Resistance to Y-90 Ibritumomab Tiuxetan Therapy

  • Koichiro AbeEmail author
Part of the Resistance to Targeted Anti-Cancer Therapeutics book series (RTACT, volume 18)


Y-90 ibritumomab tiuxetan is the first radioimmunotherapy (RIT) agent for patients with relapsed or refractory low-grade CD20-positive B-cell non-Hodgkin’s lymphoma. Although accumulated data demonstrate its excellent therapeutic efficiency, there are a certain number of patients that experience disease exacerbation during the post-RIT observation periods. Up to now, advanced disease, bulky mass, poor performance status, a history of frequent chemotherapies before RIT, etc. have been proposed as predictive factors for unfavorable prognosis after RIT. In this chapter, we focus on the bulky disease, the downregulation of the CD20 molecule, the NF-𝜅B activation, and the impaired host immune status as factors presumably related to resistance to Y-90 ibritumomab tiuxetan therapy. We also discuss the mechanisms of the resistance and rational therapeutic approaches. We further illustrate the immunological circumstances in tumor-bearing patients and comment on the immune checkpoint blockade therapy.


Y-90 ibritumomab tiuxetan Resistance Bulky mass Downregulation of CD20 NF-𝜅B activation Immunoediting Abscopal effect Immunological cell death Immune checkpoint 



Activated B-like diffuse large B-cell lymphoma


Antibody-dependent cellular cytotoxicity




Antigen-presenting cell


Adenosine triphosphate


Bulky tumor


Cluster of differentiation


Complement-dependent cytotoxicity




Complete response


Complete response rate




Cytotoxic T-lymphocyte-associated protein-4


Dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab


Damage-associated molecular patterns


Dendritic cell


Diffuse large B-cell lymphoma


Extrabeam radiotherapy


European Union


Fab prime 2


Fragment antigen-binding




Fcγ receptor


First-line indolent trial


Fms-like tyrosine kinase 3 ligand


Germinal center B cell


Granulocyte macrophage colony-stimulating factor


Heavy-chain antibody


High-mobility group box 1


Immunological cell death






International Prognostic Index


Monoclonal antibody


Mantle-cell lymphoma


Myeloid-derived suppressor cells


Major histocompatibility complex


Minimal residual disease


Nuclear factor-κB


Overall response rate


Programmed cell death-1


Programed cell death ligand 1


Progression-free survival


Purinergic receptor P2X, ligand gated ion channel, 7


Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone






Single-chain variable


T cell receptor


Transforming growth factor beta


Toll-like receptor


Tumor necrosis factor α


Regulatory T cells


Time to disease progression


US Food and Drug Administration





We are indebted to Professors M Harada and K Tamada for their helpful discussions about the immunological cell death and the immune checkpoint blockade therapy.

Conflict of Interest

No conflict statement: No potential conflicts of interest were disclosed.


  1. 1.
    Witzig TE, White CA, Wiseman GA, Gordon LI, Emmanouilides C, Raubitschek A, Janakiraman N, Gutheil J, Schilder RJ, Spies S, Silverman DH, Parker E, Grillo-López AJ. Phase I/II trial of IDEC-Y2B8 radioimmunotherapy for treatment of relapsed or refractory CD20(+) B-cell non-Hodgkin’s lymphoma. J Clin Oncol. 1999;17:3793–803.CrossRefPubMedGoogle Scholar
  2. 2.
    Witzig TE, Flinn IW, Gordon LI, Emmanouilides C, Czuczman MS, Saleh MN, Cripe L, Wiseman G, Olejnik T, Multani PS, White CA. Treatment with ibritumomab tiuxetan radioimmunotherapy in patients with rituximab-refractory follicular non-Hodgkin’s lymphoma. J Clin Oncol. 2002;20:3262–9.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Witzig TE, Gordon LI, Cabanillas F, Czuczman MS, Emmanouilides C, Joyce R, Pohlman BL, Bartlett NL, Wiseman GA, Padre N, Grillo-López AJ, Multani P, White CA. Randomized controlled trial of yttrium-90-labeled ibritumomab tiuxetan radioimmunotherapy versus rituximab immunotherapy for patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin’s lymphoma. J Clin Oncol. 2002;20:2453–63.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Tobinai K, Watanabe T, Ogura M, Morishima Y, Hotta T, Ishizawa K, Itoh K, Okamoto S, Taniwaki M, Tsukamoto N, Okumura H, Terauchi T, Nawano S, Matsusako M, Matsuno Y, Nakamura S, Mori S, Ohashi Y, Hayashi M, Endo K. Japanese phase II study of 90Y-ibritumomab tiuxetan in patients with relapsed or refractory indolent B-cell lymphoma. Cancer Sci. 2009;100:158–64.CrossRefPubMedGoogle Scholar
  5. 5.
    Uike N, Choi I, Tsuda M, Haji S, Toyoda K, Suehiro Y, Abe Y, Hayashi T, Sawamoto H, Kaneko K, Shimokawa M, Nakagawa M. Factors associated with effects of 90Y-ibritumomab tiuxetan in patients with relapsed or refractory low-grade B cell non-Hodgkin lymphoma: single-institution experience with 94 Japanese patients in rituximab era. Int J Hematol. 2014;100:386–92.CrossRefPubMedGoogle Scholar
  6. 6.
    Morschhauser F, Radford J, Van Hoof A, Botto B, Rohatiner AZ, Salles G, Soubeyran P, Tilly H, Bischof-Delaloye A, van Putten WL, Kylstra JW, Hagenbeek A. 90Yttrium-ibritumomab tiuxetan consolidation of first remission in advanced-stage follicular non-Hodgkin lymphoma: updated results after a median follow-up of 7.3 years from the International, Randomized, Phase III First-Line Indolent trial. J Clin Oncol 2013;31:1977–83.PubMedCrossRefGoogle Scholar
  7. 7.
    Witzig TE, Molina A, Gordon LI, Emmanouilides C, Schilder RJ, Flinn IW, Darif M, Macklis R, Vo K, Wiseman GA. Long-term responses in patients with recurring or refractory B-cell non-Hodgkin lymphoma treated with yttrium 90 ibritumomab tiuxetan. Cancer. 2007;109:1804–10.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Fisher RI, Kaminski MS, Wahl RL, Knox SJ, Zelenetz AD, Vose JM, Leonard JP, Kroll S, Goldsmith SJ, Coleman M. Tositumomab and iodine-131 tositumomab produces durable complete remissions in a subset of heavily pretreated patients with low-grade and transformed non-Hodgkin’s lymphomas. J Clin Oncol. 2005;23:7565–73.PubMedCrossRefGoogle Scholar
  9. 9.
    Emmanouilides C, Witzig TE, Gordon LI, Vo K, Wiseman GA, Flinn IW, Darif M, Schilder RJ, Molina A. Treatment with yttrium 90 ibritumomab tiuxetan at early relapse is safe and effective in patients with previously treated B-cell non-Hodgkin’s lymphoma. Leuk Lymphoma. 2006;47:629–36.PubMedCrossRefGoogle Scholar
  10. 10.
    Rajguru S, Kristinsdottir T, Eickhoff J, Peterson C, Meyer CM, Traynor AM, Kahl BS. Yttrium 90-ibritumomab tiuxetan plus rituximab maintenance as initial therapy for patients with high-tumor-burden follicular lymphoma: a Wisconsin Oncology Network study. Clin Adv Hematol Oncol. 2014;12:509–15.PubMedGoogle Scholar
  11. 11.
    Fruchart C, Tilly H, Morschhauser F, Ghesquières H, Bouteloup M, Fermé C, Van Den Neste E, Bordessoule D, Bouabdallah R, Delmer A, Casasnovas RO, Ysebaert L, Ciappuccini R, Briere J, Gisselbrecht C. Upfront consolidation combining yttrium-90 ibritumomab tiuxetan and high-dose therapy with stem cell transplantation in poor-risk patients with diffuse large B cell lymphoma. Biol Blood Marrow Transplant. 2014;20:1905–11.PubMedCrossRefGoogle Scholar
  12. 12.
    Wiseman GA, White CA, Sparks RB, Erwin WD, Podoloff DA, Lamonica D, Bartlett NL, Parker JA, Dunn WL, Spies SM, Belanger R, Witzig TE, Leigh BR. Biodistribution and dosimetry results from a phase III prospectively randomized controlled trial of Zevalin radioimmunotherapy for low-grade, follicular, or transformed B-cell non-Hodgkin’s lymphoma. Crit Rev Oncol Hematol. 2001;39:181–94.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Witzig TE, White CA, Wiseman GA, Gordon LI, Emmanouilides C, Raubitschek A, Janakiraman N, Gutheil J, Schilder RJ, Spies S, Silverman DH, Parker E, Grillo-López AJ. Phase I/II trial of IDEC-Y2B8 radioimmunotherapy for treatment of relapsed or refractory CD20(+) B-cell non-Hodgkin’s lymphoma. J Clinical Oncologia. 1999;17:3793–803.CrossRefGoogle Scholar
  14. 14.
    Samaniego F, Berkova Z, Romaguera JE, Fowler N, Fanale MA, Pro B, Shah JJ, McLaughlin P, Sehgal L, Selvaraj V, Braun FK, Mathur R, Feng L, Neelapu SS, Kwak LW. 90Y-ibritumomab tiuxetan radiotherapy as first-line therapy for early stage low-grade B-cell lymphomas, including bulky disease. Br J Haematol. 2014;167:207–13.PubMedCrossRefGoogle Scholar
  15. 15.
    Tamura S, Ikeda T, Kurihara T, Kakuno Y, Nasu H, Nakano Y, Oshima K, Fujimoto T. Bulky pulmonary mucosa-associated lymphoid tissue lymphoma treated with yttrium-90 ibritumomab tiuxetan. Case Rep Hematol. 2013;2013:675187. Scholar
  16. 16.
    Ibatici A, Pica GM, Nati S, Vitolo U, Botto B, Ciochetto C, Petrini M, Galimberti S, Ciabatti E, Orciuolo E, Zinzani PL, Cascavilla N, Guolo F, Fraternali Orcioni G, Carella AM. Safety and efficacy of (90) yttrium-ibritumomab-tiuxetan for untreated follicular lymphoma patients. an Italian cooperative study. Br J Haematol. 2014;164:710–6.PubMedCrossRefGoogle Scholar
  17. 17.
    Gokhale AS, Mayadev J, Pohlman B, Macklis RM. Gamma camera scans and pretreatment tumor volumes as predictors of response and progression after Y-90 anti-CD20 radioimmunotherapy. Int J Radiat Oncol Biol Phys. 2005;63:194–201.PubMedCrossRefGoogle Scholar
  18. 18.
    Jacobs SA, Harrison AM, Swerdlow SH, Foon KA, Avril N, Vidnovic N, Joyce J, DeMonaco N, McCarty KS Jr. Radioisotopic localization of (90)Yttrium-ibritumomab tiuxetan in patients with CD20+ non-Hodgkin’s lymphoma. Mol Imaging Biol. 2009;11:39–45.CrossRefPubMedGoogle Scholar
  19. 19.
    Green DJ, Shadman M, Jones JC, Frayo SL, Kenoyer AL, Hylarides MD, Hamlin DK, Wilbur DS, Balkan ER, Lin Y, Miller BW, Frost SH, Gopal AK, Orozco JJ, Gooley TA, Laird KL, Till BG, Bäck T, Sandmaier BM, Pagel JM, Press OW. Astatine-211 conjugated to an anti-CD20 monoclonal antibody eradicates disseminated B-cell lymphoma in a mouse model. Blood. 2015;125:2111–9.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Morschhauser F, Radford J, Van Hoof A, Vitolo U, Soubeyran P, Tilly H, Huijgens PC, Kolstad A, d’Amore F, Gonzalez Diaz M, Petrini M, Sebban C, Zinzani PL, van Oers MH, van Putten W, Bischof-Delaloye A, Rohatiner A, Salles G, Kuhlmann J, Hagenbeek A. Phase III trial of consolidation therapy with yttrium-90-ibritumomab tiuxetan compared with no additional therapy after first remission in advanced follicular lymphoma. J Clin Oncol. 2008;26:5156–64.CrossRefPubMedGoogle Scholar
  21. 21.
    McLaughlin P, Hagemeister FB, Romaguera JE, Sarris AH, Pate O, Younes A, Swan F, Keating M, Cabanillas F. Fludarabine, mitoxantrone, and dexamethasone: an effective new regimen for indolent lymphoma. J Clin Oncol. 1996;14:1262–8.PubMedCrossRefGoogle Scholar
  22. 22.
    Zinzani PL, Tani M, Pulsoni A, Gobbi M, Perotti A, De Luca S, Fabbri A, Zaccaria A, Voso MT, Fattori P, Guardigni L, Ronconi S, Cabras MG, Rigacci L, De Renzo A, Marchi E, Stefoni V, Fina M, Pellegrini C, Musuraca G, Derenzini E, Pileri S, Fanti S, Piccaluga PP, Baccarani M. Fludarabine and mitoxantrone followed by yttrium-90 ibritumomab tiuxetan in previously untreated patients with follicular non-Hodgkin lymphoma trial: a phase II non-randomised trial (FLUMIZ). Lancet Oncol. 2008;9:352–8.PubMedCrossRefGoogle Scholar
  23. 23.
    Jacobs SA, Swerdlow SH, Kant J, Foon KA, Jankowitz R, Land SR, DeMonaco N, Joyce J, Osborn JL, Evans TL, Schaefer PM, Luong TM. Phase II trial of short-course CHOP-R followed by 90Y-ibritumomab tiuxetan and extended rituximab in previously untreated follicular lymphoma. Clin Cancer Res. 2008;14:7088–94.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Burdick MJ, Neumann D, Pohlman B, Reddy CA, Tendulkar RD, Macklis R. External beam radiotherapy followed by 90Y ibritumomab tiuxetan in relapsed or refractory bulky follicular lymphoma. Int J Radiat Oncol Biol Phys. 2011;79:1124–30.PubMedCrossRefGoogle Scholar
  25. 25.
    Beckman RA, Weiner LM, Davis HM. Antibody constructs in cancer therapy: protein engineering strategies to improve exposure in solid tumors. Cancer. 2007;109:170–9.PubMedCrossRefGoogle Scholar
  26. 26.
    Jain RK, Stylianopoulos T. Delivering nanomedicine to solid tumors. Nat Rev Clin Oncol. 2010;7:653–64.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Oliveira S, van Dongen GA, Stigter-van Walsum M, Roovers RC, Stam JC, Mali W, van Diest PJ, van Bergen en Henegouwen PM. Rapid visualization of human tumor xenografts through optical imaging with a near-infrared fluorescent anti-epidermal growth factor receptor nanobody. Mol Imaging. 2012;11:33–46.PubMedCrossRefGoogle Scholar
  28. 28.
    Hamers-Casterman C, Atarhouch T, Muyldermans S, Robinson G, Hamers C, Songa EB, Bendahman N, Hamers R. Naturally occurring antibodies devoid of light chains. Nature. 1993;363:446–8.PubMedCrossRefGoogle Scholar
  29. 29.
    Keyaerts M, Xavier C, Heemskerk J, Devoogdt N, Everaert H, Ackaert C, Vanhoeij M, Duhoux FP, Gevaert T, Simon P, Schallier D, Fontaine C, Vaneycken I, Vanhove C, De Greve J, Lamote J, Caveliers V, Lahoutte T. Phase I Study of 68Ga-HER2-Nanobody for PET/CT Assessment of HER2 Expression in Breast Carcinoma. J Nucl Med. 2016;57:27–33.PubMedCrossRefGoogle Scholar
  30. 30.
    Chatalic KL, Veldhoven-Zweistra J, Bolkestein M, Hoeben S, Koning GA, Boerman OC, de Jong M, van Weerden WM. A Novel 111In-labeled anti-prostate-specific membrane antigen nanobody for targeted SPECT/CT imaging of prostate cancer. J Nucl Med. 2015;56:1094–9.PubMedCrossRefGoogle Scholar
  31. 31.
    Ding L, Tian C, Feng S, Fida G, Zhang C, Ma Y, Ai G, Achilefu S, Gu Y. Small sized EGFR1 and HER2 specific bifunctional antibody for targeted cancer therapy. Theranostics. 2015;5:378–98.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Kijanka M, Dorresteijn B, Oliveira S, van Bergen en Henegouwen PM. Nanobody-based cancer therapy of solid tumors. Nanomedicine (Lond). 2015;10:161–74.CrossRefGoogle Scholar
  33. 33.
    D’Huyvetter M, Vincke C, Xavier C, Aerts A, Impens N, Baatout S, De Raeve H, Muyldermans S, Caveliers V, Devoogdt N, Lahoutte T. Targeted radionuclide therapy with A 177Lu-labeled anti-HER2 nanobody. Theranostics. 2014;4:708–20.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Kraeber-Bodéré F, Rousseau C, Bodet-Milin C, Frampas E, Faivre-Chauvet A, Rauscher A, Sharkey RM, Goldenberg DM, Chatal JF, Barbet JA. pretargeting system for tumor PET imaging and radioimmunotherapy. Front Pharmacol. 2015 Mar 31;6:54. CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Axworthy DB, Reno JM, Hylarides MD, Mallett RW, Theodore LJ, Gustavson LM, Su F, Hobson LJ, Beaumier PL, Fritzberg AR. Cure of human carcinoma xenografts by a single dose of pretargeted yttrium-90 with negligible toxicity. Proc Natl Acad Sci U S A. 2000;97:1802–7.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Pagel JM, Pantelias A, Hedin N, Wilbur S, Saganic L, Lin Y, Axworthy D, Hamlin DK, Wilbur DS, Gopal AK, Press OW. Evaluation of CD20, CD22, and HLA-DR targeting for radioimmunotherapy of B-cell lymphomas. Cancer Res. 2007;67:5921–8.PubMedCrossRefGoogle Scholar
  37. 37.
    Sharkey RM, Karacay H, Litwin S, Rossi EA, McBride WJ, Chang CH, Goldenberg DM. Improved therapeutic results by pretargeted radioimmunotherapy of non-Hodgkin’s lymphoma with a new recombinant, trivalent, anti-CD20, bispecific antibody. Cancer Res. 2008;68:5282–90.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Chatal JF, Campion L, Kraeber-Bodéré F, Bardet S, Vuillez JP, Charbonnel B, Rohmer V, Chang CH, Sharkey RM, Goldenberg DM, Barbet J, French Endocrine Tumor Group. Survival improvement in patients with medullary thyroid carcinoma who undergo pretargeted anti-carcinoembryonic-antigen radioimmunotherapy: a collaborative study with the French Endocrine Tumor Group. J Clin Oncol. 2006;24:1705–11.PubMedCrossRefGoogle Scholar
  39. 39.
    Salaun PY, Campion L, Bournaud C, Faivre-Chauvet A, Vuillez JP, Taieb D, Ansquer C, Rousseau C, Borson-Chazot F, Bardet S, Oudoux A, Cariou B, Mirallié E, Chang CH, Sharkey RM, Goldenberg DM, Chatal JF, Barbet J, Kraeber-Bodéré F. Phase II trial of anticarcinoembryonic antigen pretargeted radioimmunotherapy in progressive metastatic medullary thyroid carcinoma: biomarker response and survival improvement. J Nucl Med. 2012;53:1185–92.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Deans JP, Li H, Polyak MJ. CD20-mediated apoptosis: signalling through lipid rafts. Immunology. 2002;107:176–82.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Li H, Ayer LM, Lytton J, Deans JP. Store-operated cation entry mediated by CD20 in membrane rafts. J Biol Chem. 2003;278:42427–34.PubMedCrossRefGoogle Scholar
  42. 42.
    Brown DA, London E. Structure and function of sphingolipid- and cholesterol-rich membrane rafts. J Biol Chem. 2000;275:17221–4.PubMedCrossRefGoogle Scholar
  43. 43.
    Bubien JK, Zhou LJ, Bell PD, Frizzell RA, Tedder TF. Transfection of the CD20 cell surface molecule into ectopic cell types generates a Ca2+ conductance found constitutively in B lymphocytes. J Cell Biol. 1993;121:1121–32.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Johnson NA, Boyle M, Bashashati A, Leach S, Brooks-Wilson A, Sehn LH, Chhanabhai M, Brinkman RR, Connors JM, Weng AP, Gascoyne RD. Diffuse large B-cell lymphoma: reduced CD20 expression is associated with an inferior survival. Blood. 2009;113:3773–80.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Almasri NM, Duque RE, Iturraspe J, Everett E, Braylan RC. Reduced expression of CD20 antigen as a characteristic marker for chronic lymphocytic leukemia. Am J Hematol. 1992;40:259–63.PubMedCrossRefGoogle Scholar
  46. 46.
    Golay J, Lazzari M, Facchinetti V, Bernasconi S, Borleri G, Barbui T, Rambaldi A, Introna M. CD20 levels determine the in vitro susceptibility to rituximab and complement of B-cell chronic lymphocytic leukemia: further regulation by CD55 and CD59. Blood. 2001;98:3383–9.PubMedCrossRefGoogle Scholar
  47. 47.
    van Meerten T, van Rijn RS, Hol S, Hagenbeek A, Ebeling SB. Complement-induced cell death by rituximab depends on CD20 expression level and acts complementary to antibody-dependent cellular cytotoxicity. Clin Cancer Res. 2006;12:4027–35.PubMedCrossRefGoogle Scholar
  48. 48.
    Golay J, Zaffaroni L, Vaccari T, Lazzari M, Borleri GM, Bernasconi S, Tedesco F, Rambaldi A, Introna M. Biologic response of B lymphoma cells to anti-CD20 monoclonal antibody rituximab in vitro: CD55 and CD59 regulate complement-mediated cell lysis. Blood. 2000;95:3900–8.PubMedGoogle Scholar
  49. 49.
    Iagaru A, Gambhir SS, Goris ML. 90Y-ibritumomab therapy in refractory non-Hodgkin’s lymphoma: observations from 111In-ibritumomab pretreatment imaging. J Nucl Med. 2008;49:1809–12.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Davis TA, Czerwinski DK, Levy R. Therapy of B-cell lymphoma with anti-CD20 antibodies can result in the loss of CD20 antigen expression. Clin Cancer Res. 1999;5:611–5.PubMedGoogle Scholar
  51. 51.
    Jilani I, O’Brien S, Manshuri T, Thomas DA, Thomazy VA, Imam M, Naeem S, Verstovsek S, Kantarjian H, Giles F, Keating M, Albitar M. Transient down-modulation of CD20 by rituximab in patients with chronic lymphocytic leukemia. Blood. 2003;102:3514–20.PubMedCrossRefGoogle Scholar
  52. 52.
    Hiraga J, Tomita A, Sugimoto T, Shimada K, Ito M, Nakamura S, Kiyoi H, Kinoshita T, Naoe T. Down-regulation of CD20 expression in B-cell lymphoma cells after treatment with rituximab-containing combination chemotherapies: its prevalence and clinical significance. Blood. 2009;113:4885–93.PubMedCrossRefGoogle Scholar
  53. 53.
    Nakamaki T, Fukuchi K, Nakashima H, Ariizumi H, Maeda T, Saito B, Yanagisawa K, Tomoyasu S, Homma M, Shiozawa E, Yamochi-Onizuka T, Ota H. CD20 gene deletion causes a CD20-negative relapse in diffuse large B-cell lymphoma. Eur J Haematol. 2012;89:350–5.PubMedCrossRefGoogle Scholar
  54. 54.
    Matsuda I, Hirota S. Bone marrow infiltration of CD20-negative follicular lymphoma after rituximab therapy: a histological mimicker of hematogones and B-cell acute lymphoblastic leukemia/lymphoma. Int J Clin Exp Pathol. 2015;8:9737–41.PubMedPubMedCentralGoogle Scholar
  55. 55.
    Sugimoto T, Tomita A, Hiraga J, Shimada K, Kiyoi H, Kinoshita T, Naoe T. Escape mechanisms from antibody therapy to lymphoma cells: downregulation of CD20 mRNA by recruitment of the HDAC complex and not by DNA methylation. Biochem Biophy Res Commun. 2009;390:48–53.CrossRefGoogle Scholar
  56. 56.
    Terui Y, Mishima Y, Sugimura N, Kojima K, Sakurai T, Mishima Y, Kuniyoshi R, Taniyama A, Yokoyama M, Sakajiri S, Takeuchi K, Watanabe C, Takahashi S, Ito Y, Hatake K. Identification of CD20 C-terminal deletion mutations associated with loss of CD20 expression in non-Hodgkin’s lymphoma. Clin Cancer Res. 2009;15:2523–30.PubMedCrossRefGoogle Scholar
  57. 57.
    Tsai PC, Hernandez-Ilizaliturri FJ, Bangia N, Olejniczak SH, Czuczman MS. Regulation of CD20 in rituximab-resistant cell lines and B-cell non-Hodgkin lymphoma. Clin Cancer Res. 2012;18:1039–50.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Czuczman MS, Olejniczak S, Gowda A, Kotowski A, Binder A, Kaur H, Knight J, Starostik P, Deans J, Hernandez-Ilizaliturri FJ. Acquirement of rituximab resistance in lymphoma cell lines is associated with both global CD20 gene and protein down-regulation regulated at the pretranscriptional and posttranscriptional levels. Clin Cancer Res. 2008;14:1561–70.PubMedCrossRefGoogle Scholar
  59. 59.
    Venugopal P, Sivaraman S, Huang XK, Nayini J, Gregory SA, Preisler HD. Effects of cytokines on CD20 antigen expression on tumor cells from patients with chronic lymphocytic leukemia. Leuk Res. 2000;24(5):411.PubMedCrossRefGoogle Scholar
  60. 60.
    Jahrsdörfer B, Hartmann G, Racila E, Jackson W, Mühlenhoff L, Meinhardt G, Endres S, Link BK, Krieg AM, Weiner GJ. CpG DNA increases primary malignant B cell expression of costimulatory molecules and target antigens. J Leukoc Biol. 2001;69:81–8.PubMedGoogle Scholar
  61. 61.
    Hemmi H, Takeuchi O, Kawai T, Kaisho T, Sato S, Sanjo H, Matsumoto M, Hoshino K, Wagner H, Takeda K, Akira S. A Toll-like receptor recognizes bacterial DNA. Nature. 2000;408:740–5.PubMedCrossRefGoogle Scholar
  62. 62.
    Krieg AM. Development of TLR9 agonists for cancer therapy. J Clin Invest. 2007;117:1184–94.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Hayashi K, Nagasaki E, Kan S, Ito M, Kamata Y, Homma S, Aiba K. Gemcitabine enhances rituximab-mediated complement-dependent cytotoxicity to B cell lymphoma by CD20 up-regulation. Cancer Sci. 2016. [Epub ahead of print].
  64. 64.
    Wojciechowski W, Li H, Marshall S, Dell’Agnola C, Espinoza-Delgado I. Enhanced expression of CD20 in human tumor B cells is controlled through ERK-dependent mechanisms. J Immunol. 2005;174:7859–68.PubMedCrossRefGoogle Scholar
  65. 65.
    Cragg MS, Glennie MJ. Antibody specificity controls in vivo effector mechanisms of anti-CD20 reagents. Blood. 2004;103:2738–43.PubMedCrossRefGoogle Scholar
  66. 66.
    Tipton TR, Roghanian A, Oldham RJ, Carter MJ, Cox KL, Mockridge CI, French RR, Dahal LN, Duriez PJ, Hargreaves PG, Cragg MS, Beers SA. Antigenic modulation limits the effector cell mechanisms employed by type I anti-CD20 monoclonal antibodies. Blood. 2015;125:1901–9.PubMedCrossRefGoogle Scholar
  67. 67.
    Lim SH, Vaughan AT, Ashton-Key M, Williams EL, Dixon SV, Chan HT, Beers SA, French RR, Cox KL, Davies AJ, Potter KN, Mockridge CI, Oscier DG, Johnson PW, Cragg MS, Glennie MJ. Fc gamma receptor IIb on target B cells promotes rituximab internalization and reduces clinical efficacy. Blood. 2011;118:2530–40.PubMedCrossRefGoogle Scholar
  68. 68.
    Dransfield I. Inhibitory FcγRIIb and CD20 internalization. Blood. 2014;123:606–7.PubMedCrossRefGoogle Scholar
  69. 69.
    Weng WK, Levy R. Two immunoglobulin G fragment C receptor polymorphisms independently predict response to rituximab in patients with follicular lymphoma. J Clin Oncol. 2003;21:3940–7.PubMedCrossRefGoogle Scholar
  70. 70.
    Lam WA, Rosenbluth MJ, Fletcher DA. Chemotherapy exposure increases leukemia cell stiffness. Blood. 2007;109(8):3505.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Li Y, Williams ME, Cousar JB, Pawluczkowycz AW, Lindorfer MA, Taylor RP. Rituximab-CD20 complexes are shaved from Z138 mantle cell lymphoma cells in intravenous and subcutaneous SCID mouse models. J Immunol. 2007;179:4263–71.PubMedCrossRefGoogle Scholar
  72. 72.
    Beum PV, Peek EM, Lindorfer MA, Beurskens FJ, Engelberts PJ, Parren PW, van de Winkel JG, Taylor RP. Loss of CD20 and bound CD20 antibody from opsonized B cells occurs more rapidly because of trogocytosis mediated by Fc receptor-expressing effector cells than direct internalization by the B cells. J Immunol. 2011;187:3438–47.PubMedCrossRefGoogle Scholar
  73. 73.
    Wang T, Zhang X, Li JJ. The role of NF-kappaB in the regulation of cell stress responses. Int Immunopharmacol. 2002;2:1509–20.PubMedCrossRefGoogle Scholar
  74. 74.
    Xia Y, Shen S, Verma IM. NF-κB, an active player in human cancers. Cancer Immunol Res. 2014;2:823–30.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Turturro F. Constitutive NF- κ B activation underlines major mechanism of drug resistance in relapsed refractory diffuse large B cell lymphoma. Biomed Res Int. 2015:ID484537.Google Scholar
  76. 76.
    Alizadeh AA, Eisen MB, Davis RE, Ma C, Lossos IS, Rosenwald A, Boldrick JC, Sabet H, Tran T, Yu X, Powell JI, Yang L, Marti GE, Moore T, Hudson J Jr, Lu L, Lewis DB, Tibshirani R, Sherlock G, Chan WC, Greiner TC, Weisenburger DD, Armitage JO, Warnke R, Levy R, Wilson W, Grever MR, Byrd JC, Botstein D, Brown PO, Staudt LM. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature. 2000;403:503–11.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Wilson WH, Jung SH, Porcu P, Hurd D, Johnson J, Martin SE, Czuczman M, Lai R, Said J, Chadburn A, Jones D, Dunleavy K, Canellos G, Zelenetz AD, Cheson BD, Hsi ED, Cancer Leukemia Group B. A Cancer and Leukemia Group B multi-center study of DA-EPOCH-rituximab in untreated diffuse large B-cell lymphoma with analysis of outcome by molecular subtype. Haematologica. 2012;97:758–65.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Bohers E, Mareschal S, Bouzelfen A, Marchand V, Ruminy P, Maingonnat C, Ménard AL, Etancelin P, Bertrand P, Dubois S, Alcantara M, Bastard C, Tilly H, Jardin F. Targetable activating mutations are very frequent in GCB and ABC diffuse large B-cell lymphoma. Genes Chromosomes Cancer. 2014;53:144–53.PubMedCrossRefGoogle Scholar
  79. 79.
    Fan M, Ahmed KM, Coleman MC, Spitz DR, Li JJ. Nuclear factor-kappaB and manganese superoxide dismutase mediate adaptive radioresistance in low-dose irradiated mouse skin epithelial cells. Cancer Res. 2007;67:3220–8.PubMedCrossRefGoogle Scholar
  80. 80.
    Jazirehi AR, Huerta-Yepez S, Cheng G, Bonavida B. Rituximab (chimeric anti-CD20 monoclonal antibody) inhibits the constitutive nuclear factor-{kappa}B signaling pathway in non-Hodgkin’s lymphoma B-cell lines: role in sensitization to chemotherapeutic drug-induced apoptosis. Cancer Res. 2005;65:264–76.PubMedGoogle Scholar
  81. 81.
    Odqvist L, Montes-Moreno S, Sánchez-Pacheco RE, Young KH, Martín-Sánchez E, Cereceda L, Sánchez-Verde L, Pajares R, Mollejo M, Fresno MF, Mazorra F, Ruíz-Marcellán C, Sánchez-Beato M, Piris MA. NFκB expression is a feature of both activated B-cell-like and germinal center B-cell-like subtypes of diffuse large B-cell lymphoma. Mod Pathol. 2014;27:1331–7.PubMedCrossRefGoogle Scholar
  82. 82.
    Roschewski M, Staudt LM, Wilson WH. Diffuse large B-cell lymphoma-treatment approaches in the molecular era. Nat Rev Clin Oncol. 2014;11:12–23.PubMedCrossRefGoogle Scholar
  83. 83.
    Di Bella N, Taetle R, Kolibaba K, Boyd T, Raju R, Barrera D, Cochran EW Jr, Dien PY, Lyons R, Schlegel PJ, Vukelja SJ, Boston J, Boehm KA, Wang Y, Asmar L. Results of a phase 2 study of bortezomib in patients with relapsed or refractory indolent lymphoma. Blood. 2010;115:475–80.PubMedCrossRefGoogle Scholar
  84. 84.
    Coiffier B, Osmanov EA, Hong X, Scheliga A, Mayer J, Offner F, Rule S, Teixeira A, Walewski J, de Vos S, Crump M, Shpilberg O, Esseltine DL, Zhu E, Enny C, Theocharous P, van de Velde H, Elsayed YA, Zinzani PL, LYM-3001 Study Investigators. Bortezomib plus rituximab versus rituximab alone in patients with relapsed, rituximab-naive or rituximab-sensitive, follicular lymphoma: a randomised phase 3 trial. Lancet Oncol. 2011;12:773–84.PubMedCrossRefGoogle Scholar
  85. 85.
    Fowler N, Kahl BS, Lee P, Matous JV, Cashen AF, Jacobs SA, Letzer J, Amin B, Williams ME, Smith S, Saleh A, Rosen P, Shi H, Parasuraman S, Cheson BD. Bortezomib, bendamustine, and rituximab in patients with relapsed or refractory follicular lymphoma: the phase II VERTICAL study. J Clin Oncol. 2011;29:3389–95.PubMedCrossRefGoogle Scholar
  86. 86.
    Russo SM, Tepper JE, Baldwin AS Jr, Liu R, Adams J, Elliott P, Cusack JC Jr. Enhancement of radiosensitivity by proteasome inhibition: implications for a role of NF-kappaB. Int J Radiat Oncol Biol Phys. 2001;50:183–93.PubMedCrossRefGoogle Scholar
  87. 87.
    Beaven AW, Shea TC, Moore DT, Feldman T, Ivanova A, Ferraro M, Ford P, Smith J, Goy A. A phase I study evaluating ibritumomab tiuxetan (Zevalin®) in combination with bortezomib (Velcade®) in relapsed/refractory mantle cell and low grade B-cell non-Hodgkin lymphoma. Leuk Lymphoma. 2012;53:254–8.PubMedCrossRefGoogle Scholar
  88. 88.
    Roy R, Evens AM, Patton D, Gallot L, Larson A, Rademaker A, Cilley J, Spies S, Variakojis D, Gordon LI, Winter JN. Bortezomib may be safely combined with Y-90-ibritumomab tiuxetan in patients with relapsed/refractory follicular non-Hodgkin lymphoma: a phase I trial of combined induction therapy and bortezomib consolidation. Leuk Lymphoma. 2013;54:497–502.PubMedCrossRefGoogle Scholar
  89. 89.
    Elstrom RL, Ruan J, Christos PJ, Martin P, Lebovic D, Osborne J, Goldsmith S, Greenberg J, Furman RR, Avram A, Putman R, Chapman E, Mazumdar M, Griffith K, Coleman M, Leonard JP, Kaminski MS. Phase 1 study of radiosensitization using bortezomib in patients with relapsed non-Hodgkin lymphoma receiving radioimmunotherapy with 131I-tositumomab. Leuk Lymphoma. 2015;56:342–6.PubMedCrossRefGoogle Scholar
  90. 90.
    Goy A, Bernstein SH, Kahl BS, Djulbegovic B, Robertson MJ, de Vos S, Epner E, Krishnan A, Leonard JP, Lonial S, Nasta S, O’Connor OA, Shi H, Boral AL, Fisher RI. Bortezomib in patients with relapsed or refractory mantle cell lymphoma: updated time-to-event analyses of the multicenter phase 2 PINNACLE study. Ann Oncol. 2009;20:520–5.PubMedCrossRefGoogle Scholar
  91. 91.
    Wang M, Oki Y, Pro B, Romaguera JE, Rodriguez MA, Samaniego F, McLaughlin P, Hagemeister F, Neelapu S, Copeland A, Samuels BI, Loyer EM, Ji Y, Younes A. Phase II study of yttrium-90-ibritumomab tiuxetan in patients with relapsed or refractory mantle cell lymphoma. J Clin Oncol. 2009;27:5213–8.PubMedCrossRefGoogle Scholar
  92. 92.
    Kupperman E, Lee EC, Cao Y, Bannerman B, Fitzgerald M, Berger A, Yu J, Yang Y, Hales P, Bruzzese F, Liu J, Blank J, Garcia K, Tsu C, Dick L, Fleming P, Yu L, Manfredi M, Rolfe M, Bolen J. Evaluation of the proteasome inhibitor MLN9708 in preclinical models of human cancer. Cancer Res. 2010;70:1970–80.PubMedCrossRefGoogle Scholar
  93. 93.
    Lee EC, Fitzgerald M, Bannerman B, Donelan J, Bano K, Terkelsen J, Bradley DP, Subakan O, Silva MD, Liu R, Pickard M, Li Z, Tayber O, Li P, Hales P, Carsillo M, Neppalli VT, Berger AJ, Kupperman E, Manfredi M, Bolen JB, Van Ness B, Janz S. Antitumor activity of the investigational proteasome inhibitor MLN9708 in mouse models of B-cell and plasma cell malignancies. Clin Cancer Res. 2011;17(23):7313.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Assouline SE, Chang J, Cheson BD, Rifkin R, Hamburg S, Reyes R, Hui AM, Yu J, Gupta N, Di Bacco A, Shou Y, Martin P. Phase 1 dose-escalation study of IV ixazomib, an investigational proteasome inhibitor, in patients with relapsed/refractory lymphoma. Blood Cancer J. 2014;4:e251.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Crespo J, Sun H, Welling TH, Tian Z, Zou W. T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment. Curr Opin Immunol. 2013;25:214–21.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Lee Y, Auh SL, Wang Y, Burnette B, Wang Y, Meng Y, Beckett M, Sharma R, Chin R, Tu T, Weichselbaum RR, Fu YX. Therapeutic effects of ablative radiation on local tumor require CD8+ T cells: changing strategies for cancer treatment. Blood. 2009;114:589–95.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Sahin U, Türeci O, Schmitt H, Cochlovius B, Johannes T, Schmits R, Stenner F, Luo G, Schobert I, Pfreundschuh M. Human neoplasms elicit multiple specific immune responses in the autologous host. Proc Natl Acad Sci U S A. 1995;92:11810–3.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Céfai D, Favre L, Wattendorf E, Marti A, Jaggi R, Gimmi CD. Role of Fas ligand expression in promoting escape from immune rejection in a spontaneous tumor model. Int J Cancer. 2001;15(91):529–37.CrossRefGoogle Scholar
  99. 99.
    Afreen S, Dermime S. The immunoinhibitory B7-H1 molecule as a potential target in cancer: killing many birds with one stone. Hematol Oncol Stem Cell Ther. 2014;7:1–17.PubMedCrossRefGoogle Scholar
  100. 100.
    Gajewski TF, Meng Y, Blank C, Brown I, Kacha A, Kline J, Harlin H. Immune resistance orchestrated by the tumor microenvironment. Immunol Rev. 2006;213:131–45.PubMedCrossRefGoogle Scholar
  101. 101.
    Kim R, Emi M, Tanabe K, Uchida Y, Toge T. The role of Fas ligand and transforming growth factor beta in tumor progression: molecular mechanisms of immune privilege via Fas-mediated apoptosis and potential targets for cancer therapy. Cancer. 2004;100:2281–91.PubMedCrossRefGoogle Scholar
  102. 102.
    Mannino MH, Zhu Z, Xiao H, Bai Q, Wakefield MR, Fang Y. The paradoxical role of IL-10 in immunity and cancer. Cancer Lett. 2015;367:103–7.PubMedCrossRefGoogle Scholar
  103. 103.
    Munn DH, Mellor AL. Indoleamine 2,3 dioxygenase and metabolic control of immune responses. Trends Immunol. 2013;34:137–43.PubMedCrossRefGoogle Scholar
  104. 104.
    Reits EA, Hodge JW, Herberts CA, Groothuis TA, Chakraborty M, Wansley EK, Camphausen K, Luiten RM, de Ru AH, Neijssen J, Griekspoor A, Mesman E, Verreck FA, Spits H, Schlom J, van Veelen P, Neefjes JJ. Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy. J Exp Med. 2006;203:1259–71.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Nishikawa H, Sakaguchi S. Regulatory T cells in tumor immunity. Int J Cancer. 2010;127:759–67.PubMedGoogle Scholar
  106. 106.
    Marvel D, Gabrilovich DI. Myeloid-derived suppressor cells in the tumor microenvironment: expect the unexpected. J Clin Invest. 2015;125:3356–64.PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Sica A, Schioppa T, Mantovani A, Allavena P. Tumour-associated macrophages are a distinct M2 polarised population promoting tumour progression: potential targets of anti-cancer therapy. Eur J Cancer. 2006;42:717–27.PubMedCrossRefGoogle Scholar
  108. 108.
    Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science. 2011;331:1565–70.PubMedCrossRefGoogle Scholar
  109. 109.
    Burnet FM. The concept of immunological surveillance. Prog Exp Tumor Res. 1970;13:1–27.PubMedCrossRefGoogle Scholar
  110. 110.
    Swann JB, Smyth MJ. Immune surveillance of tumors. J Clin Investig. 2007;117:1137–46.PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Shankaran V, Ikeda H, Bruce AT, White JM, Swanson PE, Old LJ, Schreiber RD. IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature. 2001;410:1107–11.PubMedCrossRefGoogle Scholar
  112. 112.
    Muenst S, Läubli H, Soysal SD, Zippelius A, Tzankov A, Hoeller S. The immune system and cancer evasion strategies: therapeutic concepts. J Intern Med. 2016. [Epub ahead of print]Int Immunol 2016 Mar 22. pii: dxw015.
  113. 113.
    Temizoz B, Kuroda E, Ishii KJ. Vaccine adjuvants as potential cancer immunotherapeutics. Int Immunol. 2016.; pii: dxw015. [Epub ahead of print].Google Scholar
  114. 114.
    Iwasaki A, Medzhitov R. Toll-like receptor control of the adaptive immune responses. Nat Immunol. 2004;5:987–95.PubMedCrossRefGoogle Scholar
  115. 115.
    Bourke E, Bosisio D, Golay J, Polentarutti N, Mantovani A. The toll-like receptor repertoire of human B lymphocytes: inducible and selective expression of TLR9 and TLR10 in normal and transformed cells. Blood. 2003;102:956–63.PubMedCrossRefGoogle Scholar
  116. 116.
    Link BK, Ballas ZK, Weisdorf D, Wooldridge JE, Bossler AD, Shannon M, Rasmussen WL, Krieg AM, Weiner GJ. Oligodeoxynucleotide CpG 7909 delivered as intravenous infusion demonstrates immunologic modulation in patients with previously treated non-Hodgkin lymphoma. J Immunother. 2006;29:558–68.PubMedCrossRefGoogle Scholar
  117. 117.
    Brody JD, Ai WZ, Czerwinski DK, Torchia JA, Levy M, Advani RH, Kim YH, Hoppe RT, Knox SJ, Shin LK, Wapnir I, Tibshirani RJ, Levy R. In situ vaccination with a TLR9 agonist induces systemic lymphoma regression: a phase I/II study. J Clin Oncol. 2010;28:4324–32.PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Zent CS, Smith BJ, Ballas ZK, Wooldridge JE, Link BK, Call TG, Shanafelt TD, Bowen DA, Kay NE, Witzig TE, Weiner GJ. Phase I clinical trial of CpG oligonucleotide 7909 (PF-03512676) in patients with previously treated chronic lymphocytic leukemia. Leuk Lymphoma. 2012;53:211–7.PubMedCrossRefGoogle Scholar
  119. 119.
    Witzig TE, Wiseman GA, Maurer MJ, Habermann TM, Micallef IN, Nowakowski GS, Ansell SM, Colgan JP, Inwards DJ, Porrata LF, Link BK, Zent CS, Johnston PB, Shanafelt TD, Allmer C, Asmann YW, Gupta M, Ballas ZK, Smith BJ, Weiner GJ. A phase I trial of immunostimulatory CpG 7909 oligodeoxynucleotide and 90 yttrium ibritumomab tiuxetan radioimmunotherapy for relapsed B-cell non-Hodgkin lymphoma. Am J Hematol. 2013;88:589–93.PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Jahrsdörfer B, Hartmann G, Racila E, Jackson W, Mühlenhoff L, Meinhardt G, Endres S, Link BK, Krieg AM, Weiner GJ. CpG DNA increases primary malignant B cell expression of costimulatory molecules and target antigens. J Leuk Biol. 2001;69:81–8.Google Scholar
  121. 121.
    Watts C, West MA, Zaru R. TLR signalling regulated antigen presentation in dendritic cells. Curr Opin Immunol. 2010;22:124–30.PubMedCrossRefGoogle Scholar
  122. 122.
    Iwasaki A, Medzhitov R. Regulation of adaptive immunity by the innate immune system. Science. 2010;327:291–5.PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Decker T, Schneller F, Sparwasser T, Tretter T, Lipford GB, Wagner H, Peschel C. Immunostimulatory CpG-oligonucleotides cause proliferation, cytokine production, and an immunogenic phenotype in chronic lymphocytic leukemia B cells. Blood. 2000;95:999–1006.PubMedGoogle Scholar
  124. 124.
    Demaria S, Ng B, Devitt ML, Babb JS, Kawashima N, Liebes L, Formenti SC. Ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune mediated. Int J Radiat Oncol Biol Phys. 2004;58:862–70.PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Dewan MZ, Galloway AE, Kawashima N, Dewyngaert JK, Babb JS, Formenti SC, Demaria S. Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody. Clin Cancer Res. 2009;15:5379–88.PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    Formenti SC, Demaria S. Combining radiotherapy and cancer immunotherapy: a paradigm shift. J Natl Cancer Inst. 2013;105:256–65.PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Lugade AA, Moran JP, Gerber SA, Rose RC, Frelinger JG, Lord EM. Local radiation therapy of B16 melanoma tumors increases the generation of tumor antigen-specific effector cells that traffic to the tumor. J Immunol. 2005;174:7516–23.CrossRefPubMedGoogle Scholar
  128. 128.
    Gerber SA, Sedlacek AL, Cron KR, Murphy SP, Frelinger JG, Lord EM. IFN-γ mediates the antitumor effects of radiation therapy in a murine colon tumor. Am J Pathol. 2013;182:2345–54.PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    Demaria S, Kawashima N, Yang AM, Devitt ML, Babb JS, Allison JP, Formenti SC. Immune-mediated inhibition of metastases after treatment with local radiation and CTLA-4 blockade in a mouse model of breast cancer. Clin Cancer Res. 2005;11:728–34.PubMedGoogle Scholar
  130. 130.
    Ma Y, Kepp O, Ghiringhelli F, Apetoh L, Aymeric L, Locher C, Tesniere A, Martins I, Ly A, Haynes NM, Smyth MJ, Kroemer G, Zitvogel L. Chemotherapy and radiotherapy: cryptic anticancer vaccines. Semin Immunol. 2010;22:113–24.CrossRefPubMedGoogle Scholar
  131. 131.
    Filatenkov A, Baker J, Mueller AM, Kenkel J, Ahn GO, Dutt S, Zhang N, Kohrt H, Jensen K, Dejbakhsh-Jones S, Shizuru JA, Negrin RN, Engleman EG, Strober S. Ablative tumor radiation can change the tumor immune cell microenvironment to induce durable complete remissions. Clin Cancer Res. 2015;21:3727–39.PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Song CW, Rhee JG, Kim T, Kersey JH, Levitt SH. Effect of x-irradiation on immunocompetency of T-lymphocytes. Cancer Clin Trials. 1981;4:331–42.PubMedGoogle Scholar
  133. 133.
    Rosen EM, Fan S, Rockwell S, Goldberg ID. The molecular and cellular basis of radiosensitivity: implications for understanding how normal tissues and tumors respond to therapeutic radiation. Cancer Investig. 1999;17:56–72.CrossRefGoogle Scholar
  134. 134.
    Dovedi SJ, Adlard AL, Lipowska-Bhalla G, McKenna C, Jones S, Cheadle EJ, Stratford IJ, Poon E, Morrow M, Stewart R, Jones H, Wilkinson RW, Honeychurch J, Illidge TM. Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade. Cancer Res. 2014;74:5458–68.PubMedCrossRefGoogle Scholar
  135. 135.
    Gandhi SJ, Minn AJ, Vonderheide RH, Wherry EJ, Hahn SM, Maity A. Awakening the immune system with radiation: Optimal dose and fractionation. Cancer Lett. 2015;368:185–90.PubMedCrossRefGoogle Scholar
  136. 136.
    Chen L, Flies DB. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat Rev Immunol. 2013;13:227–42.PubMedPubMedCentralCrossRefGoogle Scholar
  137. 137.
    Shin DS, Ribas A. The evolution of checkpoint blockade as a cancer therapy: what’s here, what’s next? Curr Opin Immunol. 2015;33:23–35.PubMedCrossRefGoogle Scholar
  138. 138.
    Wu L, Wu MO, De la Maza L, Yun Z, Yu J, Zhao Y, Cho J, de Perrot M. Targeting the inhibitory receptor CTLA-4 on T cells increased abscopal effects in murine mesothelioma model. Oncotarget. 2015;6:12468–80.PubMedPubMedCentralGoogle Scholar
  139. 139.
    Deng L, Liang H, Burnette B, Beckett M, Darga T, Weichselbaum RR, Fu YX. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest. 2014;124:687–95.PubMedPubMedCentralCrossRefGoogle Scholar
  140. 140.
    Sharabi AB, Nirschl CJ, Kochel CM, Nirschl TR, Francica BJ, Velarde E, Deweese TL, Drake CG. Stereotactic radiation therapy augments antigen-specific PD-1-mediated antitumor immune responses via cross-presentation of tumor Antigen. Cancer Immunol Res. 2015;3:345–55.PubMedCrossRefGoogle Scholar
  141. 141.
    Twyman-Saint Victor C, Rech AJ, Maity A, Rengan R, Pauken KE, Stelekati E, Benci JL, Xu B, Dada H, Odorizzi PM, Herati RS, Mansfield KD, Patsch D, Amaravadi RK, Schuchter LM, Ishwaran H, Mick R, Pryma DA, Xu X, Feldman MD, Gangadhar TC, Hahn SM, Wherry EJ, Vonderheide RH, Minn AJ. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature. 2015;520:373–7.PubMedCrossRefGoogle Scholar
  142. 142.
    Kwon ED, Drake CG, Scher HI, Fizazi K, Bossi A, van den Eertwegh AJ, Krainer M, Houede N, Santos R, Mahammedi H, Ng S, Maio M, Franke FA, Sundar S, Agarwal N, Bergman AM, Ciuleanu TE, Korbenfeld E, Sengeløv L, Hansen S, Logothetis C, Beer TM, McHenry MB, Gagnier P, Liu D, Gerritsen WR, CA184-043 Investigators. Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 2014;15:700–12.PubMedPubMedCentralCrossRefGoogle Scholar
  143. 143.
    Mathew M, Tam M, Ott PA, Pavlick AC, Rush SC, Donahue BR, Golfinos JG, Parker EC, Huang PP, Narayana A. Ipilimumab in melanoma with limited brain metastases treated with stereotactic radiosurgery. Melanoma Res. 2013;23:191–5.PubMedCrossRefGoogle Scholar
  144. 144.
    Alomari AK, Cohen J, Vortmeyer AO, Chiang A, Gettinger S, Goldberg SB, Kluger HM, Chiang VL. Possible interaction of anti-PD-1 therapy with the effects of radiosurgery on brain metastases. Cancer Immunol Res 2016. pii: canimm.0238.2015. [Epub ahead of print].Google Scholar
  145. 145.
    Ahmed KA, Stallworth DG, Kim Y, Johnstone PA, Harrison LB, Caudell JJ, Yu HH, Etame AB, Weber JS, Gibney GT. Clinical outcomes of melanoma brain metastases treated with stereotactic radiation and anti-PD-1 therapy. Ann Oncol. 2016;27:434–41.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Diagnostic Radiology and Nuclear MedicineTokyo Women’s Medical UniversityTokyoJapan

Personalised recommendations