. WHO classification of tumours of haematopoietic and lymphoid tissues. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al., editors. World Health Organization classification of tumours. 4th ed. Lyon: International Agency for Research on Cancer; 2017.

  9. Litzow MR, Ferrando AA. How I treat T-cell acute lymphoblastic leukemia in adults. Blood. 2015;126:833–41.

    Article  CAS  Google Scholar 

  10. Moskowitz AJ, Lunning MA, Horwitz SM. How I treat the peripheral T-cell lymphomas. Blood. 2014;123:2636–44.

    Article  CAS  Google Scholar 

  11. Buckley RH, Schiff SE, Schiff RI, Markert L, Williams LW, Roberts JL, et al. Hematopoietic stem-cell transplantation for the treatment of severe combined immunodeficiency. N Engl J Med. 1999;340:508–16.

    Article  CAS  Google Scholar 

  12. Leonard WJ. Cytokines and immunodeficiency diseases. Nat Rev Immunol. 2001;1:200–8.

    Article  CAS  Google Scholar 

  13. Marks DI, Paietta EM, Moorman AV, Richards SM, Buck G, DeWald G, et al. T-cell acute lymphoblastic leukemia in adults: clinical features, immunophenotype, cytogenetics, and outcome from the large randomized prospective trial (UKALL XII/ECOG 2993). Blood. 2009;114:5136–45.

    Article  CAS  Google Scholar 

  14. Marks DI, Rowntree C. Management of adults with T-cell lymphoblastic leukemia. Blood. 2017;129:1134–42.

    Article  CAS  Google Scholar 

  15. Hunger SP, Mullighan CG. Acute lymphoblastic leukemia in children. N Engl J Med. 2015;373:1541–52.

    Article  CAS  Google Scholar 

  16. Dogan A, Morice WG. Bone marrow histopathology in peripheral T-cell lymphomas. Br J Haematol. 2004;127:140–54.

    Article  Google Scholar 

  17. Asnafi V, Beldjord K, Boulanger E, Comba B, Le Tutour P, Estienne M-H, et al. Analysis of TCR, pT alpha, and RAG-1 in T-acute lymphoblastic leukemias improves understanding of early human T-lymphoid lineage commitment. Blood. 2003;101:2693–703.

    Article  CAS  Google Scholar 

  18. Ruella M, Xu J, Barrett DM, Fraietta JA, Reich TJ, Ambrose DE, et al. Induction of resistance to chimeric antigen receptor T cell therapy by transduction of a single leukemic B cell. Nat Med. 2018 Oct 1.

  19. Went P, Agostinelli C, Gallamini A, Piccaluga PP, Ascani S, Sabattini E, et al. Marker expression in peripheral T-cell lymphoma: a proposed clinical-pathologic prognostic score. J Clin Oncol Off J Am Soc. Clin Oncol. 2006;24:2472–9.

    Article  CAS  Google Scholar 

  20. D’ Amore F, Gaulard P, Trümper L, Corradini P, Kim W-S, Specht L, et al. Peripheral T-cell lymphomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol J Eur Soc Med Oncol. 2015;26(Suppl 5):v108–15.

    Article  Google Scholar 

  21. Mamonkin M, Rouce RH, Tashiro H, Brenner MK. A T-cell-directed chimeric antigen receptor for the selective treatment of T-cell malignancies. Blood. 2015;126:983–92.

    Article  CAS  Google Scholar 

  22. Pinz K, Liu H, Golightly M, Jares A, Lan F, Zieve GW, et al. Preclinical targeting of human T-cell malignancies using CD4-specific chimeric antigen receptor (CAR)-engineered T cells. Leukemia. 2016;30:701–7.

    Article  CAS  Google Scholar 

  23. Ramos CA, Ballard B, Zhang H, Dakhova O, Gee AP, Mei Z, et al. Clinical and immunological responses after CD30-specific chimeric antigen receptor-redirected lymphocytes. J Clin Invest. 2017;127:3462–71.

    Article  Google Scholar 

  24. Wang C-M, Wu Z-Q, Wang Y, Guo Y-L, Dai H-R, Wang X-H, et al. Autologous T cells expressing CD30 chimeric antigen receptors for relapsed or refractory Hodgkin lymphoma: an open-label phase I trial. Clin Cancer Res. 2017;23:1156–66.

    Article  CAS  Google Scholar 

  25. Murphy K, Weaver C. Janeway’s immunobiology. 9th ed. New York, NY: Garland Science/Taylor & Francis Group, LLC; 2016. p. 904.

    Book  Google Scholar 

  26. Lu X, Axtell RC, Collawn JF, Gibson A, Justement LB, Raman C. AP2 adaptor complex-dependent internalization of CD5: differential regulation in T and B cells. J Immunol Balt 1950. 2002;168:5612–20.

    CAS  Google Scholar 

  27. Sharpe AH. Mechanisms of costimulation. Immunol Rev. 2009;229:5–11.

    Article  CAS  Google Scholar 

  28. Chen L, Flies DB. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat Rev Immunol. 2013;13:227–42.

    Article  Google Scholar 

  29. Mamonkin M, Mukherjee M, Srinivasan M, Sharma S, Gomes-Silva D, Mo F, et al. Reversible transgene expression reduces fratricide and permits 4-1BB costimulation of CAR T cells directed to T-cell malignancies. Cancer Immunol Res. 2018;6:47–58.

    Article  CAS  Google Scholar 

  30. Falini B, Pileri S, Pizzolo G, Dürkop H, Flenghi L, Stirpe F, et al. CD30 (Ki-1) molecule: a new cytokine receptor of the tumor necrosis factor receptor superfamily as a tool for diagnosis and immunotherapy. Blood. 1995;85:1–14.

    CAS  PubMed  Google Scholar 

  31. Zheng W, Medeiros LJ, Young KH, Goswami M, Powers L, Kantarjian HH, et al. CD30 expression in acute lymphoblastic leukemia as assessed by flow cytometry analysis. Leuk Lymphoma. 2014;55:624–7.

    Article  CAS  Google Scholar 

  32. Savoldo B, Rooney CM, Di Stasi A, Abken H, Hombach A, Foster AE, et al. Epstein Barr virus specific cytotoxic T lymphocytes expressing the anti-CD30zeta artificial chimeric T-cell receptor for immunotherapy of Hodgkin disease. Blood. 2007;110:2620–30.

    Article  CAS  Google Scholar 

  33. De Claro RA, McGinn K, Kwitkowski V, Bullock J, Khandelwal A, Habtemariam B, et al. U.S. Food and Drug Administration approval summary: brentuximab vedotin for the treatment of relapsed Hodgkin lymphoma or relapsed systemic anaplastic large-cell lymphoma. Clin Cancer Res. 2012;18:5845–9.

    Article  Google Scholar 

  34. Gattinoni L, Finkelstein SE, Klebanoff CA, Antony PA, Palmer DC, Spiess PJ, et al. Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells. J Exp Med. 2005;202:907–12.

    Article  CAS  Google Scholar 

  35. Rosenberg SA, Restifo NP. Adoptive cell transfer as personalized immunotherapy for human cancer. Science. 2015;348:62–8.

    Article  CAS  Google Scholar 

  36. Yoshie O, Matsushima K. CCR4 and its ligands: from bench to bedside. Int Immunol. 2015;27:11–20.

    Article  CAS  Google Scholar 

  37. Subramaniam JM, Whiteside G, McKeage K, Croxtall JC. Mogamulizumab: first global approval. Drugs. 2012;72:1293–8.

    Article  CAS  Google Scholar 

  38. Perera LP, Zhang M, Nakagawa M, Petrus MN, Maeda M, Kadin ME, et al. Chimeric antigen receptor modified T cells that target chemokine receptor CCR4 as a therapeutic modality for T-cell malignancies. Am J Hematol. 2017;92:892–901.

    Article  CAS  Google Scholar 

  39. Ishida T, Joh T, Uike N, Yamamoto K, Utsunomiya A, Yoshida S, et al. Defucosylated anti-CCR4 monoclonal antibody (KW-0761) for relapsed adult T-cell leukemia-lymphoma: a multicenter phase II study. J Clin Oncol. 2012;30:837–42.

    Article  CAS  Google Scholar 

  40. Ishida T, Ito A, Sato F, Kusumoto S, Iida S, Inagaki H, et al. Stevens-Johnson Syndrome associated with mogamulizumab treatment of adult T-cell leukemia / lymphoma. Cancer Sci. 2013;104:647–50.

    Article  CAS  Google Scholar 

  41. Ogura M, Ishida T, Hatake K, Taniwaki M, Ando K, Tobinai K, et al. Multicenter phase II study of mogamulizumab (KW-0761), a defucosylated anti-cc chemokine receptor 4 antibody, in patients with relapsed peripheral T-cell lymphoma and cutaneous T-cell lymphoma. J Clin Oncol. 2014;32:1157–63.

    Article  CAS  Google Scholar 

  42. Gomes-Silva D, Srinivasan M, Sharma S, Lee CM, Wagner DL, Davis TH, et al. CD7-edited T cells expressing a CD7-specific CAR for the therapy of T-cell malignancies. Blood. 2017;130:285–96.

    Article  CAS  Google Scholar 

  43. Cooper ML, Choi J, Staser K, Ritchey JK, Devenport JM, Eckardt K, et al. An “off-the-shelf” fratricide-resistant CAR-T for the treatment of T cell hematologic malignancies. Leukemia. 2018;32:1970–83.

    Article  CAS  Google Scholar 

  44. Png YT, Vinanica N, Kamiya T, Shimasaki N, Coustan-Smith E, Campana D. Blockade of CD7 expression in T cells for effective chimeric antigen receptor targeting of T-cell malignancies. Blood Adv. 2017;1:2348–60.

    Article  Google Scholar 

  45. Kamiya T, Wong D, Png YT, Campana D. A novel method to generate T-cell receptor-deficient chimeric antigen receptor T cells. Blood Adv. 2018;2:517–28.

    PubMed  PubMed Central  Google Scholar 

  46. Munro S, Pelham HR. A C-terminal signal prevents secretion of luminal ER proteins. Cell. 1987;48:899–907.

    Article  CAS  Google Scholar 

  47. Jackson MR, Nilsson T, Peterson PA. Identification of a consensus motif for retention of transmembrane proteins in the endoplasmic reticulum. EMBO J. 1990;9:3153–62.

    Article  CAS  Google Scholar 

  48. Daher M, Rezvani K. Next generation natural killer cells for cancer immunotherapy: the promise of genetic engineering. Curr Opin Immunol. 2018;51:146–53.

    Article  CAS  Google Scholar 

  49. Caligiuri MA. Human natural killer cells. Blood. 2008;112:461–9.

    Article  CAS  Google Scholar 

  50. Chen KH, Wada M, Pinz KG, Liu H, Lin K-W, Jares A, et al. Preclinical targeting of aggressive T-cell malignancies using anti-CD5 chimeric antigen receptor. Leukemia. 2017;31:2151–60.

    Article  CAS  Google Scholar 

  51. Hauser A, Schrattbauer K, Najdanovic D, Schlossnickel R, Koch A, Hejtman M, et al. Optimized quantification of lymphocyte subsets by use of CD7 and CD33. Cytom Part A. 2013;83:316–23.

    Article  Google Scholar 

  52. Morvan MG, Lanier LL. NK cells and cancer: you can teach innate cells new tricks. Nat Rev Cancer. 2016;16:7–19.

    Article  CAS  Google Scholar 

  53. Rezvani K, Rouce R, Liu E, Shpall E. Engineering natural killer cells for cancer immunotherapy. Mol Ther. 2017;25:1769–81.

    Article  CAS  Google Scholar 

  54. Simonetta F, Alvarez M, Negrin RS. Natural killer cells in graft-versus-host-disease after allogeneic hematopoietic cell transplantation. Front Immunol. 2017;8:465.

    Article  Google Scholar 

  55. Klingemann H, Boissel L, Toneguzzo F. Natural killer cells for immunotherapy—advantages of the NK-92 cell line over blood NK cells. Front Immunol. 2016;7:91.

    Article  Google Scholar 

  56. Chen KH, Wada M, Firor AE, Pinz KG, Jares A, Liu H, et al. Novel anti-CD3 chimeric antigen receptor targeting of aggressive T cell malignancies. Oncotarget. 2016;7:56219–32.

    PubMed  PubMed Central  Google Scholar 

  57. Pinz KG, Yakaboski E, Jares A, Liu H, Firor AE, Chen KH, et al. Targeting T-cell malignancies using anti-CD4 CAR NK-92 cells. Oncotarget. 2017;8:112783–96.

    Article  Google Scholar 

  58. Suck G, Odendahl M, Nowakowska P, Seidl C, Wels WS, Klingemann HG, et al. NK-92: an “off-the-shelf therapeutic” for adoptive natural killer cell-based cancer immunotherapy. Cancer Immunol Immunother. 2016;65:485–92.

    Article  CAS  Google Scholar 

  59. Zhang C, Oberoi P, Oelsner S, Waldmann A, Lindner A, Tonn T, et al. Chimeric antigen receptor-engineered NK-92 cells: an off-the-shelf cellular therapeutic for targeted elimination of cancer cells and induction of protective antitumor immunity. Front Immunol. 2017;8:533.

    Article  Google Scholar 

  60. Burga RA, Nguyen T, Zulovich J, Madonna S, Ylisastigui L, Fernandes R, et al. Improving efficacy of cancer immunotherapy by genetic modification of natural killer cells. Cytotherapy. 2016;18:1410–21.

    Article  CAS  Google Scholar 

  61. Arai S, Meagher R, Swearingen M, Myint H, Rich E, Martinson J, et al. Infusion of the allogeneic cell line NK-92 in patients with advanced renal cell cancer or melanoma: a phase I trial. Cytotherapy. 2008;10:625–32.

    Article  CAS  Google Scholar 

  62. Tonn T, Schwabe D, Klingemann HG, Becker S, Esser R, Koehl U, et al. Treatment of patients with advanced cancer with the natural killer cell line NK-92. Cytotherapy. 2013;15:1563–70.

    Article  CAS  Google Scholar 

  63. Ram R, Ben-Bassat I, Shpilberg O, Polliack A, Raanani P. The late adverse events of rituximab therapy—rare but there! Leuk Lymphoma. 2009;50:1083–95.

    Article  CAS  Google Scholar 

  64. Park JH, Rivière I, Gonen M, Wang X, Sénéchal B, Curran KJ, et al. Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. N Engl J Med. 2018;378:449–59.

    Article  CAS  Google Scholar 

  65. Sims JE, Tunnacliffe A, Smith WJ, Rabbitts TH. Complexity of human T-cell antigen receptor beta-chain constant- and variable-region genes. Nature. 1984;312:541–5.

    Article  CAS  Google Scholar 

  66. Maciocia PM, Wawrzyniecka PA, Philip B, Ricciardelli I, Akarca AU, Onuoha SC, et al. Targeting the T cell receptor β-chain constant region for immunotherapy of T cell malignancies. Nat Med. 2017;23:1416–23.

    Article  CAS  Google Scholar 

  67. Svoboda J, Rheingold SR, Gill SI, Grupp SA, Lacey SF, Kulikovskaya I, et al. Non-viral RNA chimeric antigen receptor modified T cells in patients with Hodgkin lymphoma. Blood. 2018; 132:1022–6.

    Article  CAS  Google Scholar 

  68. Straathof KC, Spencer DM, Sutton RE, Rooney CM. Suicide genes as safety switches in T lymphocytes. Cytotherapy. 2003;5:227–30.

    Article  CAS  Google Scholar 

  69. Hoyos V, Savoldo B, Quintarelli C, Mahendravada A, Zhang M, Vera J, et al. Engineering CD19-specific T lymphocytes with interleukin-15 and a suicide gene to enhance their anti-lymphoma/leukemia effects and safety. Leukemia. 2010;24:1160–70.

    Article  CAS  Google Scholar 

  70. Eissenberg LG, Rettig MP, Ritchey JK, Prior JL, Schwarz SW, Frye J, et al. [(18)F]FHBG PET/CT imaging of CD34-TK75 transduced donor T cells in relapsed allogeneic stem cell transplant patients: safety and feasibility. Mol Ther. 2015;23:1110–22.

    Article  CAS  Google Scholar 

  71. Minagawa K, Jamil MO, Al-Obaidi M, Pereboeva L, Salzman D, Erba HP, et al. In vitro pre-clinical validation of suicide gene modified anti-CD33 redirected chimeric antigen receptor T-cells for acute myeloid leukemia. PLoS One. 2016;11:e0166891.

    Article  Google Scholar 

  72. Sun S, Hao H, Yang G, Zhang Y, Fu Y. Immunotherapy with CAR-modified T cells: toxicities and overcoming strategies. J Immunol Res. 2018;2018:2386187.

    PubMed  PubMed Central  Google Scholar 

  73. Blazar BR, Murphy WJ, Abedi M. Advances in graft-versus-host disease biology and therapy. Nat Rev Immunol. 2012;12:443–58.

    Article  CAS  Google Scholar 

  74. Yang Y, Jacoby E, Fry TJ. Challenges and opportunities of allogeneic donor-derived CAR T cells. Curr Opin Hematol. 2015;22:509–15.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Author contributions

M.A., M.T., C.H.J., and R.H. performed the literature review, wrote the manuscript, and created the table and figure.

Author information

Authors and Affiliations

  1. Laboratory of Onco-Hematology, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Necker-Enfants Malades, Paris, France

    Marion Alcantara

  2. Institut Necker Enfants Malades (INEM), Institut National de Recherche Médicale (INSERM) U1151, Paris, France

    Marion Alcantara & Melania Tesio

  3. Center for Cellular Immunotherapies, Perlman School of Medicine, Philadelphia, PA, USA

    Carl H. June

  4. Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia, PA, USA

    Carl H. June

  5. Department of Pathology and Laboratory Medicine, Perlman School of Medicine, Philadelphia, PA, USA

    Carl H. June

  6. CHU Rennes, Service Hématologie Clinique, 35033, Rennes, France

    Roch Houot

  7. INSERM, U1236, 35043, Rennes, France

    Roch Houot

  8. INSERM 0203, Unité d’Investigation Clinique, 35033, Rennes, France

    Roch Houot

Authors
  1. Marion Alcantara
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Melania Tesio
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Carl H. June
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Roch Houot
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Roch Houot.

Ethics declarations

Conflict of interest

M.A. received consulting fees/honoraria from Novartis. C.H.J. reports sponsored research from Novartis, patents licensed to Novartis by the University of Pennsylvania and he is a shareholder in Tmunity. R.H. received consulting fees/honoraria from Novartis and Kite/Gilead. The remaining author declares no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Alcantara, M., Tesio, M., June, C.H. et al. CAR T-cells for T-cell malignancies: challenges in distinguishing between therapeutic, normal, and neoplastic T-cells. Leukemia 32, 2307–2315 (2018). https://doi.org/10.1038/s41375-018-0285-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41375-018-0285-8

This article is cited by

Search

Advanced search

Quick links