Review Article | Published:

Immunotherapy

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

Leukemiavolume 32pages23072315 (2018) | Download Citation

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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

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

  2. 2.

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

  3. 3.

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

  4. 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.

  5. 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.

  6. 6.

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

  7. 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.

  8. 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. 9.

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

  10. 10.

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

  11. 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.

  12. 12.

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

  13. 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.

  14. 14.

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

  15. 15.

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

  16. 16.

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

  17. 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.

  18. 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. 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.

  20. 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.

  21. 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.

  22. 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.

  23. 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.

  24. 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.

  25. 25.

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

  26. 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.

  27. 27.

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

  28. 28.

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

  29. 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.

  30. 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.

  31. 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.

  32. 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.

  33. 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.

  34. 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.

  35. 35.

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

  36. 36.

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

  37. 37.

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

  38. 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.

  39. 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.

  40. 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.

  41. 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.

  42. 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.

  43. 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.

  44. 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.

  45. 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.

  46. 46.

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

  47. 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.

  48. 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.

  49. 49.

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

  50. 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.

  51. 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.

  52. 52.

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

  53. 53.

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

  54. 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.

  55. 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.

  56. 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.

  57. 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.

  58. 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.

  59. 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.

  60. 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.

  61. 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.

  62. 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.

  63. 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.

  64. 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.

  65. 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.

  66. 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.

  67. 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.

  68. 68.

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

  69. 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.

  70. 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.

  71. 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.

  72. 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.

  73. 73.

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

  74. 74.

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

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

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. Search for Marion Alcantara in:

  2. Search for Melania Tesio in:

  3. Search for Carl H. June in:

  4. Search for Roch Houot in:

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.

Corresponding author

Correspondence to Roch Houot.

About this article

Publication history

Received

Revised

Accepted

Published

DOI

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