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Principles of Immunotherapy

  • Stanton Goldman
  • Jessica HochbergEmail author
Chapter

Abstract

While cure rates for pediatric non-Hodgkin lymphoma remain to be among the highest in pediatric oncology, this often comes with a significant cost in the form of delayed effects of therapy or secondary malignancy. Various strategies have been developed to address the challenges of maintaining current overall survival rates for low and intermediate stage patients while further improving treatment outcomes for advanced-stage disease and minimizing long-term morbidities for all. Personalized therapy will be needed based on risk factor assessment and incorporation of new agents with improved toxicity profiles to upfront therapy protocols. Immunotherapy relies on delivering greater specificity to a cytotoxic agent and/or enhancing the patient’s own immune response to malignancy. This can be accomplished using precise targeted monoclonal antibodies, immune checkpoint blockade, or the development of improved chimeric antigen receptor engineered T-cells. There is increasing data for the efficacy of adding monoclonal antibody therapy, either naked or conjugated, to upfront cytotoxic chemotherapy. Checkpoint inhibition and the use of CAR T-cells are newer additions to the therapeutic paradigms for pediatric non-Hodgkin lymphoma, but results from adult trials are encouraging. It remains to be seen what best combinations will prevail as we move forward with these novel agents so that we may improve long-term outcomes for all.

Keywords

Immunotherapy Antibody Non-Hodgkin lymphoma T-cells 

References

  1. 1.
    Maloney DG, Grillo-Lopez AJ, White CA, et al. IDEC-C2B8 (Rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin’s lymphoma. Blood. 1997;90:2188–95.PubMedGoogle Scholar
  2. 2.
    Czuczman MS, Grillo-Lopez AJ, White CA, et al. Treatment of patients with low-grade B-cell lymphoma with the combination of chimeric anti-CD20 monoclonal antibody and CHOP chemotherapy. J Clin Oncol. 1999;17:268–76.CrossRefGoogle Scholar
  3. 3.
    Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002;346:235–42.CrossRefGoogle Scholar
  4. 4.
    Pfreundschuh M, Trumper L, Osterborg A, et al. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol. 2006;7:379–91.CrossRefGoogle Scholar
  5. 5.
    Rizzieri DA, Johnson JL, Byrd JC, et al. Improved efficacy using rituximab and brief duration, high intensity chemotherapy with filgrastim support for Burkitt or aggressive lymphomas: cancer and Leukemia Group B study 10 002. Br J Haematol. 2014;165:102–11.CrossRefGoogle Scholar
  6. 6.
    Hoelzer D, Walewski J, Döhner H, et al. Improved outcome of adult Burkitt lymphoma/leukemia with rituximab and chemotherapy: report of a large prospective multicenter trial. Blood. 2014;124:3870–9.CrossRefGoogle Scholar
  7. 7.
    Griffin TC, Weitzman S, Weinstein H, et al. A study of rituximab and ifosfamide, carboplatin, and etoposide chemotherapy in children with recurrent/refractory B-cell (CD20+) non-Hodgkin lymphoma and mature B-cell acute lymphoblastic leukemia: a report from the Children’s Oncology Group. Pediatr Blood Cancer. 2009;52:177–81.CrossRefGoogle Scholar
  8. 8.
    Meinhardt A, Burkhardt B, Zimmermann M, et al. Phase II window study on rituximab in newly diagnosed pediatric mature B-cell non-Hodgkin’s lymphoma and Burkitt leukemia. J Clin Oncol. 2010;28:3115–21.CrossRefGoogle Scholar
  9. 9.
    Jäger U, Fridrik M, Zeitlinger M, et al. Rituximab serum concentrations during immuno-chemotherapy of follicular lymphoma correlate with patient gender, bone marrow infiltration and clinical response. Haematologica. 2012;97:1431–8.CrossRefGoogle Scholar
  10. 10.
    Berinstein NL, Grillo-Lopez AJ, White CA, et al. Association of serum Rituximab (IDEC-C2B8) concentration and anti-tumor response in the treatment of recurrent low-grade or follicular non-Hodgkin’s lymphoma. Ann Oncol. 1998;9:995–1001.CrossRefGoogle Scholar
  11. 11.
    Goldman S, Smith L, Anderson JR, et al. Rituximab and FAB/LMB 96 chemotherapy in children with Stage III/IV B-cell non-Hodgkin lymphoma: a Children’s Oncology Group report. Leukemia. 2013;27:1174–7.CrossRefGoogle Scholar
  12. 12.
    Goldman S, Smith L, Galardy P, et al. Rituximab with chemotherapy in children and adolescents with central nervous system and/or bone marrow-positive Burkitt lymphoma/leukaemia: a Children’s Oncology Group report. Br J Haematol. 2014;167:394.CrossRefGoogle Scholar
  13. 13.
    Barth MJ, Goldman S, Smith L, et al. Rituximab pharmacokinetics in children and adolescents with de novo intermediate and advanced mature B-cell lymphoma/leukaemia: a Children’s Oncology Group report. Br J Haematol. 2013;162:678–83.CrossRefGoogle Scholar
  14. 14.
    Minard-Colin V, Auperin A, Pillon M, et al. Results of the randomized intergroup trial inter-B-NHL Ritux 2010 for children and adolescents with high risk B-cell non Hodgkin’s lymphoma and mature acute leukemia: evaluation of efficacy in addition to standard LMB chemotherapy regimen. J Clin Oncol. 2016;34:abstr 10507.CrossRefGoogle Scholar
  15. 15.
    Patte C, Auperin A, Gerrard M, et al. Results of the randomized international FAB/LMB96 trial for intermediate risk B-cell non-Hodgkin lymphoma in children and adolescents: it is possible to reduce treatment for the early responding patients. Blood. 2007;109:2773–80.PubMedPubMedCentralGoogle Scholar
  16. 16.
    Cairo MS, Gerrard M, Sposto R, et al. Results of a randomized international study of high-risk central nervous system B non-Hodgkin lymphoma and B acute lymphoblastic leukemia in children and adolescents. Blood. 2007;109:2736–43.PubMedPubMedCentralGoogle Scholar
  17. 17.
    Goldman S, Barth MJ, Oesterheld JE, et al. Preliminary results of a reduced burden of therapy trial by incorporation of rituximab and intrathecal liposomal cytarabine in children, adolescents and young adults with intermediate (FAB Group B) and high risk (FAB Group C) mature B-cell lymphoma/leukemia. Chicago: ASCO Annual Meeting; 2016 (abstract).CrossRefGoogle Scholar
  18. 18.
    Gross TG, Orjuela MA, Perkins SL, et al. Low-dose chemotherapy and rituximab for posttransplant lymphoproliferative disease (PTLD): a Children’s Oncology Group Report. Am J Transplant. 2012;12:3069–75.CrossRefGoogle Scholar
  19. 19.
    Mossner E, Brunker P, Moser S, et al. Increasing the efficacy of CD20 antibody therapy through the engineering of a new type II anti-CD20 antibody with enhanced direct and immune effector cell-mediated B-cell cytotoxicity. Blood. 2010;115:4393–402.CrossRefGoogle Scholar
  20. 20.
    Sehn LH, Goy A, Offner FC, et al. Randomized phase II trial comparing obinutuzumab (GA101) with rituximab in patients with relapsed CD20+ indolent B-cell non-Hodgkin lymphoma: final analysis of the GAUSS study. J Clin Oncol. 2015;33:3467–74.CrossRefGoogle Scholar
  21. 21.
    Morschhauser FA, Cartron G, Thieblemont C, et al. Obinutuzumab (GA101) monotherapy in relapsed/refractory diffuse large b-cell lymphoma or mantle-cell lymphoma: results from the phase II GAUGUIN study. J Clin Oncol. 2013;31:2912–9.CrossRefGoogle Scholar
  22. 22.
    Awasthi A, Ayello J, Van de Ven C, et al. Obinutuzumab (GA101) compared to rituximab significantly enhances cell death and antibody-dependent cytotoxicity and improves overall survival against CD20(+) rituximab-sensitive/-resistant Burkitt lymphoma (BL) and precursor B-acute lymphoblastic leukaemia (pre-B-ALL): potential targeted therapy in patients with poor risk CD20(+) BL and pre-B-ALL. Br J Haematol. 2015;171:763–75.CrossRefGoogle Scholar
  23. 23.
    Press OW, Leonard JP, Coiffier B, et al. Immunotherapy of non-Hodgkin’s lymphomas. Hematology Am Soc Hematol Educ Program. 2001;2001:221–40.CrossRefGoogle Scholar
  24. 24.
    Cooney-Qualter E, Krailo M, Angiolillo A, et al. A phase I study of 90yttrium-ibritumomab-tiuxetan in children and adolescents with relapsed/refractory CD20-positive non-Hodgkin’s lymphoma: a Children’s Oncology Group study. Clin Cancer Res. 2007;13:5652s–60s.CrossRefGoogle Scholar
  25. 25.
    Witzig TE, Gordon LI, Cabanillas F, et al. 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.CrossRefGoogle Scholar
  26. 26.
    Stein H, Foss HD, Durkop H, et al. CD30(+) anaplastic large cell lymphoma: a review of its histopathologic, genetic, and clinical features. Blood. 2000;96:3681–95.Google Scholar
  27. 27.
    Chiarle R, Voena C, Ambrogio C, et al. The anaplastic lymphoma kinase in the pathogenesis of cancer. Nat Rev Cancer. 2008;8:11–23.CrossRefGoogle Scholar
  28. 28.
    Lamant L, McCarthy K, d’Amore E, et al. Prognostic impact of morphologic and phenotypic features of childhood ALK-positive anaplastic large-cell lymphoma: results of the ALCL99 study. J Clin Oncol. 2011;29:4669–76.CrossRefGoogle Scholar
  29. 29.
    Alexander S, Kraveka JM, Weitzman S, et al. Advanced stage anaplastic large cell lymphoma in children and adolescents: results of ANHL0131, a randomized phase III trial of APO versus a modified regimen with vinblastine: a report from the children’s oncology group. Pediatr Blood Cancer. 2014;61:2236–42.CrossRefGoogle Scholar
  30. 30.
    Brugieres L, Quartier P, Le Deley MC, et al. Relapses of childhood anaplastic large-cell lymphoma: treatment results in a series of 41 children--a report from the French Society of Pediatric Oncology. Ann Oncol. 2000;11:53–8.CrossRefGoogle Scholar
  31. 31.
    Le Deley MC, Rosolen A, Williams DM, et al. Vinblastine in children and adolescents with high-risk anaplastic large-cell lymphoma: results of the randomized ALCL99-vinblastine trial. J Clin Oncol. 2010;28:3987–93.CrossRefGoogle Scholar
  32. 32.
    Lowe EJ, Sposto R, Perkins SL, et al. Intensive chemotherapy for systemic anaplastic large cell lymphoma in children and adolescents: final results of Children’s Cancer Group Study 5941. Pediatr Blood Cancer. 2009;52:335–9.CrossRefGoogle Scholar
  33. 33.
    Younes A, Bartlett NL, Leonard JP, et al. Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas. N Engl J Med. 2010;363:1812–21.CrossRefGoogle Scholar
  34. 34.
    Fanale MA, Forero-Torres A, Rosenblatt JD, et al. A phase I weekly dosing study of brentuximab vedotin in patients with relapsed/refractory CD30-positive hematologic malignancies. Clin Cancer Res. 2012;18:248–55.CrossRefGoogle Scholar
  35. 35.
    Pro B, Advani R, Brice P, 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;30:2190–6.CrossRefGoogle Scholar
  36. 36.
    Pro B, Advani R, Brice P, et al. Five-year results of brentuximab vedotin in patients with relapsed or refractory systemic anaplastic large cell lymphoma. Blood. 2017;130:2709–17.CrossRefGoogle Scholar
  37. 37.
    Fanale MA, Horwitz SM, Forero-Torres A, et al. Brentuximab vedotin in the front-line treatment of patients with CD30+ peripheral T-cell lymphomas: results of a phase I study. J Clin Oncol. 2014;32:3137–43.CrossRefGoogle Scholar
  38. 38.
    Blanc V, Bousseau A, Caron A, et al. SAR3419: an anti-CD19-Maytansinoid Immunoconjugate for the treatment of B-cell malignancies. Clin Cancer Res. 2011;17:6448–58.CrossRefGoogle Scholar
  39. 39.
    Ribrag V, Dupuis J, Tilly H, et al. A dose-escalation study of SAR3419, an anti-CD19 antibody maytansinoid conjugate, administered by intravenous infusion once weekly in patients with relapsed/refractory B-cell non-Hodgkin lymphoma. Clin Cancer Res. 2014;20:213–20.CrossRefGoogle Scholar
  40. 40.
    Trneny M, Verhoef G, Dyer MJ, et al. Starlyte phase II study of coltuximab ravtansine (CoR, SAR3419) single agent: clinical activity and safety in patients (pts) with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL; NCT01472887). J Clin Oncol2014 ASCO Annual Meeting Abstracts. 2014;32:8506.CrossRefGoogle Scholar
  41. 41.
    Thieblemont C, de Guibert S, Dupuis J, et al. Phase II study of anti-CD19 antibody drug conjugate (SAR3419) in combination with rituximab: clinical activity and safety in patients with relapsed/refractory diffuse large B-cell lymphoma (NCT01470456). Blood. 2013;122:4395.Google Scholar
  42. 42.
    Moskowitz CH, Fanale MA, Shah BD, et al. A phase 1 study of denintuzumab mafodotin (SGN-CD19A) in relapsed/refractory B-lineage non-Hodgkin lymphoma. Blood. 2015;126:182.CrossRefGoogle Scholar
  43. 43.
    Fathi AT, Borate U, DeAngelo DJ, et al. A phase 1 study of denintuzumab mafodotin (SGN-CD19A) in adults with relapsed or refractory B-lineage acute leukemia (B-ALL) and highly aggressive lymphoma. Blood. 2015;126:1328.Google Scholar
  44. 44.
    Fathi AT, Chen R, Trippett TM, et al. Interim analysis of a phase 1 study of the antibody-drug conjugate SGN-CD19A in relapsed or refractory B-lineage acute leukemia and highly aggressive lymphoma. Blood. 2014;124:963.CrossRefGoogle Scholar
  45. 45.
    Coleman M, Goldenberg DM, Siegel AB, et al. Epratuzumab: targeting B-cell malignancies through CD22. Clin Cancer Res. 2003;9:3991S–4S.PubMedGoogle Scholar
  46. 46.
    Leonard JP, Coleman M, Ketas JC, et al. Phase I/II trial of epratuzumab (humanized anti-CD22 antibody) in indolent non-Hodgkin’s lymphoma. J Clin Oncol. 2003;21:3051–9.CrossRefGoogle Scholar
  47. 47.
    Leonard JP, Coleman M, Ketas JC, et al. Epratuzumab, a humanized anti-CD22 antibody, in aggressive non-Hodgkin’s lymphoma: phase I/II clinical trial results. Clin Cancer Res. 2004;10:5327–34.CrossRefGoogle Scholar
  48. 48.
    Micallef IN, Maurer MJ, Wiseman GA, et al. Epratuzumab with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy in patients with previously untreated diffuse large B-cell lymphoma. Blood. 2011;118:4053–61.CrossRefGoogle Scholar
  49. 49.
    Grant BW, Jung SH, Johnson JL, et al. A phase 2 trial of extended induction epratuzumab and rituximab for previously untreated follicular lymphoma: CALGB 50701. Cancer. 2013;119:3797–804.CrossRefGoogle Scholar
  50. 50.
    Morschhauser F, Kraeber-Bodere F, Wegener WA, et al. High rates of durable responses with anti-CD22 fractionated radioimmunotherapy: results of a multicenter, phase I/II study in non-Hodgkin’s lymphoma. J Clin Oncol. 2010;28:3709–16.CrossRefGoogle Scholar
  51. 51.
    Chen AI, Lebovic D, Brunvand MW, et al. Final results of a phase I study of the anti-CD22 antibody-drug conjugate (ADC) DCDT2980S with or without rituximab (RTX) in patients (pts) with relapsed or refractory (R/R) B-cell non-Hodgkin’s lymphoma (NHL). Blood. 2013;122:4399.Google Scholar
  52. 52.
    Morschhauser F, Flinn I, Advani RH, et al. Updated results of a phase II randomized study (ROMULUS) of polatuzumab vedotin or pinatuzumab vedotin plus rituximab in patients with relapsed/refractory non-Hodgkin lymphoma. Blood. 2014;124:4457.Google Scholar
  53. 53.
    Rytting M, Triche L, Thomas D, et al. Initial experience with CMC-544 (inotuzumab ozogamicin) in pediatric patients with relapsed B-cell acute lymphoblastic leukemia. Pediatr Blood Cancer. 2014;61:369–72.CrossRefGoogle Scholar
  54. 54.
    Wagner-Johnston ND, Goy A, Rodriguez MA, et al. A phase 2 study of inotuzumab ozogamicin and rituximab, followed by autologous stem cell transplant in patients with relapsed/refractory diffuse large B-cell lymphoma. Leuk Lymphoma. 2015;56(10):2863–9.CrossRefGoogle Scholar
  55. 55.
    Palanca-Wessels MC, Czuczman M, Salles G, et al. Safety and activity of the anti-CD79B antibody-drug conjugate polatuzumab vedotin in relapsed or refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukaemia: a phase 1 study. Lancet Oncol. 2015;16:704–15.CrossRefGoogle Scholar
  56. 56.
    Haas C, Krinner E, Brischwein K, et al. Mode of cytotoxic action of T cell-engaging BiTE antibody MT110. Immunobiology. 2009;214:441–53.CrossRefGoogle Scholar
  57. 57.
    Bargou R, Leo E, Zugmaier G, et al. Tumor regression in cancer patients by very low doses of a T cell-engaging antibody. Science. 2008;321:974–7.CrossRefGoogle Scholar
  58. 58.
    Viardot A, Goebeler M-E, Hess G, et al. Phase 2 study of bispecific T-cell engager (BiTE®) antibody blinatumomab in relapsed/refractory diffuse large B cell lymphoma. Blood. 2016;127:1410.CrossRefGoogle Scholar
  59. 59.
    Teachey DT, Rheingold SR, Maude SL, et al. Cytokine release syndrome after blinatumomab treatment related to abnormal macrophage activation and ameliorated with cytokine-directed therapy. Blood. 2013;121:5154–7.CrossRefGoogle Scholar
  60. 60.
    Oak E, Bartlett NL. Blinatumomab for the treatment of B-cell lymphoma. Expert Opin Investig Drugs. 2015;24:715–24.CrossRefGoogle Scholar
  61. 61.
    Eyre TA, Collins GP. Immune checkpoint inhibition in lymphoid disease. Br J Haematol. 2015;170:291–304.CrossRefGoogle Scholar
  62. 62.
    Parry RV, Chemnitz JM, Frauwirth KA, et al. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol. 2005;25:9543–53.CrossRefGoogle Scholar
  63. 63.
    Andorsky DJ, Yamada RE, Said J, et al. Programmed death ligand 1 is expressed by non-Hodgkin lymphomas and inhibits the activity of tumor-associated T cells. Clin Cancer Res. 2011;17:4232–44.CrossRefGoogle Scholar
  64. 64.
    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;15:6446–53.CrossRefGoogle Scholar
  65. 65.
    Galligan BM, Tsao-Wei D, Groshen S, et al. Efficacy and safety of combined rituximab and ipilimumab to treat patients with relapsed/refractory CD20+ B-cell lymphoma. Blood. 2015;126:3977.Google Scholar
  66. 66.
    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;15:69–77.CrossRefGoogle Scholar
  67. 67.
    Armand P, Nagler A, Weller EA, et al. Disabling immune tolerance by programmed death-1 blockade with pidilizumab after autologous hematopoietic stem-cell transplantation for diffuse large B-cell lymphoma: results of an international phase II trial. J Clin Oncol. 2013;31:4199–206.CrossRefGoogle Scholar
  68. 68.
    Lesokhin AM, Ansell SM, Armand P, et al. Preliminary results of a phase I study of nivolumab (BMS-936558) in patients with relapsed or refractory lymphoid malignancies. Blood. 2014;124:291.Google Scholar
  69. 69.
    Kershaw MH, Teng MW, Smyth MJ, et al. Supernatural T cells: genetic modification of T cells for cancer therapy. Nat Rev Immunol. 2005;5:928–40.CrossRefGoogle Scholar
  70. 70.
    Maude SL, Laetsch TW, Buechner J, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018;378:439–48.CrossRefGoogle Scholar
  71. 71.
    Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377:2531–44.CrossRefGoogle Scholar
  72. 72.
    Lee DW, Gardner R, Porter DL, et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood. 2014;124:188–95.CrossRefGoogle Scholar
  73. 73.
    Schuster SJ, Svoboda J, Nasta S, et al. Phase IIa trial of chimeric antigen receptor modified T cells directed against CD19 (CTL019) in patients with relapsed or refractory CD19+ lymphomas. J Clin Oncol. 2015;33:abstr 8516.Google Scholar

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Authors and Affiliations

  1. 1.Texas Oncology-Medical City Dallas Pediatric Hematology-OncologyDallasUSA
  2. 2.Westchester Medical CenterValhallaUSA

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