Vol 52, No 4 (2021)
Review article
Published online: 2021-08-31

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Old and new targets for immunotherapy of B cell acute lymphoblastic leukemia

Małgorzata Firczuk1
DOI: 10.5603/AHP.2021.0056
Acta Haematol Pol 2021;52(4):291-299.

Abstract

B cell-specific antigens such as CD20 and CD19 are the leading examples of clinically utilized targets for cancer immunotherapy. Rituximab, the anti-CD20 monoclonal antibody (mAb) approved for the treatment of B cell lymphoma in 1997, was the earliest mAb drug ever registered in cancer immunotherapy. The clinical success of chimeric antigen receptor (CAR)-modified T cells has been demonstrated in patients with B cell acute lymphoblastic leukemia (B-ALL), and CD19-directed CAR-T cells were the first CAR therapy ever approved to treat cancer patients. While surface antigen-targeting immunotherapies play a significant role in the therapy of B-ALL, in particular in the treatment of relapsed and refractory patients, they have some limitations and face continuous challenges. Herein, I review the types of antigen-specific immunotherapies that are used in the treatment of B-ALL, including naked mAbs, antibody-drug conjugates, B cell-specific T cell engagers, and CAR-modified T cells. I discuss the requirements for good immunotherapy targets and summarize the main methods used to identify novel putative targets. I present an overview of B cell-specific and non-B cell-specific target antigens, both already used in clinics and tested in preclinical models. I also discuss limitations of current B-ALL immunotherapy, attempts to overcome these limitations, and future directions of immunotherapy research.

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References

  1. Majzner RG, Mackall CL. Tumor antigen escape from CAR T-cell therapy. Cancer Discov. 2018; 8(10): 1219–1226.
  2. Park JH, Rivière I, Gonen M, et al. Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. N Engl J Med. 2018; 378(5): 449–459.
  3. Fousek K, Watanabe J, Joseph SK, et al. CAR T-cells that target acute B-lineage leukemia irrespective of CD19 expression. Leukemia. 2021; 35(1): 75–89.
  4. Martino M, Alati C, Canale FA, et al. A review of clinical outcomes of CAR T-cell therapies for b-acute lymphoblastic leukemia. Int J Mol Sci. 2021; 22(4): 2150.
  5. Malard F, Mohty M. Acute lymphoblastic leukaemia. Lancet. 2020; 395(10230): 1146–1162.
  6. Du J, Chisholm KM, Tsuchiya K, et al. Lineage switch in an infant B-lymphoblastic leukemia with t(1;11)(p32;q23); KMT2A/EPS15, following blinatumomab therapy. Pediatr Dev Pathol. 2021 [Epub ahead of print]: 10935266211001308.
  7. Gardner R, Wu D, Cherian S, et al. Acquisition of a CD19-negative myeloid phenotype allows immune escape of MLL-rearranged B-ALL from CD19 CAR-T-cell therapy. Blood. 2016; 127(20): 2406–2410.
  8. Perna F, Sadelain M. Myeloid leukemia switch as immune escape from CD19 chimeric antigen receptor (CAR) therapy. Transl Cancer Res. 2016; 5(Suppl 2): S221–S225.
  9. Rayes A, McMasters RL, O'Brien MM. Lineage switch in MLL-rearranged infant leukemia following CD19-directed therapy. Pediatr Blood Cancer. 2016; 63(6): 1113–1115.
  10. Liu J, Zhong JF, Zhang Xi, et al. Allogeneic CD19-CAR-T cell infusion after allogeneic hematopoietic stem cell transplantation in B cell malignancies. J Hematol Oncol. 2017; 10(1): 35.
  11. Pastorczak A, Domka K, Fidyt K, et al. Mechanisms of immune evasion in acute lymphoblastic leukemia. Cancers (Basel). 2021; 13(7): 1536.
  12. Wei G, Wang J, Huang He, et al. Novel immunotherapies for adult patients with B-lineage acute lymphoblastic leukemia. J Hematol Oncol. 2017; 10(1): 150.
  13. First-ever CAR T-cell therapy approved in U.S. Cancer Discov. 2017; 7(10): OF1.
  14. Hong M, Clubb JD, Chen YY. Engineering CAR-T cells for next-generation cancer therapy. Cancer Cell. 2020; 38(4): 473–488.
  15. Gauthier J, Turtle CJ. Insights into cytokine release syndrome and neurotoxicity after CD19-specific CAR-T cell therapy. Curr Res Transl Med. 2018; 66(2): 50–52.
  16. Gauthier J, Turtle CJ. Chimeric antigen receptor T-cell therapy for B-cell acute lymphoblastic leukemia: current landscape in 2021. Cancer J. 2021; 27(2): 98–106.
  17. Witkowski MT, Lasry A, Carroll WL, et al. Immune-based therapies in acute leukemia. Trends Cancer. 2019; 5(10): 604–618.
  18. Oberley MJ, Gaynon PS, Bhojwani D, et al. Myeloid lineage switch following chimeric antigen receptor T-cell therapy in a patient with TCF3-ZNF384 fusion-positive B-lymphoblastic leukemia. Pediatr Blood Cancer. 2018; 65(9): e27265.
  19. Walker AJ, Majzner RG, Zhang L, et al. Tumor antigen and receptor densities regulate efficacy of a chimeric antigen receptor targeting anaplastic lymphoma kinase. Mol Ther. 2017; 25(9): 2189–2201.
  20. Gao Z, Tong C, Wang Y, et al. Blocking CD38-driven fratricide among T cells enables effective antitumor activity by CD38-specific chimeric antigen receptor T cells. J Genet Genomics. 2019; 46(8): 367–377.
  21. Chan CH, Wang J, French RR, et al. Internalization of the lymphocytic surface protein CD22 is controlled by a novel membrane proximal cytoplasmic motif. J Biol Chem. 1998; 273(43): 27809–27815.
  22. Du X, Beers R, Fitzgerald DJ, et al. Differential cellular internalization of anti-CD19 and -CD22 immunotoxins results in different cytotoxic activity. Cancer Res. 2008; 68(15): 6300–6305.
  23. Boross P, Leusen JHW. Mechanisms of action of CD20 antibodies. Am J Cancer Res. 2012; 2(6): 676–690.
  24. Lee JK, Bangayan NJ, Chai T, et al. Systemic surfaceome profiling identifies target antigens for immune-based therapy in subtypes of advanced prostate cancer. Proc Natl Acad Sci USA. 2018; 115(19): E4473–E4482.
  25. Nix MA, Mandal K, Geng H, et al. Surface proteomics reveals CD72 as a target for in vitro-evolved nanobody-based CAR-T cells in KMT2A/MLL1-rearranged B-ALL. Cancer Discov. 2021 [Epub ahead of print].
  26. Perna F, Berman SH, Soni RK, et al. Integrating proteomics and transcriptomics for systematic combinatorial chimeric antigen receptor therapy of AML. Cancer Cell. 2017; 32(4): 506–519.e5.
  27. Omasits U, Ahrens CH, Müller S, et al. Protter: interactive protein feature visualization and integration with experimental proteomic data. Bioinformatics. 2014; 30(6): 884–886.
  28. Wang K, Wei G, Liu D. CD19: a biomarker for B cell development, lymphoma diagnosis and therapy. Exp Hematol Oncol. 2012; 1(1): 36.
  29. Weiland J, Pal D, Case M, et al. BCP-ALL blasts are not dependent on CD19 expression for leukaemic maintenance. Leukemia. 2016; 30(9): 1920–1923.
  30. Kantarjian HM, Lioure B, Kim SK, et al. A phase II study of coltuximab ravtansine (SAR3419) monotherapy in patients with relapsed or refractory acute lymphoblastic leukemia. Clin Lymphoma Myeloma Leuk. 2016; 16(3): 139–145.
  31. Tian Z, Liu M, Zhang Ya, et al. Bispecific T cell engagers: an emerging therapy for management of hematologic malignancies. J Hematol Oncol. 2021; 14(1): 75.
  32. Locatelli F, Zugmaier G, Rizzari C, et al. Effect of blinatumomab vs chemotherapy on event-free survival among children with high-risk first-relapse b-cell acute lymphoblastic leukemia: a randomized clinical trial. JAMA. 2021; 325(9): 843–854.
  33. Ramdeny S, Chaudhary A, Worth A, et al. Activity of blinatumomab in lymphoblastic leukemia with impaired T-cell immunity due to congenital immunodeficiency. Blood Adv. 2021; 5(8): 2153–2155.
  34. Xu X, Sun Q, Liang X, et al. Mechanisms of relapse after CD19 CAR T-cell therapy for acute lymphoblastic leukemia and its prevention and treatment strategies. Front Immunol. 2019; 10: 2664.
  35. Zhylko A, Winiarska M, Graczyk-Jarzynka A. The great war of today: modifications of CAR-T cells to effectively combat malignancies. Cancers (Basel). 2020; 12(8): 2030.
  36. Sullivan-Chang L, O'Donnell RT, Tuscano JM. Targeting CD22 in B-cell malignancies: current status and clinical outlook. BioDrugs. 2013; 27(4): 293–304.
  37. Shan D, Press OW. Constitutive endocytosis and degradation of CD22 by human B cells. J Immunol. 1995; 154(9): 4466–4475.
  38. Boyerinas B, Zafrir M, Yesilkanal AE, et al. Adhesion to osteopontin in the bone marrow niche regulates lymphoblastic leukemia cell dormancy. Blood. 2013; 121(24): 4821–4831.
  39. O'Reilly MK, Tian H, Paulson JC. CD22 is a recycling receptor that can shuttle cargo between the cell surface and endosomal compartments of B cells. J Immunol. 2011; 186(3): 1554–1563.
  40. Uy N, Nadeau M, Stahl M, et al. Inotuzumab ozogamicin in the treatment of relapsed/refractory acute B cell lymphoblastic leukemia. J Blood Med. 2018; 9: 67–74.
  41. Aujla A, Aujla R, Liu D. Inotuzumab ozogamicin in clinical development for acute lymphoblastic leukemia and non-Hodgkin lymphoma. Biomark Res. 2019; 7: 9.
  42. Kantarjian HM, DeAngelo DJ, Advani AS, et al. Hepatic adverse event profile of inotuzumab ozogamicin in adult patients with relapsed or refractory acute lymphoblastic leukaemia: results from the open-label, randomised, phase 3 INO-VATE study. Lancet Haematol. 2017; 4(8): e387–e398.
  43. 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(1): 20–28.
  44. Haso W, Lee DW, Shah NN, et al. Anti-CD22-chimeric antigen receptors targeting B-cell precursor acute lymphoblastic leukemia. Blood. 2013; 121(7): 1165–1174.
  45. Tan Y, Cai H, Li C, et al. A novel full-human CD22-CAR T cell therapy with potent activity against CD22 B-ALL. Blood Cancer J. 2021; 11(4): 71.
  46. Velasco-Hernandez T, Zanetti SR, Roca-Ho H, et al. Efficient elimination of primary B-ALL cells in vitro and in vivo using a novel 4-1BB-based CAR targeting a membrane-distal CD22 epitope. J Immunother Cancer. 2020; 8(2): e000896.
  47. Shah NN, Highfill SL, Shalabi H, et al. CD4/CD8 T-cell selection affects chimeric antigen receptor (CAR) T-cell potency and toxicity: updated results from a phase i anti-CD22 CAR T-cell trial. J Clin Oncol. 2020; 38(17): 1938–1950.
  48. Singh N, Frey NV, Engels B, et al. Antigen-independent activation enhances the efficacy of 4-1BB-costimulated CD22 CAR T cells. Nat Med. 2021; 27(5): 842–850.
  49. Pavlasova G, Mraz M. The regulation and function of CD20: an "enigma" of B-cell biology and targeted therapy. Haematologica. 2020; 105(6): 1494–1506.
  50. Jeha S, Behm F, Pei D, et al. Prognostic significance of CD20 expression in childhood B-cell precursor acute lymphoblastic leukemia. Blood. 2006; 108(10): 3302–3304.
  51. Maury S, Huguet F, Leguay T, et al. Group for Research on Adult Acute Lymphoblastic Leukemia. Adverse prognostic significance of CD20 expression in adults with Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukemia. Haematologica. 2010; 95(2): 324–328.
  52. Maury S, Chevret S, Thomas X, et al. for GRAALL. Rituximab in B-lineage adult acute lymphoblastic leukemia. N Engl J Med. 2016; 375(11): 1044–1053.
  53. 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(5): 763–775.
  54. Martyniszyn A, Krahl AC, André MC, et al. CD20-CD19 bispecific CAR T cells for the treatment of B-cell malignancies. Hum Gene Ther. 2017; 28(12): 1147–1157.
  55. Giordano Attianese GM, Marin V, Hoyos V, et al. In vitro and in vivo model of a novel immunotherapy approach for chronic lymphocytic leukemia by anti-CD23 chimeric antigen receptor. Blood. 2011; 117(18): 4736–4745.
  56. Ormhøj M, Scarfò I, Cabral ML, et al. Chimeric antigen receptor t cells targeting cd79b show efficacy in lymphoma with or without cotargeting CD19. Clin Cancer Res. 2019; 25(23): 7046–7057.
  57. Scarfò I, Ormhøj M, Frigault MJ, et al. Anti-CD37 chimeric antigen receptor T cells are active against B- and T-cell lymphomas. Blood. 2018; 132(14): 1495–1506.
  58. Dong Z, Cheng WA, Smith DL, et al. Antitumor efficacy of BAFF-R targeting CAR T cells manufactured under clinic-ready conditions. Cancer Immunol Immunother. 2020; 69(10): 2139–2145.
  59. Ali SA, Shi V, Maric I, et al. T cells expressing an anti-B-cell maturation antigen chimeric antigen receptor cause remissions of multiple myeloma. Blood. 2016; 128(13): 1688–1700.
  60. Astsaturov IA, Matutes E, Morilla R, et al. Differential expression of B29 (CD79b) and mb-1 (CD79a) proteins in acute lymphoblastic leukaemia. Leukemia. 1996; 10(5): 769–773.
  61. Dogan A, Siegel D, Tran N, et al. B-cell maturation antigen expression across hematologic cancers: a systematic literature review. Blood Cancer J. 2020; 10(6): 73.
  62. Tsuganezawa K, Kiyokawa N, Matsuo Y, et al. Flow cytometric diagnosis of the cell lineage and developmental stage of acute lymphoblastic leukemia by novel monoclonal antibodies specific to human pre-B-cell receptor. Blood. 1998; 92(11): 4317–4324.
  63. Sevdali E, Katsantoni E, Smulski CR, et al. BAFF/APRIL system is functional in B-cell acute lymphoblastic leukemia in a disease subtype manner. Front Oncol. 2019; 9: 594.
  64. Harrer DC, Dörrie J, Schaft N. CSPG4 as target for CAR-T-cell therapy of various tumor entities-merits and challenges. Int J Mol Sci. 2019; 20(23): 5942.
  65. Prieto C, López-Millán B, Roca-Ho H, et al. NG2 antigen is involved in leukemia invasiveness and central nervous system infiltration in MLL-rearranged infant B-ALL. Leukemia. 2018; 32(3): 633–644.
  66. Lopez-Millan B, Sanchéz-Martínez D, Roca-Ho H, et al. NG2 antigen is a therapeutic target for MLL-rearranged B-cell acute lymphoblastic leukemia. Leukemia. 2019; 33(7): 1557–1569.
  67. Rippe C, Morén B, Liu Li, et al. NG2/CSPG4, CD146/MCAM and VAP1/AOC3 are regulated by myocardin-related transcription factors in smooth muscle cells. Sci Rep. 2021; 11(1): 5955.
  68. Li D, Hu Y, Jin Z, et al. TanCAR T cells targeting CD19 and CD133 efficiently eliminate MLL leukemic cells. Leukemia. 2018; 32(9): 2012–2016.
  69. Mak AB, Nixon AML, Moffat J. The mixed lineage leukemia (MLL) fusion-associated gene AF4 promotes CD133 transcription. Cancer Res. 2012; 72(8): 1929–1934.
  70. Bueno C, Velasco-Hernandez T, Gutiérrez-Agüera F, et al. CD133-directed CAR T-cells for MLL leukemia: on-target, off-tumor myeloablative toxicity. Leukemia. 2019; 33(8): 2090–2125.
  71. Rabilloud T, Potier D, Pankaew S, et al. Single-cell profiling identifies pre-existing CD19-negative subclones in a B-ALL patient with CD19-negative relapse after CAR-T therapy. Nat Commun. 2021; 12(1): 865.
  72. Schneider D, Xiong Y, Wu D, et al. Trispecific CD19-CD20-CD22-targeting duoCAR-T cells eliminate antigen-heterogeneous B cell tumors in preclinical models. Sci Transl Med. 2021; 13(586): eabc6401.
  73. Hu Y, Zhou Y, Zhang M, et al. CRISPR/Cas9-engineered universal CD19/CD22 dual-targeted CAR-T cell therapy for relapsed/refractory B-cell acute lymphoblastic leukemia. Clin Cancer Res. 2021; 27(10): 2764–2772.