search for




 

Review Article
Immunotherapy in Pediatric Hematologic Malignant Neoplasms
Clin Pediatr Hematol Oncol 2020;27:14-21.
Published online April 30, 2020
© 2020 Korean Society of Pediatric Hematology-Oncology

Kyung Taek Hong

Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Cancer Research Institute, Seoul, Korea
Correspondence to: Kyung Taek Hong
Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Cancer Research Institute, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea
Tel: +82-2-2072-3631
Fax: +82-2-743-3455
E-mail: hongkt@snu.ac.kr
ORCID ID: orcid.org/0000-0002-8822-1988
Received March 31, 2020; Revised April 14, 2020; Accepted April 16, 2020.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Childhood acute leukemia has achieved tremendous treatment outcome improvement over the past several decades. Given that pediatric leukemia remains the most common type of childhood malignant tumors, there are still unmet needs in relapsed/refractory diseases. Moreover, reducing the toxic adverse effects of chemotherapy is another big challenge. Over the past decades, immunotherapy in pediatric leukemia has achieved significant improvement. This review will focus on the recent development and achievement of bi-specific T-cell engagers, antibody-drug conjugates, and chimeric antigen receptor T cell therapies in pediatric leukemia. Moreover, several prevalent obstacles in administering these treatments will also be discussed. Based on the characteristics of each treatment, a variety of clinical trials are currently underway. As a new treatment modality, immunotherapy should be optimally applied based on disease conditions.
Keywords: Childhood leukemia, Immunotherapy, Bi-specific T-cell engagers, Antibody-drug conjugates, Chimeric antigen receptor T cell
Figures
Fig. 1. Schema of immunotherapeutic modalities for hematologic malignancy. Antibody-based and cell-based immunotherapies including blinatumomab, inotuzumab, and chimeric antigen receptor (CAR) T cell, have been clinically translated (Adopted from Schultz L et al. Hematology Am Soc Hematol Educ Program. 2019;2019:226-32.).
References
  1. Hunger SP, Mullighan CG. Acute lymphoblastic leukemia in children. N Engl J Med 2015;373:1541-52.
    Pubmed CrossRef
  2. Pui CH, Yang JJ, Hunger SP, et al. Childhood acute lymphoblastic leukemia: progress through collaboration. J Clin Oncol 2015;33:2938-48.
    Pubmed KoreaMed CrossRef
  3. Pui CH, Nichols KE, Yang JJ. Somatic and germline genomics in paediatric acute lymphoblastic leukaemia. Nat Rev Clin Oncol 2019;16:227-40.
    Pubmed CrossRef
  4. Zwaan CM, Kolb EA, Reinhardt D, et al. Collaborative efforts driving progress in pediatric acute myeloid leukemia. J Clin Oncol 2015;33:2949-62.
    Pubmed KoreaMed CrossRef
  5. Gustafsson Jernberg A, Remberger M, Ringdén O, Winiarski J. Graft-versus-leukaemia effect in children: chronic GVHD has a significant impact on relapse and survival. Bone Marrow Transplant 2003;31:175-81.
    Pubmed CrossRef
  6. Horowitz MM, Gale RP, Sondel PM, et al. Graft-versus-leukemia reactions after bone marrow transplantation. Blood 1990;75:555-62.
    Pubmed CrossRef
  7. Velasquez MP, Bonifant CL, Gottschalk S. Redirecting T cells to hematological malignancies with bispecific antibodies. Blood 2018;131:30-8.
    Pubmed KoreaMed CrossRef
  8. Winters A, Gore L. Moving immunotherapy into the front line in ALL. Hematology Am Soc Hematol Educ Program 2019;2019:209-17.
    Pubmed CrossRef
  9. Löffler A, Kufer P, Lutterbüse R, et al. A recombinant bispecific single-chain antibody, CD19 x CD3, induces rapid and high lymphoma-directed cytotoxicity by unstimulated T lymphocytes. Blood 2000;95:2098-103.
    Pubmed CrossRef
  10. von Stackelberg A, Locatelli F, Zugmaier G, et al. Phase I/phase II study of blinatumomab in pediatric patients with relapsed/refractory acute lymphoblastic leukemia. J Clin Oncol 2016;34:4381-9.
    Pubmed CrossRef
  11. Gore L, Locatelli F, Zugmaier G, et al. Survival after blinatumomab treatment in pediatric patients with relapsed/refractory B-cell precursor acute lymphoblastic leukemia. Blood Cancer J 2018;8:80.
    Pubmed KoreaMed CrossRef
  12. Locatelli F, Zugmaier G, Vora A, et al. Blinatumomab use in pediatric patients (pts) with relapsed/refractory B-precursor acute lymphoblastic leukemia (r/r ALL) from an open-label, multicenter, expanded access study. J Clin Oncol 2017;35(15 Suppl):10530.
    CrossRef
  13. Keating AK, Gossai N, Phillips CL, et al. Reducing minimal residual disease with blinatumomab prior to HCT for pediatric patients with acute lymphoblastic leukemia. Blood Adv 2019;3:1926-9.
    Pubmed KoreaMed CrossRef
  14. Kantarjian H, Stein A, Gökbuget N, et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med 2017;376:836-47.
    Pubmed KoreaMed CrossRef
  15. Gökbuget N, Dombret H, Bonifacio M, et al. Blinatumomab for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukemia. Blood 2018;131:1522-31.
    Pubmed KoreaMed CrossRef
  16. Martinelli G, Boissel N, Chevallier P, et al. Complete hematologic and molecular response in adult patients with relapsed/refractory Philadelphia chromosome-positive b-precursor acute lymphoblastic leukemia following treatment with blinatumomab: results from a phase II, single-arm, multicenter study. J Clin Oncol 2017;35:1795-802.
    Pubmed CrossRef
  17. Rambaldi A, Ribera JM, Kantarjian HM, et al. Blinatumomab compared with standard of care for the treatment of adult patients with relapsed/refractory Philadelphia chromosomepositive B-precursor acute lymphoblastic leukemia. Cancer 2020;126:304-10.
    Pubmed KoreaMed CrossRef
  18. DiJoseph JF, Armellino DC, Boghaert ER, et al. Antibody-targeted chemotherapy with CMC-544: a CD22-targeted immunoconjugate of calicheamicin for the treatment of B-lymphoid malignancies. Blood 2004;103:1807-14.
    Pubmed CrossRef
  19. Piccaluga PP, Arpinati M, Candoni A, et al. Surface antigens analysis reveals significant expression of candidate targets for immunotherapy in adult acute lymphoid leukemia. Leuk Lymphoma 2011;52:325-7.
    Pubmed CrossRef
  20. Kantarjian HM, DeAngelo DJ, Stelljes M, et al. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med 2016;375:740-53.
    Pubmed KoreaMed CrossRef
  21. Kantarjian H, Ravandi F, Short NJ, et al. Inotuzumab ozogamicin in combination with low-intensity chemotherapy for older patients with Philadelphia chromosome-negative acute lymphoblastic leukaemia: a single-arm, phase 2 study. Lancet Oncol 2018;19:240-8.
    Pubmed CrossRef
  22. Bhojwani D, Sposto R, Shah NN, et al. Inotuzumab ozogamicin in pediatric patients with relapsed/refractory acute lymphoblastic leukemia. Leukemia 2019;33:884-92.
    Pubmed KoreaMed CrossRef
  23. Paul MR, Wong V, Aristizabal P, Kuo DJ. Treatment of recurrent refractory pediatric pre-B acute lymphoblastic leukemia using inotuzumab ozogamicin monotherapy resulting in CD22 antigen expression loss as a mechanism of therapy resistance. J Pediatr Hematol Oncol 2019;41:e546-e9.
    Pubmed CrossRef
  24. O’Brien MM, Ji L, Shah NN, et al. A phase 2 trial of inotuzumab ozogamicin (InO) in children and young adults with relapsed or refractory (R/R) CD22+ B-acute lymphoblastic leukemia (B-ALL): results from Children’s Oncology Group Protocol AALL1621. Blood 2019;134(Suppl 1):741.
    CrossRef
  25. Aplenc R, Alonzo TA, Gerbing RB, et al. Safety and efficacy of gemtuzumab ozogamicin in combination with chemotherapy for pediatric acute myeloid leukemia: a report from the Children’s Oncology Group. J Clin Oncol 2008;26:2390-3295.
    Pubmed KoreaMed CrossRef
  26. Gamis AS, Alonzo TA, Meshinchi S, et al. Gemtuzumab ozogamicin in children and adolescents with de novo acute myeloid leukemia improves event-free survival by reducing relapse risk: results from the randomized phase III Children’s Oncology Group trial AAML0531. J Clin Oncol 2014;32:3021-32.
    Pubmed KoreaMed CrossRef
  27. Pollard JA, Loken M, Gerbing RB, et al. CD33 expression and its association with gemtuzumab ozogamicin response: results from the Randomized Phase III Children’s Oncology Group trial AAML0531. J Clin Oncol 2016;34:747-55.
    Pubmed KoreaMed CrossRef
  28. Lamba JK, Chauhan L, Shin M, et al. CD33 Splicing polymorphism determines gemtuzumab ozogamicin response in de novo acute myeloid leukemia: report from Randomized Phase III Children’s Oncology Group trial AAML0531. J Clin Oncol 2017;35:2674-82.
    Pubmed KoreaMed CrossRef
  29. Imai C, Mihara K, Andreansky M, et al. Chimeric receptors with 4-1BB signaling capacity provoke potent cytotoxicity against acute lymphoblastic leukemia. Leukemia 2004;18:676-84.
    Pubmed CrossRef
  30. Savoldo B, Ramos CA, Liu E, et al. CD28 costimulation improves expansion and persistence of chimeric antigen receptor-modified T cells in lymphoma patients. J Clin Invest 2011;121:1822-6.
    Pubmed KoreaMed CrossRef
  31. Milone MC, Fish JD, Carpenito C, et al. Chimeric receptors containing CD137 signal transduction domains mediate enhanced survival of T cells and increased antileukemic efficacy in vivo. Mol Ther 2009;17:1453-64.
    Pubmed KoreaMed CrossRef
  32. Maher J, Brentjens RJ, Gunset G, Rivière I, Sadelain M. Human T-lymphocyte cytotoxicity and proliferation directed by a single chimeric TCRzeta /CD28 receptor. Nat Biotechnol 2002;20:70-5.
    Pubmed CrossRef
  33. Grupp SA, Kalos M, Barrett D, et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med 2013;368:1509-18.
    Pubmed KoreaMed CrossRef
  34. Maude SL, Frey N, Shaw PA, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med 2014;371:1507-17.
    Pubmed KoreaMed CrossRef
  35. Lee DW, Kochenderfer JN, Stetler-Stevenson M, et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet 2015;385:517-28.
    Pubmed KoreaMed CrossRef
  36. 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.
    Pubmed KoreaMed CrossRef
  37. Gardner RA, Finney O, Annesley C, et al. Intent-to-treat leukemia remission by CD19 CAR T cells of defined formulation and dose in children and young adults. Blood 2017;129:3322-31.
    Pubmed KoreaMed CrossRef
  38. Ghorashian S, Kramer AM, Onuoha S, et al. Enhanced CAR T cell expansion and prolonged persistence in pediatric patients with ALL treated with a low-affinity CD19 CAR. Nat Med 2019;25:1408-14.
    Pubmed CrossRef
  39. Fry TJ, Shah NN, Orentas RJ, et al. CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy. Nat Med 2018;24:20-8.
    Pubmed KoreaMed CrossRef
  40. Curran KJ, Margossian SP, Kernan NA, et al. Toxicity and response after CD19-specific CAR T-cell therapy in pediatric/young adult relapsed/refractory B-ALL. Blood 2019;134:2361-8.
    Pubmed CrossRef
  41. Pan J, Niu Q, Deng B, et al. CD22 CAR T-cell therapy in refractory or relapsed B acute lymphoblastic leukemia. Leukemia 2019;33:2854-66.
    Pubmed CrossRef
  42. Lee DW, Gardner R, Porter DL, et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood 2014;124:188-95.
    Pubmed KoreaMed CrossRef
  43. Gardner RA, Ceppi F, Rivers J, et al. Preemptive mitigation of CD19 CAR T-cell cytokine release syndrome without attenuation of antileukemic efficacy. Blood 2019;134:2149-58.
    Pubmed CrossRef
  44. Santomasso BD, Park JH, Salloum D, et al. Clinical and biological correlates of neurotoxicity associated with CAR T-cell therapy in patients with B-cell acute lymphoblastic leukemia. Cancer Discov 2018;8:958-71.
    Pubmed KoreaMed CrossRef
  45. Lee DW, Santomasso BD, Locke FL, et al. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol Blood Marrow Transplant 2019;25:625-38.
    Pubmed CrossRef
  46. Long AH, Haso WM, Shern JF, et al. 4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors. Nat Med 2015;21:581-90.
    Pubmed KoreaMed CrossRef
  47. Gardner R, Wu D, Cherian S, et al. Acquisition of a CD19-negative myeloid phenotype allows immune escape of MLLrearranged B-ALL from CD19 CAR-T-cell therapy. Blood 2016;127:2406-10.
    Pubmed KoreaMed CrossRef
  48. Qasim W, Zhan H, Samarasinghe S, et al. Molecular remission of infant B-ALL after infusion of universal TALEN gene-edited CAR T cells. Sci Transl Med 2017;9.
    Pubmed CrossRef
  49. Ruella M, Xu J, Barrett DM, et al. Induction of resistance to chimeric antigen receptor T cell therapy by transduction of a single leukemic B cell. Nat Med 2018;24:1499-503.
    Pubmed KoreaMed CrossRef


April 2020, 27 (1)
Full Text PDF
Citation
Send to a friend
Twitter
Facebook

Cited By Articles
  • CrossRef (0)

Author ORCID Information
  • Kyung Taek Hong