The emerging role of immune checkpoint inhibition in malignant lymphoma

Haematologica

Volumn 102, Issue 1, 2017, Pages 30-42

  Hude, Ida ^a   Sasse, Stephanie ^b   Engert, Andreas ^b   Bröckelmann, Paul J ^b  

^a KBC Zagreb   (Croatia)

^b UNIVERSITY HOSPITAL OF COLOGNE   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

ACALABRUTINIB; ATEZOLIZUMAB; BENDAMUSTINE; CYTOTOXIC T LYMPHOCYTE ANTIGEN 4; DINACICLIB; DURVALUMAB; EPACADOSTAT; IBRUTINIB; IDELALISIB; IPILIMUMAB; LENALIDOMIDE; LIRILUMAB; NIVOLUMAB; OBINUTUZUMAB; PEMBROLIZUMAB; POLATUZUMAB VEDOTIN; PROGRAMMED DEATH 1 RECEPTOR; TICILIMUMAB; URELUMAB; ANTINEOPLASTIC AGENT; MONOCLONAL ANTIBODY; PROGRAMMED DEATH 1 LIGAND 1; TUMOR MARKER;

ABDOMINAL PAIN; ANEMIA; CANCER IMMUNOTHERAPY; CHRONIC LYMPHATIC LEUKEMIA; CLASSICAL HODGKIN LYMPHOMA; DIARRHEA; DYSPNEA; FATIGUE; FEVER; FOLLICULAR LYMPHOMA; HUMAN; HYPOTHYROIDISM; IMMUNE CHECKPOINT INHIBITION; IMMUNE RESPONSE; IMMUNOMODULATION; IMMUNOSURVEILLANCE; LARGE CELL LYMPHOMA; LYMPHOMA; MANTLE CELL LYMPHOMA; META ANALYSIS (TOPIC); NAUSEA AND VOMITING; NEUROPATHY; NONHUMAN; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PNEUMONIA; PROTEIN TARGETING; PRURITUS; RANDOMIZED CONTROLLED TRIAL (TOPIC); RASH; RECEPTOR BLOCKING; REVIEW; THROMBOCYTOPENIA; THYROIDITIS; TREATMENT OUTCOME; TUMOR MICROENVIRONMENT; ADVERSE EFFECTS; ANTAGONISTS AND INHIBITORS; DRUG EFFECTS; IMMUNOLOGY; METABOLISM; MOLECULARLY TARGETED THERAPY; MULTIMODALITY CANCER THERAPY; PROCEDURES; SIGNAL TRANSDUCTION; T LYMPHOCYTE SUBPOPULATION;

ANTIBODIES, MONOCLONAL; ANTIGENS, CD274; ANTINEOPLASTIC AGENTS; ANTINEOPLASTIC COMBINED CHEMOTHERAPY PROTOCOLS; BIOMARKERS, TUMOR; COMBINED MODALITY THERAPY; CTLA-4 ANTIGEN; HUMANS; IMMUNOMODULATION; LYMPHOMA; MOLECULAR TARGETED THERAPY; PROGRAMMED CELL DEATH 1 RECEPTOR; SIGNAL TRANSDUCTION; T-LYMPHOCYTE SUBSETS; TREATMENT OUTCOME;

EID: 85008373481     PISSN: 03906078     EISSN: 15928721     Source Type: Journal    
DOI: 10.3324/haematol.2016.150656     Document Type: Review

References (99)

1. Ferlay J, Soerjomataram I, Ervik M, et al. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide. IARC CancerBase No 11 2013 [cited 2016 29.04.2016.]; Available from: http://globocan.iarc.fr/Pages/fact_sheets_population.aspx
2. Swerdlow SH, Campo E, Harris NL, et al., eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, Fourth Edition. Lyon, France: IARC Press, 2008.
3. Meng F, Zhong D, Zhang L, Shao Y, Ma Q. Efficacy and safety of rituximab combined with chemotherapy in the treatment of diffuse large B-cell lymphoma: a meta-analysis. Int J Clin Exp Med. 2015;8(10):17515-17522.
4. Hainsworth JD. Rituximab as first-line and maintenance therapy for patients with indolent non-Hodgkin's lymphoma: interim follow- up of a multicenter phase II trial. Semin Oncol. 2002;29(1 Suppl 2):25-29.
5. Younes A, Gopal AK, Smith SE, et al. Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin's lymphoma. J Clin Oncol. 2012;30(18):2183-2189.
6. Moskowitz CH, Nademanee A, Masszi T, et al. Brentuximab vedotin as consolidation therapy after autologous stem-cell transplantation in patients with Hodgkin's lymphoma at risk of relapse or progression (AETHERA): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2015;385(9980):1853-1862.
7. Salihoglu A, Ar MC, Soysal T. Novelties in the management of B-cell malignancies: Bcell receptor signaling inhibitors and lenalidomide. Expert Rev Hematol. 2015;8(6):765-783.
8. Intlekofer AM, Thompson CB. At the bench: preclinical rationale for CTLA-4 and PD-1 blockade as cancer immunotherapy. J Leukoc Biol. 2013;94(1):25-39.
9. Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I, Kobayashi SV, et al. CTLA-4 and PD-1 receptors inhibit Tcell activation by distinct mechanisms. Mol Cell Biol. 2005;25(21):9543-9553.
10. Chen L, Flies DB. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat Rev Immunol. 2013;13(4):227-242.
11. Dong H, Strome SE, Salomao DR, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002;8(8):793-800.
12. Wherry EJ, Kurachi M. Molecular and cellular insights into T cell exhaustion. Nat Rev Immunol. 2015;15(8):486-99.
13. Hodi FS, O'Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711-723.
14. Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364(26):2517-2526.
15. Barbee MS, Ogunniyi A, Horvat TZ, Dang T-O. Current status and future directions of the immune checkpoint inhibitors ipilimumab, pembrolizumab, and nivolumab in oncology. Ann Pharmacother. 2015;49(8): 907-937.
16. Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008;26:677-704.
17. Kourie HR, Awada G, Awada AH. Learning from the “tsunami” of immune checkpoint inhibitors in 2015. Crit Rev Oncol Hematol. 2016;101:213-220.
18. Ansell SM, Lesokhin AM, Borrello I, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. N Engl J Med. 2015;372(4):311-319.
19. Bröckelmann PJ, Borchmann P, Engert A. Current and future immunotherapeutic approaches in Hodgkin lymphoma. Leuk Lymphoma. 2016;57(9):2014-2024.
20. Chemnitz JM, Eggle D, Driesen J, et al. RNA fingerprints provide direct evidence for the inhibitory role of TGFbeta and PD-1 on CD4+ T cells in Hodgkin lymphoma. Blood. 2007;110(9):3226-3233.
21. Yamamoto R, Nishikori M, Kitawaki T, et al. PD-1-PD-1 ligand interaction contributes to immunosuppressive microenvironment of Hodgkin lymphoma. Blood. 2008;111(6):3220-3224.
22. Green MR, Monti S, Rodig SJ, et al. Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma. Blood. 2010;116(17):3268-3277.
23. Green MR, Rodig S, Juszczynski P, et al. Constitutive AP-1 activity and EBV infection induce PD-L1 in Hodgkin lymphomas and posttransplant lymphoproliferative disorders: implications for targeted therapy. Clin Cancer Res. 2012;18(6):1611-1618.
24. Chen BJ, Chapuy B, Ouyang J, et al. PD-L1 expression is characteristic of a subset of aggressive B-cell lymphomas and virus-associated malignancies. Clin Cancer Res. 2013;19(13):3462-3473.
25. Roemer MG, Advani RH, Ligon AH, et al. PD-L1 and PD-L2 genetic alterations define classical Hodgkin lymphoma and predict outcome. J Clin Oncol. 2016;34(23):2690-2697.
26. Muenst S, Hoeller S, Dirnhofer S, Tzankov A. Increased programmed death-1+ tumorinfiltrating lymphocytes in classical Hodgkin lymphoma substantiate reduced overall survival. Hum Pathol. 2009;40(12):1715-1722.
27. Greaves P, Clear A, Owen A, et al. Defining characteristics of classical Hodgkin lymphoma microenvironment T-helper cells. Blood. 2013;122(16):2856-2863.
28. Moskowitz CH, Ribrag V, Michot JM, et al. PD-1 blockade with the monoclonal antibody pembrolizumab (MK-3475) in patients with classical Hodgkin lymphoma after brentuximab vedotin failure: preliminary results from a phase 1b study (keynote-013). Blood. 2014;124(21): Abstract 290.
29. Kosmaczewska A, Frydecka I, Bocko D, Ciszak L, Teodorowska R. Correlation of blood lymphocyte CTLA-4 (CD152) induction in Hodgkin's disease with proliferative activity, interleukin 2 and interferon-gamma production. Br J Haematol. 2002;118(1):202-209.
30. Bashey A, Medina B, Corringham S, et al. CTLA4 blockade with ipilimumab to treat relapse of malignancy after allogeneic hematopoietic cell transplantation. Blood. 2009;113(7):1581-1588.
31. Diefenbach CS, Hong F, Cohen JB, et al. Preliminary safety and efficacy of the combination of brentuximab vedotin and ipilimumab in relapsed/refractory Hodgkin lymphoma: a trial of the ECOG-ACRIN Cancer Research Group (E4412). Blood. 2015;126(23):Abstract 585.
32. Ansell S, Armand P, Timmerman JM, et al. Nivolumab in patients (Pts) with relapsed or refractory classical Hodgkin lymphoma (R/R cHL): clinical outcomes from extended follow- up of a phase 1 study (CA209-039). Blood. 2015;126(23):Abstract 583.
33. Engert A, Santoro A, Shipp M, et al. CHECKMATE 205: a phase 2 study of nivolumab in patients with classical Hodgkin lymphoma following autologous stem cell transplantation and brentuximab vedotin. EHA 2016 (abstract S793). Copenhagen, Denmark, 2016.
34. Saha A, Aoyama K, Taylor PA, et al. Host programmed death ligand 1 is dominant over programmed death ligand 2 expression in regulating graft-versus-host disease lethality. Blood. 2013;122(17):3062-3073.
35. Herbaux C, Gauthier J, Brice P, et al. Nivolumab is effective and reasonably safe in relapsed or refractory Hodgkin's lymphoma after allogeneic hematopoietic cell transplantation: a study from the Lysa and SFGM-TC. Blood. 2015;126(23): Abstract 3979.
36. Armand P, Shipp MA, Ribrag V, et al. Programmed death-1 blockade with pembrolizumab in patients with classical Hodgkin lymphoma after brentuximab vedotin failure. J Clin Oncol. 2016 June 27. [Epub ahead of print]
37. Moskowitz C, Zinzani PL, Fanale MA, et al. Multicohort phase 2 study of pembrolizumab for relapsed/refractory classical Hodgkin lymphoma (r/r cHL): Keynote-087 EHA 21 (abstract S794). Copenhagen, Denmark, 2016.
38. Andorsky DJ, Yamada RE, Said J, Pinkus GS, Betting DJ, Timmerman JM. Programmed death ligand 1 is expressed by non-Hodgkin lymphomas and inhibits the activity of tumor-associated T cells. Clin Cancer Res. 2011;17(13):4232-4244.
39. Kiyasu J, Miyoshi H, Hirata A, et al. Expression of programmed cell death ligand 1 is associated with poor overall survival in patients with diffuse large B-cell lymphoma. Blood. 2015;126(19):2193-2201.
40. Keane C, Vari F, Hertzberg M, et al. Ratios of T-cell immune effectors and checkpoint molecules as prognostic biomarkers in diffuse large B-cell lymphoma: a populationbased study. Lancet Haematol. 2015;2(10): e445-455.
41. Rossille D, Gressier M, Damotte D, et al. High level of soluble programmed cell death ligand 1 in blood impacts overall survival in aggressive diffuse large B-cell lymphoma: results from a French multicenter clinical trial. Leukemia. 2014;28(12):2367-2375.
42. Twa DD, Chan FC, Ben-Neriah S, et al. Genomic rearrangements involving programmed death ligands are recurrent in primary mediastinal large B-cell lymphoma. Blood. 2014;123(13):2062-2065.
43. Twa DD, Mottok A, Chan FC, et al. Recurrent genomic rearrangements in primary testicular lymphoma. J Pathol. 2015;236(2):136-141.
44. Chapuy B, Roemer MG, Stewart C, et al. Targetable genetic features of primary testicular and primary central nervous system lymphomas. Blood. 2016;127(7):869-881.
45. Georgiou K, Chen L, Berglund M, et al. Genetic basis of PD-L1 overexpression in diffuse large B-cell lymphomas. Blood. 2016;127(24):3026-3034.
46. Ansell SM, Hurvitz SA, Koenig PA, et al. Phase I study of ipilimumab, an anti-CTLA- 4 monoclonal antibody, in patients with relapsed and refractory B-cell non-Hodgkin lymphoma. Clin Cancer Res. 2009;15(20):6446-6453.
47. Lesokhin AM, Ansell SM, Armand P, et al. Nivolumab in patients with relapsed or refractory hematologic malignancy: preliminary results of a phase Ib study. J Clin Oncol. 2016;34(23):2698-2704.
48. Zinzani P, Ribrag V, Moskowitz CH, et al. Phase 1B study of pembrolizumab in patients with relapsed/refractory primary mediastinal large B-cell lymphoma: keynote- 013. EHA 2016 (abstract S797). Copenhagen, Denmark, 2016.
49. Yang ZZ, Novak AJ, Stenson MJ, Witzig TE, Ansell SM. Intratumoral CD4+CD25+ regulatory T-cell-mediated suppression of infiltrating CD4+ T cells in B-cell non-Hodgkin lymphoma. Blood. 2006;107(9):3639-3646.
50. Wang L, Qian J, Lu Y, et al. Immune evasion of mantle cell lymphoma: expression of B7- H1 leads to inhibited T-cell response to and killing of tumor cells. Haematologica. 2013;98(9):1458-1466.
51. Advani RH, Buggy JJ, Sharman JP, et al. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies. J Clin Oncol. 2013;31(1):88-94.
52. Sagiv-Barfi I, Kohrt HEK, Czerwinski DK, Ng PP, Chang BY, Levy R. Therapeutic antitumor immunity by checkpoint blockade is enhanced by ibrutinib, an inhibitor of both BTK and ITK. Proc Natl Acad Sci USA. 2015;112(9):E966-E972.
53. de Jong D, Fest T. The microenvironment in follicular lymphoma. Best Pract Res Clin Haematol. 2011;24(2):135-146.
54. Dave SS, Wright G, Tan B, et al. Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells. N Engl J Med. 2004;351 (21):2159-2169.
55. Fend F, Quintanilla-Martínez L. Assessing the prognostic impact of immune cell infiltrates in follicular lymphoma. Haematologica. 2014;99(4):599-602.
56. Yang ZZ, Grote DM, Ziesmer SC, Xiu B, Novak AJ, Ansell SM. PD-1 expression defines two distinct T-cell sub-populations in follicular lymphoma that differentially impact patient survival. Blood Cancer J. 2015;5:e281.
57. Carreras J, Lopez-Guillermo A, Roncador G, et al. High numbers of tumor-infiltrating programmed cell death 1-positive regulatory lymphocytes are associated with improved overall survival in follicular lymphoma. J Clin Oncol. 2009;27(9):1470-1476.
58. Muenst S, Hoeller S, Willi N, Dirnhofera S, Tzankov A. Diagnostic and prognostic utility of PD-1 in B cell lymphomas. Dis Markers. 2010;29(1):47-53.
59. Richendollar BG, Pohlman B, Elson P, Hsi ED. Follicular programmed death 1-positive lymphocytes in the tumor microenvironment are an independent prognostic factor in follicular lymphoma. Hum Pathol. 2011;42(4):552-557.
60. Kosmaczewska A, Ciszak L, Suwalska K, Wolowiec D, Frydecka I. CTLA-4 overexpression in CD19+/CD5+ cells correlates with the level of cell cycle regulators and disease progression in B-CLL patients. Leukemia. 2005;19(2):301-304.
61. Grzywnowicz M, Karczmarczyk A, Skorka K, et al. Expression of programmed death 1 ligand in different compartments of chronic lymphocytic leukemia. Acta Haematol. 2015;134(4):255-262.
62. Riches JC, Davies JK, McClanahan F, et al. T cells from CLL patients exhibit features of Tcell exhaustion but retain capacity for cytokine production. Blood. 2013;121(9): 1612-1621.
63. Brusa D, Serra S, Coscia M, et al. The PD- 1/PD-L1 axis contributes to T-cell dysfunction in chronic lymphocytic leukemia. Haematologica. 2013;98(6):953-963.
64. McClanahan F, Hanna B, Miller S, et al. PDL1 checkpoint blockade prevents immune dysfunction and leukemia development in a mouse model of chronic lymphocytic leukemia. Blood. 2015;126(2):203-211.
65. McClanahan F, Riches JC, Miller S, et al. Mechanisms of PD-L1/PD-1–mediated CD8 T-cell dysfunction in the context of agingrelated immune defects in the Eμ-TCL1 CLL mouse model. Blood. 2015;126(2):212-221.
66. Jitschin R, Braun M, Büttner M, et al. CLLcells induce IDOhi CD14+HLA-DRlo myeloid-derived suppressor cells that inhibit T-cell responses and promote TRegs. Blood. 2014;124(5):750-760.
67. Ding W, Dong H, Call TG, et al. PD-1 blockade with pembrolizumab (MK-3475) in relapsed/refractory CLL including richter transformation: an early efficacy report from a phase 2 trial (MC1485) ASH 57th Annual Meeting and Exibition. Orlando, Florida, USA, 2015.
68. Trautmann L, Janbazian L, Chomont N, et al. Upregulation of PD-1 expression on HIVspecific CD8+ T cells leads to reversible immune dysfunction. Nat Med. 2006;12(10):1198-1202.
69. Velu V, Shetty RD, Larsson M, Shankar EM. Role of PD-1 co-inhibitory pathway in HIV infection and potential therapeutic options. Retrovirology. 2015;12:14.
70. Ni L, Ma CJ, Zhang Y, et al. PD-1 modulates regulatory T cells and suppresses T cell responses in HCV-associated lymphoma. Immunol Cell Biol. 2011;89(4):535-539.
71. Mahadevan D, Vick E, Huber B, et al. Aurora plus PI3K inhibition abrogates PD-L1 induction in peripheral T-cell non-Hodgkin lymphoma. Blood. 2015;126(23):Abstract 1560.
72. Dorfman DM, Brown JA, Shahsafaei A, Freeman GJ. Programmed death-1 (PD-1) is a marker of germinal center-associated T cells and angioimmunoblastic T-cell lymphoma. Am J Surg Pathol. 2006;30(7):802-810.
73. Naidoo J, Page DB, Li BT, et al. Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. Ann Oncol. 2015;26(12):2375-2391.
74. Weber JS, Dummer R, de Pril V, Lebbe C, Hodi FS. Patterns of onset and resolution of immune-related adverse events of special interest with ipilimumab: detailed safety analysis from a phase 3 trial in patients with advanced melanoma. Cancer. 2013;119(9): 1675-1682.
75. Beck KE, Blansfield JA, Tran KQ, et al. Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte- associated antigen 4. J Clin Oncol. 2006;24(15):2283-2289.
76. Johnston RL, Lutzky J, Chodhry A, Barkin JS. Cytotoxic T-lymphocyte-associated antigen 4 antibody-induced colitis and its management with infliximab. Dig Dis Sci. 2009;54(11):2538-2540.
77. Abdel-Rahman O, ElHalawani H, Fouad M. Risk of endocrine complications in cancer patients treated with immune check point inhibitors: a meta-analysis. Future Oncol. 2016;12(3):413-425.
78. El Osta BE, Hu F, Sadek RF, Chintalapally R, Tang SC. Immune checkpoint inhibitors (ICI): a meta-analysis of immune-related adverse events (irAE) from cancer clinical trials. J Clin Oncol. 2016;(suppl; abstr e14562).
79. Robert C, Schachter J, Long GV, et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015;372(26):2521-2532.
80. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443-2454.
81. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373(1):23-34.
82. Fevery S, Billiau AD, Sprangers B, et al. CTLA-4 blockade in murine bone marrow chimeras induces a host-derived antileukemic effect without graft-versushost disease. Leukemia. 2007;21(7):1451-1459.
83. Davids MS, Kim HT, Costello CL, et al. A Multicenter phase I/Ib study of ipilimumab for relapsed hematologic malignancies after allogeneic hematopoietic stem cell transplantation. Blood. 2015;126(23): Abstract 860.
84. Castro M. The use of rituximab to manage B cell-mediated autoimmune thrombocytopenia (AITP) during concurrent program death ligand-1 (PD-L1) immunotherapy. J Clin Onco. 2016;34 (suppl; abstr e14545).
85. Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant lymphoma. J Clin Oncol. 2007;25(5):579-586.
86. Wolchok JD, Hoos A, O'Day S, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immunerelated response criteria. Clin Cancer Res. 2009;15(23):7412-7420.
87. Herbst RS, Soria JC, Kowanetz M, et al. Predictive correlates of response to the anti- PD-L1 antibody MPDL3280A in cancer patients. Nature. 2014;515(7528):563-567.
88. Campesato LF, Barroso-Sousa R, Jimenez L, et al. Comprehensive cancer-gene panels can be used to estimate mutational load and predict clinical benefit to PD-1 blockade in clinical practice. Oncotarget. 2015;6(33):34221-34227.
89. Steidl C, Shah SP, Woolcock BW, et al. MHC class II transactivator CIITA is a recurrent gene fusion partner in lymphoid cancers. Nature. 2011;471(7338):377-381.
90. Vetizou M, Pitt JM, Daillere R, et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science. 2015;350(6264):1079-1084.
91. Sivan A, Corrales L, Hubert N, et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science. 2015;350(6264):1084-1089.
92. Jing W, Gershan JA, Weber J, et al. Combined immune checkpoint protein blockade and low dose whole body irradiation as immunotherapy for myeloma. J Immunother Cancer. 2015;3(1):2.
93. Bracci L, Schiavoni G, Sistigu A, Belardelli F. Immune-based mechanisms of cytotoxic chemotherapy: implications for the design of novel and rationale-based combined treatments against cancer. Cell Death Differ. 2014;21(1):15-25.
94. Falchi L, Sawas A, Deng C, et al. Rate of complete metabolic responses to immune checkpoint inhibitors in extremely heavily pre-treated patients with classical Hodgkin’s lymphoma and immunoepigenetic priming. J Clin Oncol. 2016;34 (suppl; abstr e19012).
95. Chiappinelli KB, Strissel PL, Desrichard A, et al. Inhibiting DNA methylation causes an interferon response in cancer via dsRNA including endogenous retroviruses. Cell. 2015;162(5):974-986.
96. Armand P, Nagler A, Weller EA, et al. Disabling immune tolerance by programmed death-1 blockade with pidilizumab after autologous hematopoietic stemcell transplantation for diffuse large B-cell lymphoma: results of an international phase II trial. J Clin Oncol. 2013;31(33): 4199-4206.
97. Westin JR, Chu F, Zhang M, et al. Safety and activity of PD1 blockade by pidilizumab in combination with rituximab in patients with relapsed follicular lymphoma: a single group, open-label, phase 2 trial. Lancet Oncol. 2014;15(1):69-77.
98. Derer A, Frey B, Fietkau R, Gaipl US. Immune-modulating properties of ionizing radiation: rationale for the treatment of cancer by combination radiotherapy and immune checkpoint inhibitors. Cancer Immunol Immunother. 2016;65(7):779-786.
99. Zitvogel L, Apetoh L, Ghiringhelli F, Kroemer G. Immunological aspects of cancer chemotherapy. Nat Rev Immunol. 2008;8(1):59-73.