Current Immunotherapeutic Approaches in T Cell Non-Hodgkin Lymphomas

T cell non-Hodgkin lymphoma (T-NHL) is a rare and heterogeneous group of neoplasms of the lymphoid system. With the exception of a few relatively indolent entities, T-NHL is typically aggressive, treatment resistant, and associated with poor prognosis. Relatively few options with proven clinical benefit are available for patients with relapsed or refractory disease. Immunotherapy has emerged as a promising treatment for the management of patients with hematological malignancies. The identification of tumor antigens has provided a large number of potential targets. Therefore, several monoclonal antibodies (alemtuzumab, SGN-30, brentuximab vedotin, and mogamulizumab), directed against tumor antigens, have been investigated in different subtypes of T-NHL. In addition to targeting antigens involved in cancer cell physiology, antibodies can stimulate immune effector functions or counteract immunosuppressive mechanisms. Chimeric antigen receptor (CAR)-T cells directed against CD30 and immune checkpoint inhibitors are currently being investigated in clinical trials. In this review, we summarize the currently available clinical evidence for immunotherapy in T-NHL, focusing on the results of clinical trials using first generation monoclonal antibodies, new immunotherapeutic agents, immune checkpoint inhibitors, and CAR-T cell therapies.

[1]  Shaohua Chen,et al.  Different aberrant expression pattern of immune checkpoint receptors in patients with PTCL and NK/T‐CL , 2018, Asia-Pacific journal of clinical oncology.

[2]  R. Advani,et al.  Five-year outcomes for frontline brentuximab vedotin with CHP for CD30-expressing peripheral T-cell lymphomas. , 2018, Blood.

[3]  B. Geoerger,et al.  Efficacy of nivolumab in a patient with systemic refractory ALK+ anaplastic large cell lymphoma , 2018, Pediatric blood & cancer.

[4]  Bing Wang,et al.  An ‘off-the-shelf’ fratricide-resistant CAR-T for the treatment of T cell hematologic malignancies , 2018, Leukemia.

[5]  R. Advani,et al.  Five-year results of brentuximab vedotin in patients with relapsed or refractory systemic anaplastic large cell lymphoma. , 2017, Blood.

[6]  Stephen J. Schuster,et al.  Chimeric Antigen Receptor T Cells in Refractory B‐Cell Lymphomas , 2017, The New England journal of medicine.

[7]  R. Levy,et al.  Axicabtagene Ciloleucel CAR T‐Cell Therapy in Refractory Large B‐Cell Lymphoma , 2017, The New England journal of medicine.

[8]  C. Elmets,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 , 2017 .

[9]  R. Rad,et al.  PD-1 is a haploinsufficient suppressor of T cell lymphomagenesis , 2017, Nature.

[10]  M. Piris,et al.  Targeting the T cell receptor β-chain constant region for immunotherapy of T cell malignancies , 2017, Nature Medicine.

[11]  Hao Liu,et al.  Clinical and immunological responses after CD30-specific chimeric antigen receptor-redirected lymphocytes. , 2017, The Journal of clinical investigation.

[12]  M. Weichenthal,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 , 2017, The Lancet.

[13]  Ciaran M. Lee,et al.  CD7-edited T cells expressing a CD7-specific CAR for the therapy of T-cell malignancies. , 2017, Blood.

[14]  M. Matsuoka,et al.  Stat3 inhibitor abrogates the expression of PD-1 ligands on lymphoma cell lines. , 2017, Journal of clinical and experimental hematopathology : JCEH.

[15]  P. Khong,et al.  PD1 blockade with pembrolizumab is highly effective in relapsed or refractory NK/T-cell lymphoma failing l-asparaginase. , 2017, Blood.

[16]  D. Grandér,et al.  PD-L1 is commonly expressed and transcriptionally regulated by STAT3 and MYC in ALK-negative anaplastic large-cell lymphoma , 2017, Leukemia.

[17]  J. Vose,et al.  Angioimmunoblastic T-cell lymphoma: the many-faced lymphoma. , 2017, Blood.

[18]  Mithat Gönen,et al.  Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection , 2017, Nature.

[19]  S. Riddell,et al.  Fully human CD19-specific chimeric antigen receptors for T-cell therapy , 2017, Leukemia.

[20]  Adrian J. Thrasher,et al.  Molecular remission of infant B-ALL after infusion of universal TALEN gene-edited CAR T cells , 2017, Science Translational Medicine.

[21]  Mingzhi Zhang,et al.  Prognostic significance of CD30 expression in nasal natural killer/T-cell lymphoma , 2017, Oncology letters.

[22]  Ash A. Alizadeh,et al.  Pembrolizumab for Treatment of Relapsed/Refractory Mycosis Fungoides and Sezary Syndrome: Clinical Efficacy in a Citn Multicenter Phase 2 Study , 2016 .

[23]  Y. Okuno,et al.  An IL‐27/Stat3 axis induces expression of programmed cell death 1 ligands (PD‐L1/2) on infiltrating macrophages in lymphoma , 2016, Cancer science.

[24]  M. Shipp,et al.  Programmed Death-1 Blockade With Pembrolizumab in Patients With Classical Hodgkin Lymphoma After Brentuximab Vedotin Failure. , 2016, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[25]  H. Hebart,et al.  Nivolumab for Refractory Anaplastic Large Cell Lymphoma: A Case Report , 2016, Annals of Internal Medicine.

[26]  Wen-Qi Jiang,et al.  PD-L1 is upregulated by EBV-driven LMP1 through NF-κB pathway and correlates with poor prognosis in natural killer/T-cell lymphoma , 2016, Journal of Hematology & Oncology.

[27]  M. Millenson,et al.  Nivolumab in Patients With Relapsed or Refractory Hematologic Malignancy: Preliminary Results of a Phase Ib Study. , 2016, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[28]  S. Heimfeld,et al.  Immunotherapy of non-Hodgkin’s lymphoma with a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen receptor–modified T cells , 2016, Science Translational Medicine.

[29]  D. Heo,et al.  Expression of programmed cell death ligand 1 (PD-L1) in advanced stage EBV-associated extranodal NK/T cell lymphoma is associated with better prognosis , 2016, Virchows Archiv.

[30]  Yang Liu,et al.  Autologous T Cells Expressing CD30 Chimeric Antigen Receptors for Relapsed or Refractory Hodgkin Lymphoma: An Open-Label Phase I Trial , 2016, Clinical Cancer Research.

[31]  P. Khong,et al.  Pembrolizumab for relapsed anaplastic large cell lymphoma after allogeneic haematopoietic stem cell transplantation: efficacy and safety , 2016, Annals of Hematology.

[32]  Satoru Miyano,et al.  Aberrant PD-L1 expression through 3′-UTR disruption in multiple cancers , 2016, Nature.

[33]  R. Advani,et al.  The World Health Organization Classification of Lymphoid Neoplasms , 2013 .

[34]  Wen-Qi Jiang,et al.  High post-treatment serum levels of soluble programmed cell death ligand 1 predict early relapse and poor prognosis in extranodal NK/T cell lymphoma patients , 2016, Oncotarget.

[35]  R. Advani,et al.  A phase II study of cyclophosphamide, etoposide, vincristine and prednisone (CEOP) Alternating with Pralatrexate (P) as front line therapy for patients with peripheral T‐cell lymphoma (PTCL): final results from the T‐ cell consortium trial , 2016, British journal of haematology.

[36]  R. Advani,et al.  Phase II Investigator-Initiated Study of Brentuximab Vedotin in Mycosis Fungoides and Sézary Syndrome With Variable CD30 Expression Level: A Multi-Institution Collaborative Project. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[37]  J. Jorgensen,et al.  Phase 1/2 study of mogamulizumab, a defucosylated anti-CCR4 antibody, in previously treated patients with cutaneous T-cell lymphoma. , 2015, Blood.

[38]  Sadik H. Kassim,et al.  Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[39]  Seth M Steinberg,et al.  T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial , 2015, The Lancet.

[40]  M. Millenson,et al.  PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. , 2015, The New England journal of medicine.

[41]  W. Chan,et al.  Peripheral T‐cell and NK cell lymphoproliferative disorders: cell of origin, clinical and pathological implications , 2015, Immunological reviews.

[42]  Sonali M. Smith,et al.  Peripheral T-cell lymphomas in a large US multicenter cohort: prognostication in the modern era including impact of frontline therapy. , 2014, Annals of oncology : official journal of the European Society for Medical Oncology.

[43]  Pamela A Shaw,et al.  Chimeric antigen receptor T cells for sustained remissions in leukemia. , 2014, The New England journal of medicine.

[44]  R. Advani,et al.  Brentuximab vedotin in the front-line treatment of patients with CD30+ peripheral T-cell lymphomas: results of a phase I study. , 2014, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[45]  R. Advani,et al.  Objective responses in relapsed T-cell lymphomas with single-agent brentuximab vedotin. , 2014, Blood.

[46]  M. Taniwaki,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. , 2014, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[47]  J. Cayuela,et al.  Long‐term efficacy and safety of alemtuzumab in advanced primary cutaneous T‐cell lymphomas , 2014, The British journal of dermatology.

[48]  D. Quail,et al.  Microenvironmental regulation of tumor progression and metastasis , 2014 .

[49]  M. Shipp,et al.  PD-L1 Expression Is Characteristic of a Subset of Aggressive B-cell Lymphomas and Virus-Associated Malignancies , 2013, Clinical Cancer Research.

[50]  R. Gascoyne,et al.  Survival of patients with peripheral T-cell lymphoma after first relapse or progression: spectrum of disease and rare long-term survivors. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[51]  Michel Sadelain,et al.  The basic principles of chimeric antigen receptor design. , 2013, Cancer discovery.

[52]  Juan F. García,et al.  EBV-positive diffuse large B-cell lymphoma of the elderly is an aggressive post-germinal center B-cell neoplasm characterized by prominent nuclear factor-kB activation , 2012, Modern Pathology.

[53]  R. Advani,et al.  Brentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic large-cell lymphoma: results of a phase II study. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[54]  Drew M. Pardoll,et al.  The blockade of immune checkpoints in cancer immunotherapy , 2012, Nature Reviews Cancer.

[55]  R. Ueda,et al.  Defucosylated anti-CCR4 monoclonal antibody (KW-0761) for relapsed adult T-cell leukemia-lymphoma: a multicenter phase II study. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[56]  M. Wasik,et al.  Expression patterns of the immunosuppressive proteins PD-1/CD279 and PD-L1/CD274 at different stages of cutaneous T-cell lymphoma/mycosis fungoides. , 2012, The American Journal of dermatopathology.

[57]  Keunchil Park,et al.  Dose modification of alemtuzumab in combination with dexamethasone, cytarabine, and cisplatin in patients with relapsed or refractory peripheral T-cell lymphoma: analysis of efficacy and toxicity , 2012, Investigational New Drugs.

[58]  M. Borowitz,et al.  Simplified flow cytometric assessment in mycosis fungoides and Sézary syndrome. , 2011, American journal of clinical pathology.

[59]  H. Kluin-Nelemans,et al.  Intensified alemtuzumab-CHOP therapy for peripheral T-cell lymphoma. , 2011, Annals of oncology : official journal of the European Society for Medical Oncology.

[60]  C. Flowers,et al.  A Systematic Review and Meta-Analysis of Front-line Anthracycline-Based Chemotherapy Regimens for Peripheral T-Cell Lymphoma , 2011, ISRN hematology.

[61]  S. Altiok,et al.  Chemotherapy enhances tumor cell susceptibility to CTL-mediated killing during cancer immunotherapy in mice. , 2010, The Journal of clinical investigation.

[62]  J. Zic,et al.  A Phase II Study of SGN-30 in Cutaneous Anaplastic Large Cell Lymphoma and Related Lymphoproliferative Disorders , 2009, Clinical Cancer Research.

[63]  A. Feldman,et al.  B7-H1 (PD-L1, CD274) suppresses host immunity in T-cell lymphoproliferative disorders. , 2009, Blood.

[64]  J. Leonard,et al.  A Phase II study of SGN‐30 (anti‐CD30 mAb) in Hodgkin lymphoma or systemic anaplastic large cell lymphoma , 2009, British journal of haematology.

[65]  H. Heslop,et al.  T lymphocytes coexpressing CCR4 and a chimeric antigen receptor targeting CD30 have improved homing and antitumor activity in a Hodgkin tumor model. , 2009, Blood.

[66]  S. Devesa,et al.  Cutaneous lymphoma incidence patterns in the United States: a population-based study of 3884 cases. , 2009, Blood.

[67]  M. Wasik,et al.  Oncogenic kinase NPM/ALK induces through STAT3 expression of immunosuppressive protein CD274 (PD-L1, B7-H1) , 2008, Proceedings of the National Academy of Sciences.

[68]  D. Weisenburger,et al.  International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[69]  Lieping Chen,et al.  Inhibitory B7-family molecules in the tumour microenvironment , 2008, Nature Reviews Immunology.

[70]  K. Hemminki,et al.  Risk of subsequent solid tumors after non-Hodgkin's lymphoma: effect of diagnostic age and time since diagnosis. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[71]  P. Gobbi,et al.  Secondary malignancies after treatment for indolent non-Hodgkin’s lymphoma: a 16-year follow-up study , 2008, Haematologica.

[72]  K. Karube,et al.  Usefulness of flow cytometry for differential diagnosis of precursor and peripheral T‐cell and NK‐cell lymphomas: Analysis of 490 cases , 2008, Pathology international.

[73]  R. Ueda,et al.  VCAP-AMP-VECP compared with biweekly CHOP for adult T-cell leukemia-lymphoma: Japan Clinical Oncology Group Study JCOG9801. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[74]  C. Ronckers,et al.  Cause-specific mortality and second cancer incidence after non-Hodgkin lymphoma: a report from the Childhood Cancer Survivor Study. , 2007, Blood.

[75]  S. Pileri,et al.  Alemtuzumab (Campath-1H) and CHOP chemotherapy as first-line treatment of peripheral T-cell lymphoma: results of a GITIL (Gruppo Italiano Terapie Innovative nei Linfomi) prospective multicenter trial. , 2007, Blood.

[76]  H. Heslop,et al.  Epstein Barr virus specific cytotoxic T lymphocytes expressing the anti-CD30zeta artificial chimeric T-cell receptor for immunotherapy of Hodgkin disease. , 2007, Blood.

[77]  Sukjoong Oh,et al.  Alemtuzumab plus CHOP as front-line chemotherapy for patients with peripheral T-cell lymphomas: a phase II study , 2007, Cancer Chemotherapy and Pharmacology.

[78]  J. Tward,et al.  The risk of secondary malignancies over 30 years after the treatment of non‐Hodgkin lymphoma , 2006, Cancer.

[79]  A. Swerdlow,et al.  Risk of second malignancy after non-Hodgkin's lymphoma: a British Cohort Study. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[80]  J. Raemaekers,et al.  Late non-neoplastic events in patients with aggressive non-Hodgkin's lymphoma in four randomized European Organisation for Research and Treatment of Cancer trials. , 2005, Clinical lymphoma & myeloma.

[81]  Nicola Pimpinelli,et al.  WHO-EORTC classification for cutaneous lymphomas. , 2005, Blood.

[82]  Damon L. Meyer,et al.  Effects of Drug Loading on the Antitumor Activity of a Monoclonal Antibody Drug Conjugate , 2004, Clinical Cancer Research.

[83]  S. Iida,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 , 2004, Clinical Cancer Research.

[84]  M. Erlanson,et al.  A pilot study of alemtuzumab (anti-CD52 monoclonal antibody) therapy for patients with relapsed or chemotherapy-refractory peripheral T-cell lymphomas. , 2004, Blood.

[85]  P. Gaulard,et al.  Second cancers and late toxicities after treatment of aggressive non-Hodgkin lymphoma with the ACVBP regimen: a GELA cohort study on 2837 patients. , 2003, Blood.

[86]  S. Iida,et al.  Clinical significance of CCR4 expression in adult T-cell leukemia/lymphoma: its close association with skin involvement and unfavorable outcome. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[87]  G. Juliusson,et al.  Phase 2 study of alemtuzumab (anti-CD52 monoclonal antibody) in patients with advanced mycosis fungoides/Sezary syndrome. , 2003, Blood.

[88]  M. Raffeld,et al.  Cancer Regression and Autoimmunity in Patients After Clonal Repopulation with Antitumor Lymphocytes , 2002, Science.

[89]  Scott W. Lowe,et al.  Apoptosis A Link between Cancer Genetics and Chemotherapy , 2002, Cell.

[90]  J. Muche,et al.  T cells engrafted with a recombinant anti-CD30 receptor target autologous CD30+ cutaneous lymphoma cells , 2001, Gene Therapy.

[91]  F. Behm,et al.  Immunophenotyping of leukemia. , 2000, Journal of immunological methods.

[92]  D. Dorfman,et al.  Expression pattern of T-cell-associated chemokine receptors and their chemokines correlates with specific subtypes of T-cell non-Hodgkin lymphoma. , 2000, Blood.

[93]  S. Pileri,et al.  Expression of the CD30 antigen in non‐lymphoid tissues and cells , 2000, The Journal of pathology.

[94]  P. Gaulard,et al.  Prognostic significance of T-cell phenotype in aggressive non-Hodgkin's lymphomas. Groupe d'Etudes des Lymphomes de l'Adulte (GELA). , 1998, Blood.

[95]  V. Diehl,et al.  An anti-CD30 chimeric receptor that mediates CD3-zeta-independent T-cell activation against Hodgkin's lymphoma cells in the presence of soluble CD30. , 1998, Cancer research.

[96]  J. Sitzia,et al.  Side effects of CHOP in the treatment of non-hodgkin's lymphoma. , 1997, Cancer nursing.

[97]  A. Hagenbeek,et al.  Bladder and kidney cancer following cyclophosphamide therapy for non-Hodgkin's lymphoma. , 1995, Journal of the National Cancer Institute.

[98]  K. Lennert,et al.  The expression of the Hodgkin's disease associated antigen Ki-1 in reactive and neoplastic lymphoid tissue: evidence that Reed-Sternberg cells and histiocytic malignancies are derived from activated lymphoid cells. , 1985, Blood.

[99]  V. Diehl,et al.  Production of a monoclonal antibody specific for Hodgkin and Sternberg–Reed cells of Hodgkin's disease and a subset of normal lymphoid cells , 1982, Nature.

[100]  A. Jemal,et al.  Cancer statistics, 2018 , 2018, CA: a cancer journal for clinicians.

[101]  S. Pileri,et al.  Preliminary observations of a phase II study of reduced-dose alemtuzumab treatment in patients with pretreated T-cell lymphoma. , 2005, Haematologica.