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Monoclonal Antibodies Targeting the Immune System

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Immunotherapy for Pediatric Malignancies

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Abstract

Scientific advances during the past decades have demonstrated the critical role of host immune system in the elimination of cancer. Better knowledge of immune cancer evasion has enabled the development of new cancer immunotherapy targeted to inhibitory immune checkpoints: PD-1, PD-L1 and CTLA4. Dramatic results were obtained in advanced melanoma (34% survival at 5 years with anti-PD-1) and non-small cell lung cancer, and proof of efficacy has been demonstrated with PD-1/PD-L1 antibodies in more than 20 cancer types in adults. By contrast, there are still limited clinical trials focusing on immunotherapies targeting the host immune system in pediatric oncology although some outstanding results have been reported in specific tumor histology/genetic predisposition syndrome. The first phase 1 in children and adolescents with recurrent/refractory solid tumors has been recently published with anti-CTL4A (ipilimumab). Toxicity profile was similar to adults and 6 (18%) of patients experienced stable disease. Translational research will allow understanding and analyzing mechanisms of action of immune checkpoints regulators and define biomarkers predictive of response. These drugs are already challenging our practice like for evaluation of tumor response or for management of immune related toxicities. Many other immune checkpoints have been identified and could potentially be targeted in pediatric cancers. Future studies will help to identify predictive factors but also to coordinate these new immunotherapies with our classic treatment strategies.

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References

  1. Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science. 2011;331(6024):1565–70.

    Article  CAS  PubMed  Google Scholar 

  2. Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD. Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol nov. 2002;3(11):991–8.

    Article  CAS  Google Scholar 

  3. Teng MWL, Galon J, Fridman W-H, Smyth MJ. From mice to humans: developments in cancer immunoediting. J Clin Invest. 2015;125(9):3338–46.

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Postel-Vinay S, Aspeslagh S, Lanoy E, Robert C, Soria J-C, Marabelle A. Challenges of phase 1 clinical trials evaluating immune checkpoint-targeted antibodies. Ann Oncol. 2016;27(2):214–24.

    Article  CAS  PubMed  Google Scholar 

  6. Menon S, Shin S, Dy G. Advances in cancer immunotherapy in solid tumors. Cancers. 2016;8(12):106.

    Article  PubMed Central  Google Scholar 

  7. OASIS [Internet]. (cité 29 avr 2017). Disponible sur: http://www.abstractsonline.com/Plan/ViewAbstract.aspx?mID=4017&sKey=371fa616-a0cf-4bf8-993d-ce424853b52c&cKey=616f965e-a236-4bd2-9f7a-6399bd6f3f6c&mKey=1d10d749-4b6a-4ab3-bcd4-f80fb1922267

  8. Merchant MS, Wright M, Baird K, Wexler LH, Rodriguez-Galindo C, Bernstein D, et al. Phase I clinical trial of ipilimumab in pediatric patients with advanced solid tumors. Clin Cancer Res Off J Am Assoc Cancer Res. 2016;22(6):1364–70.

    Article  CAS  Google Scholar 

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

    Article  PubMed  Google Scholar 

  10. Chen R, Zinzani PL, Fanale MA, Armand P, Johnson NA, Brice P, et al. Phase II study of the efficacy and safety of pembrolizumab for relapsed/refractory classic hodgkin lymphoma. J Clin Oncol. 2017;35(19):2125–32. doi:10.1200/JCO.2016.72.1316.

    Article  PubMed  Google Scholar 

  11. Foran AE, Nadel HR, Lee AF, Savage KJ, Deyell RJ. Nivolumab in the treatment of refractory pediatric hodgkin lymphoma. J Pediatr Hematol Oncol. 2017;39(5):e263–e266.

    Google Scholar 

  12. Hebart H, Lang P, Woessmann W. Nivolumab for refractory anaplastic large cell lymphoma: a case report. Ann Intern Med. 2016;165(8):607–8.

    Article  PubMed  Google Scholar 

  13. Bouffet E, Larouche V, Campbell BB, Merico D, de Borja R, Aronson M, et al. Immune checkpoint inhibition for hypermutant glioblastoma multiforme resulting from germline biallelic mismatch repair deficiency. J Clin Oncol. 2016;34(19):2206–11.

    Article  CAS  PubMed  Google Scholar 

  14. Lin AY, Lin E. Programmed death 1 blockade, an Achilles heel for MMR-deficient tumors? J Hematol Oncol J Hematol Oncol. 2015;8:124.

    Article  PubMed  Google Scholar 

  15. Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002;8(8):793–800.

    CAS  PubMed  Google Scholar 

  16. Galluzzi L, Buqué A, Kepp O, Zitvogel L, Kroemer G. Immunogenic cell death in cancer and infectious disease. Nat Rev Immunol. 2017;17(2):97–111.

    Article  CAS  PubMed  Google Scholar 

  17. Dowling DJ, Levy O. Ontogeny of early life immunity. Trends Immunol. 2014;35(7):299–310.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Mold JE, Michaëlsson J, Burt TD, Muench MO, Beckerman KP, Busch MP, et al. Maternal alloantigens promote the development of tolerogenic fetal regulatory T cells in utero. Science. 2008;322(5907):1562–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Levy O. Innate immunity of the newborn: basic mechanisms and clinical correlates. Nat Rev Immunol. 2007;7(5):379–90.

    Article  CAS  PubMed  Google Scholar 

  20. Kollmann TR, Levy O, Montgomery RR, Goriely S. Innate immune function by Toll-like receptors: distinct responses in newborns and the elderly. Immunity. 2012;37(5):771–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Zitvogel L, Ayyoub M, Routy B, Kroemer G. Microbiome and anticancer immunosurveillance. Cell. 2016;165(2):276–87.

    Article  CAS  PubMed  Google Scholar 

  22. Vétizou M, Pitt JM, Daillère R, Lepage P, Waldschmitt N, Flament C, et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science. 2015;350(6264):1079–84.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Korpela K, de Vos WM. Antibiotic use in childhood alters the gut microbiota and predisposes to overweight. Microb Cell Graz Austria. 2016;3(7):296–8.

    Article  Google Scholar 

  24. Tun HM, Konya T, Takaro TK, Brook JR, Chari R, Field CJ, et al. Exposure to household furry pets influences the gut microbiota of infant at 3–4 months following various birth scenarios. Microbiome. 2017;5(1):40.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Sivan A, Corrales L, Hubert N, Williams JB, Aquino-Michaels K, Earley ZM, et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science. 2015;350(6264):1084–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Umbrello G, Esposito S. Microbiota and neurologic diseases: potential effects of probiotics. J Transl Med. 2016;14(1):298.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Blanton LV, Barratt MJ, Charbonneau MR, Ahmed T, Gordon JI. Childhood undernutrition, the gut microbiota, and microbiota-directed therapeutics. Science. 2016;352(6293):1533.

    Article  CAS  PubMed  Google Scholar 

  28. Downing JR, Wilson RK, Zhang J, Mardis ER, Pui C-H, Ding L, et al. The pediatric cancer genome project. Nat Genet. 2012;44(6):619–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Shern JF, Chen L, Chmielecki J, Wei JS, Patidar R, Rosenberg M, et al. Comprehensive genomic analysis of rhabdomyosarcoma reveals a landscape of alterations affecting a common genetic axis in fusion-positive and fusion-negative tumors. Cancer Discov. 2014;4(2):216–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. van Rooij N, van Buuren MM, Philips D, Velds A, Toebes M, Heemskerk B, et al. Tumor exome analysis reveals neoantigen-specific T-cell reactivity in an ipilimumab-responsive melanoma. J Clin Oncol. 2013;31(32):e439–42.

    Article  PubMed  Google Scholar 

  31. Schumacher TN, Schreiber RD. Neoantigens in cancer immunotherapy. Science. 2015;348(6230):69–74.

    Article  CAS  PubMed  Google Scholar 

  32. Strønen E, Toebes M, Kelderman S, van Buuren MM, Yang W, van Rooij N, et al. Targeting of cancer neoantigens with donor-derived T cell receptor repertoires. Science. 2016;352(6291):1337–41.

    Article  PubMed  Google Scholar 

  33. Zhang J, Walsh MF, Wu G, Edmonson MN, Gruber TA, Easton J, et al. Germline mutations in predisposition genes in pediatric cancer. N Engl J Med. 2015;373(24):2336–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Lavoine N, Colas C, Muleris M, Bodo S, Duval A, Entz-Werle N, et al. Constitutional mismatch repair deficiency syndrome: clinical description in a French cohort. J Med Genet. 2015;52(11):770–8.

    Article  CAS  PubMed  Google Scholar 

  35. Shlien A, Campbell BB, de Borja R, Alexandrov LB, Merico D, Wedge D, et al. Combined hereditary and somatic mutations of replication error repair genes result in rapid onset of ultra-hypermutated cancers. Nat Genet. 2015;47(3):257–62.

    Article  CAS  PubMed  Google Scholar 

  36. Aoki T, Hino M, Koh K, Kyushiki M, Kishimoto H, Arakawa Y, et al. Low frequency of programmed death ligand 1 expression in pediatric cancers. Pediatr Blood Cancer. 2016;63(8):1461–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Mina M, Boldrini R, Citti A, Romania P, D’Alicandro V, De Ioris M, et al. Tumor-infiltrating T lymphocytes improve clinical outcome of therapy-resistant neuroblastoma. Oncoimmunology. 2015;4(9):e1019981.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Fritzsching B, Fellenberg J, Moskovszky L, Sápi Z, Krenacs T, Machado I, et al. CD8(+)/FOXP3(+)-ratio in osteosarcoma microenvironment separates survivors from non-survivors: a multicenter validated retrospective study. Oncoimmunology. 2015;4(3):e990800.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Yabe H, Tsukahara T, Kawaguchi S, Wada T, Torigoe T, Sato N, et al. Prognostic significance of HLA class I expression in Ewing’s sarcoma family of tumors. J Surg Oncol. 2011;103(5):380–5.

    Article  CAS  PubMed  Google Scholar 

  40. Sundara YT, Kostine M, Cleven AHG, Bovée JVMG, Schilham MW, Cleton-Jansen A-M. Increased PD-L1 and T-cell infiltration in the presence of HLA class I expression in metastatic high-grade osteosarcoma: a rationale for T-cell-based immunotherapy. Cancer Immunol Immunother. 2017;66(1):119–28.

    Article  CAS  PubMed  Google Scholar 

  41. Haworth KB, Leddon JL, Chen C-Y, Horwitz EM, Mackall CL, Cripe TP. Going back to class I: MHC and immunotherapies for childhood cancer. Pediatr Blood Cancer. 2015;62(4):571–6.

    Article  CAS  PubMed  Google Scholar 

  42. Cho D, Shook DR, Shimasaki N, Chang Y-H, Fujisaki H, Campana D. Cytotoxicity of activated natural killer cells against pediatric solid tumors. Clin Cancer Res Off J Am Assoc Cancer Res. 2010;16(15):3901–9.

    Article  CAS  Google Scholar 

  43. Buddingh EP, Kuijjer ML, Duim RAJ, Bürger H, Agelopoulos K, Myklebost O, et al. Tumor-infiltrating macrophages are associated with metastasis suppression in high-grade osteosarcoma: a rationale for treatment with macrophage activating agents. Clin Cancer Res Off J Am Assoc Cancer Res. 2011;17(8):2110–9.

    Article  CAS  Google Scholar 

  44. Dumars C, Ngyuen J-M, Gaultier A, Lanel R, Corradini N, Gouin F, et al. Dysregulation of macrophage polarization is associated with the metastatic process in osteosarcoma. Oncotarget. 2016;7(48):78343–54.

    PubMed  PubMed Central  Google Scholar 

  45. Asgharzadeh S, Salo JA, Ji L, Oberthuer A, Fischer M, Berthold F, et al. Clinical significance of tumor-associated inflammatory cells in metastatic neuroblastoma. J Clin Oncol. 2012;30(28):3525–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Mao Y, Eissler N, Blanc KL, Johnsen JI, Kogner P, Kiessling R. Targeting suppressive myeloid cells potentiates checkpoint inhibitors to control spontaneous neuroblastoma. Clin Cancer Res Off J Am Assoc Cancer Res. 2016;22(15):3849–59.

    Article  CAS  Google Scholar 

  47. Highfill SL, Cui Y, Giles AJ, Smith JP, Zhang H, Morse E, et al. Disruption of CXCR2-mediated MDSC tumor trafficking enhances anti-PD1 efficacy. Sci Transl Med. 2014;6(237):237ra67.

    Article  PubMed  Google Scholar 

  48. Bilbao-Aldaiturriaga N, Patino-Garcia A, Martin-Guerrero I, Garcia-Orad A. Cytotoxic T lymphocyte-associated antigen 4 rs231775 polymorphism and osteosarcoma. Neoplasma. 2017;64(2):299–304.

    Article  CAS  PubMed  Google Scholar 

  49. Feng D, Yang X, Li S, Liu T, Wu Z, Song Y, et al. Cytotoxic T-lymphocyte antigen-4 genetic variants and risk of Ewing’s sarcoma. Genet Test Mol Biomark. 2013;17(6):458–63.

    Article  CAS  Google Scholar 

  50. Hingorani P, Maas ML, Gustafson MP, Dickman P, Adams RH, Watanabe M, et al. Increased CTLA-4(+) T cells and an increased ratio of monocytes with loss of class II (CD14(+) HLA-DR(lo/neg)) found in aggressive pediatric sarcoma patients. J Immunother Cancer. 2015;3:35.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Lussier DM, Johnson JL, Hingorani P, Blattman JN. Combination immunotherapy with α-CTLA-4 and α-PD-L1 antibody blockade prevents immune escape and leads to complete control of metastatic osteosarcoma. J Immunother Cancer. 2015;3:21.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Nishimura H, Nose M, Hiai H, Minato N, Honjo T. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity. 1999;11(2):141–51.

    Article  CAS  PubMed  Google Scholar 

  53. Nishimura H, Okazaki T, Tanaka Y, Nakatani K, Hara M, Matsumori A, et al. Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science. 2001;291(5502):319–22.

    Article  CAS  PubMed  Google Scholar 

  54. Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 2000;192(7):1027–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Assessment of PD-L1 expression and tumor associated immune cells in pediatric cancer tissues. | 2016 ASCO Annual Meeting | Abstracts | Meeting Library [Internet]. (cité 29 avr 2017) Disponible sur: http://meetinglibrary.asco.org/content/167514-176

  56. Routh JC, Ashley RA, Sebo TJ, Lohse CM, Husmann DA, Kramer SA, et al. B7-H1 expression in Wilms tumor: correlation with tumor biology and disease recurrence. J Urol. 2008;179(5):1954–9. discussion 1959-1960

    Article  PubMed  PubMed Central  Google Scholar 

  57. The PD-L1 Expression Increases After Consecutive Multimodal Therapies In Neuroblastoma: P-392 [Internet]. (cité 29 avr 2017). Disponible sur: https://insights.ovid.com/pediatric-blood-cancer/pedbc/2015/11/004/pd-l1-expression-increases-consecutive-multimodal/769/01445489

  58. Shen JK, Cote GM, Choy E, Yang P, Harmon D, Schwab J, et al. Programmed cell death ligand 1 expression in osteosarcoma. Cancer Immunol Res. 2014;2(7):690–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Chowdhury F, et al. PD-L1 and CD8+PD1+ lymphocytes exist as targets in the pediatric tumor microenvironment for immunomodulatory therapy. OncoImmunology. 2015;4(10) doi:10.1080/2162402X.2015.1029701. [Internet]. (cité 29 avr 2017)

  60. Roemer MGM, Advani RH, Ligon AH, Natkunam Y, Redd RA, Homer H, et al. PD-L1 and PD-L2 genetic alterations define classical Hodgkin lymphoma and predict outcome. J Clin Oncol. 2016;34(23):2690–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Marzec M, Zhang Q, Goradia A, Raghunath PN, Liu X, Paessler M, et al. Oncogenic kinase NPM/ALK induces through STAT3 expression of immunosuppressive protein CD274 (PD-L1, B7-H1). Proc Natl Acad Sci U S A. 2008;105(52):20852–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Castriconi R, Dondero A, Augugliaro R, Cantoni C, Carnemolla B, Sementa AR, et al. Identification of 4Ig-B7-H3 as a neuroblastoma-associated molecule that exerts a protective role from an NK cell-mediated lysis. Proc Natl Acad Sci U S A. 2004;101(34):12640–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Wang L, Zhang Q, Chen W, Shan B, Ding Y, Zhang G, et al. B7-H3 is overexpressed in patients suffering osteosarcoma and associated with tumor aggressiveness and metastasis. PLoS One. 2013;8(8):e70689.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Forlenza CJ, Boudreau JE, Zheng J, Le Luduec J-B, Chamberlain E, Heller G, et al. KIR3DL1 allelic polymorphism and HLA-B epitopes modulate response to anti-GD2 monoclonal antibody in patients with neuroblastoma. J Clin Oncol. 2016;34(21):2443–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Michot JM, Bigenwald C, Champiat S, Collins M, Carbonnel F, Postel-Vinay S, et al. Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur J Cancer Oxf Engl 1990. 2016;54:139–48.

    CAS  Google Scholar 

  66. Champiat S, Lambotte O, Barreau E, Belkhir R, Berdelou A, Carbonnel F, et al. Management of immune checkpoint blockade dysimmune toxicities: a collaborative position paper. Ann Oncol Off J Eur Soc Med Oncol. 2016;27(4):559–74.

    Article  CAS  Google Scholar 

  67. Komaki Y, Komaki F, Yamada A, Micic D, Ido A, Sakuraba A. Meta-analysis of the risk of immune-related adverse events with anti-cytotoxic T-lymphocyte-associated antigen 4 and anti-programmed death 1 therapies. Clin Pharmacol Ther. 2017; doi:10.1002/cpt.633.

  68. Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, et al. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med. 2015;373(1):23–34.

    Article  PubMed  Google Scholar 

  69. Paoluzzi L, Cacavio A, Ghesani M, Karambelkar A, Rapkiewicz A, Weber J, et al. Response to anti-PD1 therapy with nivolumab in metastatic sarcomas. Clin Sarcoma Res. 2016;6:24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Armand P, Shipp MA, Ribrag V, Michot J-M, Zinzani PL, Kuruvilla J, et al. Programmed death-1 blockade with pembrolizumab in patients with classical hodgkin lymphoma after brentuximab vedotin failure. J Clin Oncol. 2016;34(31):3733–9.

    Article  Google Scholar 

  71. Rosenberg JE, Hoffman-Censits J, Powles T, van der Heijden MS, Balar AV, Necchi A, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet Lond Engl. 2016;387(10031):1909–20.

    Article  CAS  Google Scholar 

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  1. Département de Cancérologie de l’enfant et de l’adolescent, Institut Gustave Roussy, 114 rue Édouard-Vaillant, 94805, Villejuif Cedex, France

    Véronique Minard-Colin M.D., Ph.D.

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  1. Cancer Sciences Unit, University of Southampton, Southampton, United Kingdom

    Juliet C. Gray

  2. Département d’Innovation Thérapeutique et d'Essais Précoces, University of Paris-Saclay Gustave Roussy, Villejuif, France

    Aurélien Marabelle

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Minard-Colin, V. (2018). Monoclonal Antibodies Targeting the Immune System. In: Gray, J., Marabelle, A. (eds) Immunotherapy for Pediatric Malignancies. Springer, Cham. https://doi.org/10.1007/978-3-319-43486-5_7

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