Novel Immunotherapies for T Cell Lymphoma and Leukemia


Purpose of Review

Novel immunotherapies such as checkpoint inhibitors, bispecific antibodies, and chimeric antigen receptor T cells are leading to promising responses when treating solid tumors and hematological malignancies. T cell neoplasms include leukemia and lymphomas that are derived from T cells and overall are characterized by poor clinical outcomes. This review describes the rational and preliminary results of immunotherapy for patients with T cell lymphoma and leukemia.

Recent Findings

For T cell neoplasms, despite significant research effort, only few agents, such as monoclonal antibodies and allogeneic stem cell transplantation, showed some clinical activity. One of the major hurdles to targeting T cell neoplasms is that activation or elimination of T cells, either normal or neoplastic, can cause significant toxicity. A need to develop novel safe and effective immunotherapies for T cell neoplasms exists.


In this review, we will discuss the rationale for immunotherapy of T cell leukemia and lymphoma and present the most recent therapeutic approaches.

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Fig. 1


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

  1. 1.

    June CH, O'Connor RS, Kawalekar OU, Ghassemi S, Milone MC. CAR T cell immunotherapy for human cancer. Science. 2018;359(6382):1361–5.

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Maloney DG. Anti-CD20 antibody therapy for B-cell lymphomas. N Engl J Med. 2012;366(21):2008–16.

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Brody J, Kohrt H, Marabelle A, Levy R. Active and passive immunotherapy for lymphoma: proving principles and improving results. J Clin Oncol. 2011;29(14):1864–75.

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Xu-Monette ZY, Zhou J, Young KH. PD-1 expression and clinical PD-1 blockade in B-cell lymphomas. Blood. 2018;131(1):68–83.

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Horwitz SM, Ansell SM, Ai WZ, Barnes J, Barta SK, Choi M, et al. NCCN guidelines insights: T-cell lymphomas, version 2.2018. J Natl Compr Cancer Netw. 2018;16(2):123–35.

    Article  Google Scholar 

  6. 6.

    Mehta-Shah N, Ratner L, Horwitz SM. Adult T-cell leukemia/lymphoma. J Oncol Pract. 2017;13(8):487–92.

    Article  PubMed  Google Scholar 

  7. 7.

    A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin’s lymphoma. The Non-Hodgkin’s Lymphoma Classification Project. Blood. 1997;89(11):3909–18.

  8. 8.

    Vose J, Armitage J, Weisenburger D. International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes. J Clin Oncol. 2008;26(25):4124–30.

    Article  PubMed  Google Scholar 

  9. 9.

    Piccaluga PP, Agostinelli C, Califano A, Rossi M, Basso K, Zupo S, et al. Gene expression analysis of peripheral T cell lymphoma, unspecified, reveals distinct profiles and new potential therapeutic targets. J Clin Investig. 2007;117(3):823–34.

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Piccaluga PP, Agostinelli C, Califano A, Carbone A, Fantoni L, Ferrari S, et al. Gene expression analysis of angioimmunoblastic lymphoma indicates derivation from T follicular helper cells and vascular endothelial growth factor deregulation. Cancer Res. 2007;67(22):10703–10.

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Teras LR, DeSantis CE, Cerhan JR, Morton LM, Jemal A, Flowers CR. 2016 US lymphoid malignancy statistics by World Health Organization subtypes. CA Cancer J Clin. 2016;66:443–59.

    Article  Google Scholar 

  12. 12.

    Au WY, Weisenburger DD, Intragumtornchai T, Nakamura S, Kim WS, Sng I, et al. Clinical differences between nasal and extranasal natural killer/T-cell lymphoma: a study of 136 cases from the International Peripheral T-Cell Lymphoma Project. Blood. 2009;113(17):3931–7.

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Matutes E, Brito-Babapulle V, Swansbury J, Ellis J, Morilla R, Dearden C, et al. Clinical and laboratory features of 78 cases of T-prolymphocytic leukemia. Blood. 1991;78(12):3269–74.

    CAS  PubMed  Google Scholar 

  14. 14.

    Drobna M, Szarzynska-Zawadzka B, Dawidowska M. T-cell acute lymphoblastic leukemia from miRNA perspective: basic concepts, experimental approaches, and potential biomarkers. Blood Rev. 2018.

  15. 15.

    Belver L, Ferrando A. The genetics and mechanisms of T cell acute lymphoblastic leukaemia. Nat Rev Cancer. 2016;16(8):494–507.

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Bellei M, Foss FM, Shustov AR, Horwitz SM, Marcheselli L, Kim WS, et al. The outcome of peripheral T-cell lymphoma patients failing first line therapy: a report from the prospective, international T-cell project. Haematologica. 2018;103:1191–7.

    Article  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Murray D, Eldershaw SA, Pearce H, Davies N, McMurray J, Scarisbrick JJ, et al. T cell versus T cell; a study of the immune checkpoint landscape in cutaneous T cell lymphoma. Blood. 2754;130(Suppl 1):2017.

    Google Scholar 

  18. 18.

    Miyatake Y, Oliveira AL, Jarboui MA, Ota S, Tomaru U, Teshima T, et al. Protective roles of epithelial cells in the survival of adult T-cell leukemia/lymphoma cells. Am J Pathol. 2013;182(5):1832–42.

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Kinpara S, Hasegawa A, Utsunomiya A, Nishitsuji H, Furukawa H, Masuda T, et al. Stromal cell-mediated suppression of human T-cell leukemia virus type 1 expression in vitro and in vivo by type I interferon. J Virol. 2009;83(10):5101–8.

    Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Vicario M, Mattiolo A, Montini B, Piano MA, Cavallari I, Amadori A, et al. A preclinical model for the ATLL lymphoma subtype with insights into the role of microenvironment in HTLV-1-mediated lymphomagenesis. Front Microbiol. 2018;9:1215.

    Article  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Thumann P, Luftl M, Moc I, Bagot M, Bensussan A, Schuler G, et al. Interaction of cutaneous lymphoma cells with reactive T cells and dendritic cells: implications for dendritic cell-based immunotherapy. Br J Dermatol. 2003;149(6):1128–42.

    CAS  Article  Google Scholar 

  22. 22.

    Miyagaki T, Sugaya M, Fujita H, Ohmatsu H, Kakinuma T, Kadono T, et al. Eotaxins and CCR3 interaction regulates the Th2 environment of cutaneous T-cell lymphoma. J Investig Dermatol. 2010;130(9):2304–11.

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Rubio Gonzalez B, Zain J, Rosen ST, Querfeld C. Tumor microenvironment in mycosis fungoides and Sezary syndrome. Curr Opin Oncol. 2016;28(1):88–96.

    Article  PubMed  Google Scholar 

  24. 24.

    Querfeld C, Curran SA, Leung S, Myskowski PL, Horwitz SM, Halpern AC, et al. T cells in CTCL have an exhausted phenotype while cutaneous dendritic cells display a normally activated mature phenotype. Blood. 2014;124(21):1695.

    Google Scholar 

  25. 25.

    Russ A, Hua AB, Montfort WR, Rahman B, Riaz IB, Khalid MU, et al. Blocking “don’t eat me” signal of CD47-SIRPalpha in hematological malignancies, an in-depth review. Blood Rev. 2018.

  26. 26.

    Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. The N Engl J Med. 2012;366(26):2455–65.

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Kulpa DA, Lawani M, Cooper A, Peretz Y, Ahlers J, Sekaly RP. PD-1 coinhibitory signals: the link between pathogenesis and protection. Semin Immunol. 2013;25(3):219–27.

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Ruella M, Kalos M. Adoptive immunotherapy for cancer. Immunol Rev. 2014;257(1):14–38.

    Article  PubMed  Google Scholar 

  29. 29.

    Sugaya M, Miyagaki T, Ohmatsu H, Suga H, Kai H, Kamata M, et al. Association of the numbers of CD163(+) cells in lesional skin and serum levels of soluble CD163 with disease progression of cutaneous T cell lymphoma. J Dermatol Sci. 2012;68(1):45–51.

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    Assaf C, Hwang ST. Mac attack: macrophages as key drivers of cutaneous T-cell lymphoma pathogenesis. Exp Dermatol. 2016;25(2):105–6.

    Article  PubMed  Google Scholar 

  31. 31.

    Tada K, Hamada T, Asagoe K, Umemura H, Mizuno-Ikeda K, Aoyama Y, et al. Increase of DC-LAMP+ mature dendritic cell subsets in dermatopathic lymphadenitis of mycosis fungoides. Eur J Dermatol. 2014;24(6):670–5.

    Article  PubMed  Google Scholar 

  32. 32.

    Pizzi M, Margolskee E, Inghirami G. Pathogenesis of peripheral T cell lymphoma. Annu Rev Pathol. 2018;13:293–320.

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    Fox CP, Shannon-Lowe C, Gothard P, Kishore B, Neilson J, O’Connor N, et al. Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis in adults characterized by high viral genome load within circulating natural killer cells. Clin Infect Dis. 2010;51(1):66–9.

    CAS  Article  PubMed  Google Scholar 

  34. 34.

    Shannon-Lowe C, Rickinson AB, Bell AI. Epstein-Barr virus-associated lymphomas. Philos Trans R Soc Lond Ser B Biol Sci. 2017;372(1732):20160271.

    CAS  Article  Google Scholar 

  35. 35.

    Tan GW, Visser L, Tan LP, van den Berg A, Diepstra A. The microenvironment in Epstein-Barr virus-associated malignancies. Pathogens. 2018;7(2).

  36. 36.

    van Beek J, zur Hausen A, Snel SN, Berkhof J, Kranenbarg EK, van de Velde CJ, et al. Morphological evidence of an activated cytotoxic T-cell infiltrate in EBV-positive gastric carcinoma preventing lymph node metastases. Am J Surg Pathol. 2006;30(1):59–65.

    Article  Google Scholar 

  37. 37.

    Kamper P, Bendix K, Hamilton-Dutoit S, Honore B, Nyengaard JR, d’Amore F. Tumor-infiltrating macrophages correlate with adverse prognosis and Epstein-Barr virus status in classical Hodgkin’s lymphoma. Haematologica. 2011;96(2):269–76.

    Article  PubMed  Google Scholar 

  38. 38.

    Barros MH, Hassan R, Niedobitek G. Tumor-associated macrophages in pediatric classical Hodgkin lymphoma: association with Epstein-Barr virus, lymphocyte subsets, and prognostic impact. Clin Cancer Res. 2012;18(14):3762–71.

    CAS  Article  PubMed  Google Scholar 

  39. 39.

    Barros MH, Segges P, Vera-Lozada G, Hassan R, Niedobitek G. Macrophage polarization reflects T cell composition of tumor microenvironment in pediatric classical Hodgkin lymphoma and has impact on survival. PLoS One. 2015;10(5):e0124531.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Kim YR, Kim SJ, Cheong JW, Chung H, Jang JE, Kim Y, et al. Pretreatment Epstein-Barr virus DNA in whole blood is a prognostic marker in peripheral T-cell lymphoma. Oncotarget. 2017;8(54):92312–23.

    Article  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Chuang HC, Lay JD, Hsieh WC, Wang HC, Chang Y, Chuang SE, et al. Epstein-Barr virus LMP1 inhibits the expression of SAP gene and upregulates Th1 cytokines in the pathogenesis of hemophagocytic syndrome. Blood. 2005;106(9):3090–6.

    CAS  Article  PubMed  Google Scholar 

  42. 42.

    • Ratner L, Waldmann TA, Janakiram M, Brammer JE. Rapid progression of adult T-cell leukemia-lymphoma after PD-1 inhibitor therapy. N Engl J Med. 2018;378(20):1947–8. In this letter, Ratner and colleagues report the unfortunate experience of anti-PD1 for ATLL: the drug had probably an activating role on the lymphoma cells. The trial was closed after only three patients enrolled.

    Article  PubMed  Google Scholar 

  43. 43.

    Wartewig T, Kurgyis Z, Keppler S, Pechloff K, Hameister E, Ollinger R, et al. PD-1 is a haploinsufficient suppressor of T cell lymphomagenesis. Nature. 2017;552(7683):121–5.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Horwitz SM, Koch R, Porcu P, Oki Y, Moskowitz A, Perez M, et al. Activity of the PI3K-delta,gamma inhibitor duvelisib in a phase 1 trial and preclinical models of T-cell lymphoma. Blood. 2018;131(8):888–98.

    CAS  Article  PubMed  Google Scholar 

  45. 45.

    Lundin J, Hagberg H, Repp R, Cavallin-Stahl E, Freden S, Juliusson G, et al. Phase 2 study of alemtuzumab (anti-CD52 monoclonal antibody) in patients with advanced mycosis fungoides/Sezary syndrome. Blood. 2003;101(11):4267–72.

    CAS  Article  PubMed  Google Scholar 

  46. 46.

    Dearden CE, Matutes E, Cazin B, Tjonnfjord GE, Parreira A, Nomdedeu B, et al. High remission rate in T-cell prolymphocytic leukemia with CAMPATH-1H. Blood. 2001;98(6):1721–6.

    CAS  Article  Google Scholar 

  47. 47.

    Krishnan B, Else M, Tjonnfjord GE, Cazin B, Carney D, Carter J, et al. Stem cell transplantation after alemtuzumab in T-cell prolymphocytic leukaemia results in longer survival than after alemtuzumab alone: a multicentre retrospective study. Br J Haematol. 2010;149(6):907–10.

    Article  PubMed  Google Scholar 

  48. 48.

    Hopfinger G, Busch R, Pflug N, Weit N, Westermann A, Fink AM, et al. Sequential chemoimmunotherapy of fludarabine, mitoxantrone, and cyclophosphamide induction followed by alemtuzumab consolidation is effective in T-cell prolymphocytic leukemia. Cancer. 2013;119(12):2258–67.

    CAS  Article  PubMed  Google Scholar 

  49. 49.

    Sharma K, Janik JE, O'Mahony D, Stewart D, Pittaluga S, Stetler-Stevenson M, et al. Phase II study of alemtuzumab (CAMPATH-1) in patients with HTLV-1-associated adult T-cell leukemia/lymphoma. Clin Cancer Res : an official journal of the American Association for Cancer Research. 2017;23(1):35–42.

    CAS  Article  Google Scholar 

  50. 50.

    • Pro B, Advani R, Brice P, Bartlett NL, Rosenblatt JD, Illidge T, et al. Brentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic large-cell lymphoma: results of a phase II study. J Clin Oncol. 2012;30(18):2190–6. Provides the first evidence of the activity of the monoclonal antibody immunoconjugate brentuximab vedotin in patients with relapsed/refractory ALCL.

    CAS  Article  PubMed  Google Scholar 

  51. 51.

    Horwitz SM, Advani RH, Bartlett NL, Jacobsen ED, Sharman JP, O'Connor OA, et al. Objective responses in relapsed T-cell lymphomas with single-agent brentuximab vedotin. Blood. 2014;123(20):3095–100.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Prince HM, Kim YH, Horwitz SM, Dummer R, Scarisbrick J, Quaglino P, et al. Brentuximab vedotin or physician’s choice in CD30-positive cutaneous T-cell lymphoma (ALCANZA): an international, open-label, randomised, phase 3, multicentre trial. Lancet. 2017;390(10094):555–66.

    CAS  Article  PubMed  Google Scholar 

  53. 53.

    Horwitz SM, Scarisbrick JJ, Dummer R, Duvic M, Kim YH, Walewski J, et al. Updated analyses of the international, open-label, randomized, phase 3 Alcanza study: longer-term evidence for superiority of brentuximab vedotin versus methotrexate or bexarotene for CD30-positive cutaneous T-cell lymphoma (CTCL). Blood. 2017;130(Suppl 1):1509.

    Google Scholar 

  54. 54.

    Yamamoto K, Utsunomiya A, Tobinai K, Tsukasaki K, Uike N, Uozumi K, et al. Phase I study of KW-0761, a defucosylated humanized anti-CCR4 antibody, in relapsed patients with adult T-cell leukemia-lymphoma and peripheral T-cell lymphoma. J Clin Oncol. 2010;28(9):1591–8.

    CAS  Article  PubMed  Google Scholar 

  55. 55.

    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(11):1157–63.

    CAS  Article  PubMed  Google Scholar 

  56. 56.

    Ishida T, Inagaki H, Utsunomiya A, Takatsuka Y, Komatsu H, Iida S, et al. CXC chemokine receptor 3 and CC chemokine receptor 4 expression in T-cell and NK-cell lymphomas with special reference to clinicopathological significance for peripheral T-cell lymphoma, unspecified. Clin Cancer Res. 2004;10(16):5494–500.

    CAS  Article  PubMed  Google Scholar 

  57. 57.

    Al-Zahrani M, Savage KJ. Peripheral T-cell lymphoma, not otherwise specified: a review of current disease understanding and therapeutic approaches. Hematol Oncol Clin North Am. 2017;31(2):189–207.

    Article  PubMed  Google Scholar 

  58. 58.

    Kim YH, Bagot M, Pinter-Brown L, Rook AH, Porcu P, Horwitz SM, et al. Anti-CCR4 monoclonal antibody, mogamulizumab, demonstrates significant improvement in PFS compared to vorinostat in patients with previously treated cutaneous T-cell lymphoma (CTCL): results from the phase III MAVORIC study. Blood. 2017;130(Suppl 1):817.

    Google Scholar 

  59. 59.

    Bride KL, Vincent TL, Im SY, Aplenc R, Barrett DM, Carroll WL, et al. Preclinical efficacy of daratumumab in T-cell acute lymphoblastic leukemia. Blood. 2018;131(9):995–9.

    CAS  Article  PubMed  Google Scholar 

  60. 60.

    Hari P, Raj RV, Olteanu H. Targeting CD38 in refractory extranodal natural killer cell-T-cell lymphoma. N Engl J Med. 2016;375(15):1501–2.

    Article  PubMed  Google Scholar 

  61. 61.

    Horwitz SM, Hamadani M, Fanale MA, Feingold J, Spira AI, Fields PA, et al. Interim results from a phase 1 study of ADCT-301 (camidanlumab tesirine) show promising activity of a novel pyrrolobenzodiazepine-based antibody drug conjugate in relapsed/refractory Hodgkin/non-Hodgkin lymphoma. Blood. 2017;130(Suppl 1):1510.

    Google Scholar 

  62. 62.

    Li X, Cheng Y, Zhang M, Yan J, Li L, Fu X, et al. Activity of pembrolizumab in relapsed/refractory NK/T-cell lymphoma. J Hematol Oncol. 2018;11(1):15.

    Article  PubMed  PubMed Central  Google Scholar 

  63. 63.

    • Kwong YL, Chan TSY, Tan D, Kim SJ, Poon LM, Mow B, et al. PD1 blockade with pembrolizumab is highly effective in relapsed or refractory NK/T-cell lymphoma failing l-asparaginase. Blood. 2017;129(17):2437–42. In this publication, Kwong and colleagues report the positive experience (100% ORR) of PD1 blockade in relapsed/refractory NKTL nasal type.

    CAS  Article  PubMed  Google Scholar 

  64. 64.

    Chan TSY, Li J, Loong F, Khong PL, Tse E, Kwong YL. PD1 blockade with low-dose nivolumab in NK/T cell lymphoma failing L-asparaginase: efficacy and safety. Ann Hematol. 2018;97(1):193–6.

    CAS  Article  PubMed  Google Scholar 

  65. 65.

    Lesokhin AM, Ansell SM, Armand P, Scott EC, Halwani A, Gutierrez M, et al. Nivolumab in patients with relapsed or refractory hematologic malignancy: preliminary results of a phase Ib study. J Clin Oncol. 2016;34(23):2698–704.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  66. 66.

    Khodadoust M, Rook AH, Porcu P, Foss FM, Moskowitz AJ, Shustov AR, et al. Pembrolizumab for treatment of relapsed/refractory mycosis fungoides and sezary syndrome: clinical efficacy in a Citn multicenter phase 2 study. Blood. 2016;128(22):181.

    Google Scholar 

  67. 67.

    Heslop HE, Slobod KS, Pule MA, Hale GA, Rousseau A, Smith CA, et al. Long-term outcome of EBV-specific T-cell infusions to prevent or treat EBV-related lymphoproliferative disease in transplant recipients. Blood. 2010;115(5):925–35.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  68. 68.

    Rooney CM, Smith CA, Ng CY, Loftin S, Li C, Krance RA, et al. Use of gene-modified virus-specific T lymphocytes to control Epstein-Barr-virus-related lymphoproliferation. Lancet. 1995;345(8941):9–13.

    CAS  Article  Google Scholar 

  69. 69.

    Morales O, Mrizak D, Francois V, Mustapha R, Miroux C, Depil S, et al. Epstein-Barr virus infection induces an increase of T regulatory type 1 cells in Hodgkin lymphoma patients. Br J Haematol. 2014;166(6):875–90.

    CAS  Article  PubMed  Google Scholar 

  70. 70.

    Bollard CM, Gottschalk S, Torrano V, Diouf O, Ku S, Hazrat Y, et al. Sustained complete responses in patients with lymphoma receiving autologous cytotoxic T lymphocytes targeting Epstein-Barr virus latent membrane proteins. J Clin Oncol. 2014;32(8):798–808.

    CAS  Article  PubMed  Google Scholar 

  71. 71.

    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(7):2620–30.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  72. 72.

    Di Stasi A, De Angelis B, Rooney CM, Zhang L, Mahendravada A, Foster AE, et al. T lymphocytes coexpressing CCR4 and a chimeric antigen receptor targeting CD30 have improved homing and antitumor activity in a Hodgkin tumor model. Blood. 2009;113(25):6392–402.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  73. 73.

    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(8):983–92.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  74. 74.

    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(35):56219–32.

    Article  PubMed  PubMed Central  Google Scholar 

  75. 75.

    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(3):701–7.

    CAS  Article  PubMed  Google Scholar 

  76. 76.

    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(9):892–901.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  77. 77.

    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(3):285–96.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  78. 78.

    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.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  79. 79.

    Maciocia PM, Wawrzyniecka PA, Philip B, Ricciardelli I, Akarca AU, Onuoha SC, et al. Targeting the T cell receptor beta-chain constant region for immunotherapy of T cell malignancies. Nat Med. 2017;23(12):1416–23.

    CAS  Article  PubMed  Google Scholar 

  80. 80.

    Langerak AW, van Den Beemd R, Wolvers-Tettero IL, Boor PP, van Lochem EG, Hooijkaas H, et al. Molecular and flow cytometric analysis of the Vbeta repertoire for clonality assessment in mature TCRalphabeta T-cell proliferations. Blood. 2001;98(1):165–73.

    CAS  Article  Google Scholar 

  81. 81.

    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. The J Clin Investig. 2017;127(9):3462–71.

    Article  PubMed  Google Scholar 

  82. 82.

    Wu J, Fu J, Zhang M, Liu D. AFM13: a first-in-class tetravalent bispecific anti-CD30/CD16A antibody for NK cell-mediated immunotherapy. J Hematol Oncol. 2015;8:96.

    Article  PubMed  PubMed Central  Google Scholar 

  83. 83.

    Ansell SM, Chen RW, Forero-Torres A, Armand P, Lossos IS, Reeder CB, et al. A phase 1 study investigating the combination of AFM13 and the monoclonal anti-PD-1 antibody pembrolizumab in patients with relapsed/refractory Hodgkin lymphoma after brentuximab vedotin failure: data from the dose escalation part of the study. Blood. 2017;130(Suppl 1):1522.

    Google Scholar 

  84. 84.

    Kim YH, Gratzinger D, Harrison C, Brody JD, Czerwinski DK, Ai WZ, et al. In situ vaccination against mycosis fungoides by intratumoral injection of a TLR9 agonist combined with radiation: a phase 1/2 study. Blood. 2012;119(2):355–63.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  85. 85.

    Maier T, Tun-Kyi A, Tassis A, Jungius KP, Burg G, Dummer R, et al. Vaccination of patients with cutaneous T-cell lymphoma using intranodal injection of autologous tumor-lysate-pulsed dendritic cells. Blood. 2003;102(7):2338–44.

    CAS  Article  PubMed  Google Scholar 

  86. 86.

    Bourlon C, Lacayo-Lenero D, Inclan-Alarcon SI, Demichelis-Gomez R. Hematopoietic stem cell transplantation for adult Philadelphia-negative acute lymphoblastic leukemia in the first complete remission in the era of minimal residual disease. Curr Oncol Rep. 2018;20(4):36.

    Article  PubMed  Google Scholar 

  87. 87.

    Cudillo L, Cerretti R, Picardi A, Mariotti B, De Angelis G, Cantonetti M, et al. Allogeneic hematopoietic stem cell transplantation in primary cutaneous T cell lymphoma. Ann Hematol. 2018;97(6):1041–8.

    Article  PubMed  Google Scholar 

  88. 88.

    Li C, Yang D, Chen J, Wang P, Zhang Y, Wu D. Outcome of allogeneic stem cell transplantation in T cell lymphoblastic lymphoma. Blood. 2017;130(Suppl 1):5535.

    Google Scholar 

  89. 89.

    Mehta-Shah N, Teja S, Tao Y, Cashen AF, Beaven A, Alpdogan O, et al. Successful treatment of mature T-cell lymphoma with allogeneic stem cell transplantation: the largest multicenter retrospective analysis. Blood. 2017;130(Suppl 1):4597.

    Google Scholar 

  90. 90.

    Inamoto Y, Fefer A, Sandmaier BM, Gooley TA, Warren EH, Petersdorf SH, et al. A phase I/II study of chemotherapy followed by donor lymphocyte infusion plus interleukin-2 for relapsed acute leukemia after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2011;17(9):1308–15.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  91. 91.

    Miyamoto T, Fukuda T, Nakashima M, Henzan T, Kusakabe S, Kobayashi N, et al. Donor lymphocyte infusion for relapsed hematological malignancies after unrelated allogeneic bone marrow transplantation facilitated by the Japan Marrow Donor Program. Biol Blood Marrow Transplant. 2017;23(6):938–44.

    Article  PubMed  Google Scholar 

  92. 92.

    Slavin S, Naparstek E, Nagler A, Ackerstein A, Samuel S, Kapelushnik J, et al. Allogeneic cell therapy with donor peripheral blood cells and recombinant human interleukin-2 to treat leukemia relapse after allogeneic bone marrow transplantation. Blood. 1996;87(6):2195–204.

    CAS  Google Scholar 

  93. 93.

    Kolb HJ, Schattenberg A, Goldman JM, Hertenstein B, Jacobsen N, Arcese W, et al. Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients. Blood. 1995;86(5):2041–50.

    CAS  Google Scholar 

  94. 94.

    Zhao Y, Su H, Shen X, Du J, Zhang X, Zhao Y. The immunological function of CD52 and its targeting in organ transplantation. Inflamm Res. 2017;66(7):571–8.

    CAS  Article  PubMed  Google Scholar 

  95. 95.

    Rao SP, Sancho J, Campos-Rivera J, Boutin PM, Severy PB, Weeden T, et al. Human peripheral blood mononuclear cells exhibit heterogeneous CD52 expression levels and show differential sensitivity to alemtuzumab mediated cytolysis. PLoS One. 2012;7(6):e39416.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  96. 96.

    Karlin L, Coiffier B. The changing landscape of peripheral T-cell lymphoma in the era of novel therapies. Semin Hematol. 2014;51(1):25–34.

    Article  PubMed  Google Scholar 

  97. 97.

    Ishida T, Utsunomiya A, Jo T, Yamamoto K, Kato K, Yoshida S, et al. Mogamulizumab for relapsed adult T-cell leukemia-lymphoma: updated follow-up analysis of phase I and II studies. Cancer Sci. 2017;108(10):2022–9.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  98. 98.

    Asano N, Suzuki R, Ohshima K, Kagami Y, Ishida F, Yoshino T, et al. Linkage of expression of chemokine receptors (CXCR3 and CCR4) and cytotoxic molecules in peripheral T cell lymphoma, not otherwise specified and ALK-negative anaplastic large cell lymphoma. Int J Hematol. 2010;91(3):426–35.

    CAS  Article  PubMed  Google Scholar 

  99. 99.

    Capriotti E, Vonderheid EC, Thoburn CJ, Bright EC, Hess AD. Chemokine receptor expression by leukemic T cells of cutaneous T-cell lymphoma: clinical and histopathological correlations. J Invest Dermatol. 2007;127(12):2882–92.

    CAS  Article  PubMed  Google Scholar 

  100. 100.

    Ishida T, Utsunomiya A, Iida S, Inagaki H, Takatsuka Y, Kusumoto S, et al. Clinical significance of CCR4 expression in adult T-cell leukemia/lymphoma: its close association with skin involvement and unfavorable outcome. Clin Cancer Res. 2003;9(10 Pt 1):3625–34.

    CAS  PubMed  Google Scholar 

  101. 101.

    Tobinai K, Uike N, Saburi Y, Chou T, Etoh T, Masuda M, et al. Phase II study of cladribine (2-chlorodeoxyadenosine) in relapsed or refractory adult T-cell leukemia-lymphoma. Int J Hematol. 2003;77(5):512–7.

    CAS  Article  Google Scholar 

  102. 102.

    Tsukasaki K, Tobinai K, Shimoyama M, Kozuru M, Uike N, Yamada Y, et al. Deoxycoformycin-containing combination chemotherapy for adult T-cell leukemia-lymphoma: Japan Clinical Oncology Group Study (JCOG9109). Int J Hematol. 2003;77(2):164–70.

    CAS  Article  Google Scholar 

  103. 103.

    Ohno R, Kobayashi T, Tanimoto M, Hiraoka A, Imai K, Asou N, et al. Randomized study of individualized induction therapy with or without vincristine, and of maintenance-intensification therapy between 4 or 12 courses in adult acute myeloid leukemia. AML-87 Study of the Japan Adult Leukemia Study Group. Cancer. 1993;71(12):3888–95.

    CAS  Article  Google Scholar 

  104. 104.

    Wang L, Wang H, Li PF, Lu Y, Xia ZJ, Huang HQ, et al. CD38 expression predicts poor prognosis and might be a potential therapy target in extranodal NK/T cell lymphoma, nasal type. Ann Hematol. 2015;94(8):1381–8.

    CAS  Article  PubMed  Google Scholar 

  105. 105.

    Mustafa N, Nee HFA, Lee XTJ, Jin W, Yu Y, Chen Y, et al. Daratumumab efficiently targets NK/T cell lymphoma with high CD38 expression. Blood. 2017;130(Suppl 1):2814.

    Google Scholar 

  106. 106.

    Triplett TA, Curti BD, Bonafede PR, Miller WL, Walker EB, Weinberg AD. Defining a functionally distinct subset of human memory CD4+ T cells that are CD25POS and FOXP3NEG. Eur J Immunol. 2012;42(7):1893–905.

    CAS  Article  PubMed  Google Scholar 

  107. 107.

    Dhandha MM, Sufficool KE, Vidal CI, Robbins KJ, Fesler MJ, Batanian JR, et al. Immunophenotype expression change from CD52+ to CD52- on erythrodermic peripheral T-cell lymphoma, not otherwise specified after treatment with alemtuzumab. Am J Dermatopathol. 2018;40(7):547–50.

    Article  PubMed  Google Scholar 

  108. 108.

    Tuset E, Matutes E, Brito-Babapulle V, Morilla R, Catovsky D. Immunophenotype changes and loss of CD52 expression in two patients with relapsed T-cell prolymphocytic leukaemia. Leuk Lymphoma. 2001;42(6):1379–83.

    CAS  Article  PubMed  Google Scholar 

  109. 109.

    Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008;26:677–704.

    CAS  Article  PubMed  Google Scholar 

  110. 110.

    Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252–64.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  111. 111.

    Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. The N Engl J Med. 2010;363(8):711–23.

    CAS  Article  PubMed  Google Scholar 

  112. 112.

    Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, et al. Nivolumab in previously untreated melanoma without BRAF mutation. The N Engl J Med. 2015;372(4):320–30.

    CAS  Article  PubMed  Google Scholar 

  113. 113.

    Weber J, Mandala M, Del Vecchio M, Gogas HJ, Arance AM, Cowey CL, et al. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med. 2017;377(19):1824–35.

    CAS  Article  PubMed  Google Scholar 

  114. 114.

    Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, et al. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med. 2017;377(20):1919–29.

    CAS  Article  PubMed  Google Scholar 

  115. 115.

    Chen R, Zinzani PL, Fanale MA, Armand P, Johnson NA, Brice P, et al. Phase II study of the efficacy and safety of pembrolizumab for relapsed/refractory classic Hodgkin lymphoma. J Clin Oncol. 2017;35(19):2125–32.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  116. 116.

    Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC, Gutierrez M, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med. 2015;372(4):311–9.

    CAS  Article  PubMed  Google Scholar 

  117. 117.

    Younes A, Santoro A, Shipp M, Zinzani PL, Timmerman JM, Ansell S, et al. Nivolumab for classical Hodgkin’s lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin: a multicentre, multicohort, single-arm phase 2 trial. Lancet Oncol. 2016;17(9):1283–94.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  118. 118.

    Hargadon KM, Johnson CE, Williams CJ. Immune checkpoint blockade therapy for cancer: an overview of FDA-approved immune checkpoint inhibitors. Int Immunopharmacol. 2018;62:29–39.

    CAS  Article  PubMed  Google Scholar 

  119. 119.

    Wilcox RA, Feldman AL, Wada DA, Yang ZZ, Comfere NI, Dong H, et al. B7-H1 (PD-L1, CD274) suppresses host immunity in T-cell lymphoproliferative disorders. Blood. 2009;114(10):2149–58.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  120. 120.

    Phillips T, Devata S, Wilcox RA. Challenges and opportunities for checkpoint blockade in T-cell lymphoproliferative disorders. J Immunother Cancer. 2016;4, 95.

  121. 121.

    Merryman RW, Armand P. Immune checkpoint blockade and hematopoietic stem cell transplant. Curr Hematol Malig Rep. 2017;12(1):44–50.

    Article  PubMed  Google Scholar 

  122. 122.

    Ruella M, June CH. Chimeric antigen receptor T cells for B cell neoplasms: choose the right CAR for you. Curr Hematol Malig Rep. 2016;11(5):368–84.

    Article  PubMed  Google Scholar 

  123. 123.

    Steidl C, Lee T, Shah SP, Farinha P, Han G, Nayar T, et al. Tumor-associated macrophages and survival in classic Hodgkin’s lymphoma. The N Engl J Med. 2010;362(10):875–85.

    CAS  Article  PubMed  Google Scholar 

  124. 124.

    Barclay AN, Van den Berg TK. The interaction between signal regulatory protein alpha (SIRPalpha) and CD47: structure, function, and therapeutic target. Annu Rev Immunol. 2014;32:25–50.

    CAS  Article  PubMed  Google Scholar 

  125. 125.

    Lin GHY, Chai V, Lee V, Dodge K, Truong T, Wong M, et al. TTI-621 (SIRPalphaFc), a CD47-blocking cancer immunotherapeutic, triggers phagocytosis of lymphoma cells by multiple polarized macrophage subsets. PLoS One. 2017;12(10):e0187262.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  126. 126.

    Ansell S, Chen RW, Flinn IW, Maris MB, Connor OA, Johnson LDS, et al. A phase 1 study of TTI-621, a novel immune checkpoint inhibitor targeting CD47, in patients with relapsed or refractory hematologic malignancies. Blood. 2016;128(22):1812.

    Google Scholar 

  127. 127.

    Trautinger F, Eder J, Assaf C, Bagot M, Cozzio A, Dummer R, et al. European Organisation for Research and Treatment of Cancer consensus recommendations for the treatment of mycosis fungoides/Sezary syndrome—update 2017. Eur J Cancer. 2017;77:57–74.

    Article  PubMed  Google Scholar 

  128. 128.

    Bunn PA Jr, Foon KA, Ihde DC, Longo DL, Eddy J, Winkler CF, et al. Recombinant leukocyte A interferon: an active agent in advanced cutaneous T-cell lymphomas. Ann Intern Med. 1984;101(4):484–7.

    Article  Google Scholar 

  129. 129.

    Knobler RM, Trautinger F, Radaszkiewicz T, Kokoschka EM, Micksche M. Treatment of cutaneous T cell lymphoma with a combination of low-dose interferon alfa-2b and retinoids. J Am Acad Dermatol. 1991;24(2 Pt 1):247–52.

    CAS  Article  Google Scholar 

  130. 130.

    Olsen EA, Bunn PA. Interferon in the treatment of cutaneous T-cell lymphoma. Hematol Oncol Clin North Am. 1995;9(5):1089–107.

    CAS  Article  Google Scholar 

  131. 131.

    Gramatzki M, Burger R, Strobel G, Trautmann U, Bartram CR, Helm G, et al. Therapy with OKT3 monoclonal antibody in refractory T cell acute lymphoblastic leukemia induces interleukin-2 responsiveness. Leukemia. 1995;9(3):382–90.

    CAS  PubMed  Google Scholar 

  132. 132.

    O’Mahony D, Morris JC, Stetler-Stevenson M, Matthews H, Brown MR, Fleisher T, et al. EBV-related lymphoproliferative disease complicating therapy with the anti-CD2 monoclonal antibody, siplizumab, in patients with T-cell malignancies. Clin Cancer Res : an official journal of the American Association for Cancer Research. 2009;15(7):2514–22.

    Article  Google Scholar 

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This research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA008748, the Gabrielle’s Angel Foundation grant (PI: M.R.), the Parker Institute for Cancer Immunotherapy (PI: M.R.), the ASH Scholar Award (PI: M.R.), and the NCI CDA (K99 CA212302-01A1, PI: M.R.).

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Correspondence to Marco Ruella.

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Conflict of Interest

Steven M. Horwitz reports grants and personal fees from ADC Therapeutics, grants and personal fees from Aileron, grants and personal fees from Seattle Genetics, grants and personal fees from Takeda, grants and personal fees from Kyowa Hakka Kirin, grants and personal fees from Verastem, personal fees from Portola, personal fees from Corvus, grants from Celgene, grants from Spectrum, and grants from Forty-Seven outside the submitted work. Alison J. Moskowitz reports grants from Merck, grants from BMS, grants from Incyte, grants and personal fees from Seattle Genetics, personal fees from Bristol-Meyers Squibb, personal fees from Cell Medica, and personal fees from Kyowa Hakko Kirin Pharma outside the submitted work. Paola Ghione, Nadia E.K. De Paola, and Marco Ruella declare that they have no conflict of interest. Marco Ruella reports grants from Novartis and Tmunity, and intellectual property in CART-related patents.

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This article does not contain any studies with human or animal subjects performed by any of the authors.

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This article is part of the Topical Collection on CART and Immunotherapy

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Ghione, P., Moskowitz, A.J., De Paola, N.E.K. et al. Novel Immunotherapies for T Cell Lymphoma and Leukemia. Curr Hematol Malig Rep 13, 494–506 (2018).

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  • Immunotherapy
  • T cell lymphoma
  • T-ALL
  • Immune checkpoint inhibitors
  • CART cell therapy