Фармакоэкономический анализ терапии CAR Т-клетками при диффузной В-крупноклеточной лимфоме и В-линейных острых лимфобластных лейкозах

И.В. Грибкова, А.А. Завьялов

ГБУ «НИИ организации здравоохранения и медицинского менеджмента ДЗМ», ул. Шарикоподшипниковская, д. 9, Москва, Российская Федерация, 115088

Для переписки: Ирина Владимировна Грибкова, канд. биол. наук, ул. Шарикоподшипниковская, д. 9, Москва, Российская Федерация, 115088; тел.: +7(916)078-73-90; e-mail: igribkova@yandex.ru

Для цитирования: Грибкова И.В., Завьялов А.А. Фармакоэкономический анализ терапии CAR Т-клетками при диффузной В-крупноклеточной лимфоме и В-линейных острых лимфобластных лейкозах. Клиническая онкогематология. 2022;15(2):205–12.

DOI: 10.21320/2500-2139-2022-15-2-205-212


РЕФЕРАТ

Генетически модифицированные Т-лимфоциты с химерными антигенными рецепторами (CAR T-клетки) представляют собой новую стратегию лечения пациентов с рецидивами или рефрактерным течением В-клеточных злокачественных новообразований. В 2017–2018 гг. два препарата CAR T-клеточной терапии: тисагенлеклейсел и аксикабтаген силолейсел — были одобрены Управлением по контролю за качеством пищевых продуктов и лекарственных средств США (FDA) и Европейским агентством по лекарственным средствам (EMA) для клинического применения у пациентов с рефрактерным острым лимфобластным лейкозом и рецидивами/рефрактерными В-клеточными лимфомами. К настоящему времени CAR Т-клеточная терапия все более становится неотъемлемой частью клинической практики благодаря своей высокой эффективности. Однако стоимость этого метода противоопухолевого воздействия чрезвычайно высока. Средняя стоимость тисагенлеклейсела составляет 475 000 долларов США ($), а аксикабтагена силолейсела — 373 000 $. Следует отметить, что это только цены на лекарственные препараты без учета других затрат, связанных с данным методом терапии. В работах 2018–2020 гг. группы исследователей предприняли попытки оценить затраты, связанные с CAR T-клеточной терапией. Цель настоящего обзора — анализ этих исследований, оценка общей стоимости терапии и структуры затрат, рассмотрение факторов, ведущих к увеличению затрат, обсуждение возможности повышения доступности технологии CAR-T в целом. Результаты показали, что в среднем общая стоимость терапии тисагенлеклейселом при В-клеточной лимфоме составила 515 150 $, аксикабтагеном силолейселом — 503 955 $. Стоимость терапии острого лимфобластного лейкоза составила 580 459 $. Основными факторами, влияющими на общую стоимость лечения, были цены на препараты CAR T-клеток, высокая степень тяжести нежелательных явлений и большая опухолевая нагрузка до инфузии CAR T-клеточного продукта. Признается, что в качестве основных возможностей повышения доступности терапии CAR T-клетками может служить понижение цены на препараты (например, за счет собственного производства на базе медицинского учреждения), дальнейшее совершенствование терапии с целью снизить ее токсичность, а также применение на ранних стадиях опухолевого заболевания.

Ключевые слова: В-клеточная лимфома, острый лимфобластный лейкоз, CAR T-клеточная терапия, химерный антигенный рецептор, тисагенлеклейсел, аксикабтаген силолейсел, затраты, обзор.

Получено: 29 октября 2021 г.

Принято в печать: 15 февраля 2022 г.

Читать статью в PDF

Статистика Plumx русский

ЛИТЕРАТУРА

  1. Crump M, Neelapu SS, Farooq U, et al. Outcomes in refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study. Blood. 2017;130(16):1800–8. doi: 10.1182/blood-2017-03-769620.
  2. Topp MS, Gokbuget N, Stein AS, et al. Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study. Lancet Oncol. 2015;16(1):57–66. doi: 10.1016/S1470-2045(14)71170-2.
  3. Roex G, Feys T, Beguin Y, et al. Chimeric Antigen Receptor-T-Cell Therapy for B-Cell Hematological Malignancies: An Update of the Pivotal Clinical Trial Data. Pharmaceutics. 2020;12(2):194. doi: 10.3390/pharmaceutics12020194.
  4. Zheng XH, Zhang XY, Dong QQ, et al. Efficacy and safety of chimeric antigen receptor-T cells in the treatment of B cell lymphoma: a systematic review and meta-analysis. Chin Med J (Engl). 2020;133(1):74–85. doi: 10.1097/CM9.0000000000000568.
  5. Ершов А.В., Демьянов Г.В., Насруллаева Д.А. и др. Новейшие тенденции в совершенствовании CAR-T-клеточной терапии: от лейкозов к солидным злокачественным новообразованиям. Российский журнал детской гематологии и онкологии. 2021;8(2):84–95. doi: 10.21682/2311-1267-2021-8-2-84-95.
    [Ershov AV, Demyanov GV, Nasrullaeva DA, et al. The latest trends in improving CAR-T cell therapy: from leukemias to solid malignant neoplasms. Russian Journal of Pediatric Hematology and Oncology. 2021;8(2):84–95. doi: 10.21682/2311-1267-2021-8-2-84-95. (In Russ)]
  6. Грибкова И.В., Завьялов А.А. CAR Т-клетки для лечения хронического лимфоцитарного лейкоза: обзор литературы. Клиническая онкогематология. 2021;14(2):225–30. doi: 10.21320/2500-2139-2021-14-2-225-230.
    [Gribkova IV, Zavyalov CAR-Т Cells for the Treatment of Chronic Lymphocytic Leukemia: Literature Review. Clinical oncohematology. 2021;14(2):225–30. doi: 10.21320/2500-2139-2021-14-2-225-230. (In Russ)]
  7. Грибкова И.В., Завьялов А.А. Терапия Т-лимфоцитами с химерным антигенным рецептором (CAR) В-клеточной неходжкинской лимфомы: возможности и проблемы. Вопросы онкологии. 2021;67(3):350–60. doi: 10.37469/0507-3758-2021-67-3-350-360.
    [Gribkova IV, Zavyalov AA. Chimeric Antigen Receptor T-Cell Therapy for B-Cell Non-Hodgkin Lymphoma: Opportunities And Challenges. Voprosy onkologii. 2021;67(3):350–60. doi: 10.37469/0507-3758-2021-67-3-350-360. (In Russ)]
  8. Orlowski RJ, Porter DL, Frey NV. The promise of chimeric antigen receptor T cells (CARTs) in leukaemia. Br J Haematol. 2017;177(1):13–26. doi: 10.1111/bjh.14475.
  9. Park JH, Riviere I, Gonen M, et al. Long-Term Follow-up of CD19 CAR Therapy in Acute Lymphoblastic Leukemia. N Engl J Med. 2018;378(5):449–59. doi: 10.1056/NEJMoa1709919.
  10. 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(5):439–48. doi: 10.1056/NEJMoa1709866.
  11. 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(26):2531–44. doi: 10.1056/NEJMoa1707447.
  12. Schuster SJ, Bishop MR, Tam CS, et al. Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B-Cell Lymphoma. N Engl J Med. 2019;380(1):45–56. doi: 10.1056/NEJMoa1804980.
  13. Locke FL, Ghobadi A, Jacobson CA, et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1–2 trial. Lancet Oncol. 2019;20:31–42. doi: 10.1016/S1470-2045(18)30864-7.
  14. Bach PB, Giralt SA, Saltz LB. FDA Approval of Tisagenlecleucel: Promise and Complexities of a $475 000 Cancer Drug. JAMA. 2017;318(19):1861–2. doi: 10.1001/jama.2017.15218.
  15. Nastoupil LJ, Jain MD, Feng L, et al. Standard-of-Care Axicabtagene Ciloleucel for Relapsed or Refractory Large B-Cell Lymphoma: Results From the US Lymphoma CAR T Consortium. J Clin Oncol. 2020;38(27):3119–28. doi: 10.1200/JCO.19.02104.
  16. de Lima Lopes G, Nahas GR. Chimeric antigen receptor T cells, a savior with a high price. Chin Clin Oncol. 2018;7(2):21. doi: 10.21037/cco.2018.04.02.
  17. Makita S, Imaizumi K, Kurosawa S, Tobinai K. Chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma: opportunities and challenges. Drugs Context. 2019;8:212567. doi: 10.7573/dic.212567.
  18. Yakoub-Agha I, Chabannon C, Bader P, et al. Management of adults and children undergoing chimeric antigen receptor T-cell therapy: best practice recommendations of the European Society for Blood and Marrow Transplantation (EBMT) and the Joint Accreditation Committee of ISCT and EBMT (JACIE). Haematologica. 2020;105(2):297–316. doi: 10.3324/haematol.2019.229781.
  19. Lyman GH, Nguyen A, Snyder S, et al. Economic Evaluation of Chimeric Antigen Receptor T-Cell Therapy by Site of Care Among Patients With Relapsed or Refractory Large B-Cell Lymphoma. JAMA Netw Open. 2020;3(4):e202072. doi: 10.1001/jamanetworkopen.2020.2072.
  20. Lin JK, Muffly LS, Spinner MA, et al. Cost Effectiveness of Chimeric Antigen Receptor T-Cell Therapy in Multiply Relapsed or Refractory Adult Large B-Cell Lymphoma. J Clin Oncol. 2019;37(24):2105–19. doi: 10.1200/JCO.18.02079.
  21. Harris AH, Hohmann S, Dolan C. Real-World Quality and Cost Burden of Cytokine Release Syndrome Requiring Tocilizumab or Steroids during CAR-T Infusion Encounter. Biol Blood Marrow Transplant. 2020;26(3):S312. doi: 10.1016/j.bbmt.2019.12.389.
  22. Hernandez I, Prasad V, Gellad WF. Total Costs of Chimeric Antigen Receptor T-Cell Immunotherapy. JAMA Oncol. 2018;4(7):994–6. doi: 10.1001/jamaoncol.2018.0977.
  23. Roth JA, Sullivan SD, Lin VW, et al. Cost-effectiveness of axicabtagene ciloleucel for adult patients with relapsed or refractory large B-cell lymphoma in the United States. J Med Econ. 2018;21(12):1238–45. doi: 10.1080/13696998.2018.1529674.
  24. Whittington MD, McQueen RB, Ollendorf DA, et al. Long-term Survival and Cost-effectiveness Associated With Axicabtagene Ciloleucel vs Chemotherapy for Treatment of B-Cell Lymphoma. JAMA Netw Open. 2019;2(2):e190035. doi: 10.1001/jamanetworkopen.2019.0035.
  25. Sarkar RR, Gloude NJ, Schiff D, Murphy JD. Cost-Effectiveness of Chimeric Antigen Receptor T-Cell Therapy in Pediatric Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia. J Natl Cancer Inst. 2019;111(7):719–26. doi: 10.1093/jnci/djy193.
  26. Thielen FW, van Dongen-Leunis A, Arons AMM, et al. Cost-effectiveness of anti-CD19 chimeric antigen receptor T-cell therapy in pediatric relapsed/refractory B-cell acute lymphoblastic leukemia. A societal view. Eur J Haematol. 2020;105(2):203–15. doi: 10.1111/ejh.13427.
  27. Yang H, Hao Y, Qi CZ, et al. Estimation of Total Costs in Pediatric and Young Adult Patients with Relapsed or Refractory Acute Lymphoblastic Leukemia Receiving Tisagenlecleucel from a U.S. Hospital’s Perspective. J Manag Care Spec Pharm. 2020;26(8):971–80. doi: 10.18553/jmcp.2020.20052.
  28. Lin JK, Lerman BJ, Barnes JI, et al. Cost Effectiveness of Chimeric Antigen Receptor T-Cell Therapy in Relapsed or Refractory Pediatric B-Cell Acute Lymphoblastic Leukemia. J Clin Oncol. 2018;36(32):3192–202. doi: 10.1200/JCO.2018.79.0642.
  29. Whittington MD, McQueen RB, Ollendorf DA, et al. Long-term Survival and Value of Chimeric Antigen Receptor T-Cell Therapy for Pediatric Patients With Relapsed or Refractory Leukemia. JAMA Pediatr. 2018;172(12):1161–8. doi: 10.1001/jamapediatrics.2018.2530.
  30. Furzer J, Gupta S, Nathan PC, et al. Cost-effectiveness of Tisagenlecleucel vs Standard Care in High-risk Relapsed Pediatric Acute Lymphoblastic Leukemia in Canada. JAMA Oncol. 2020;6(3):393–401. doi: 10.1001/jamaoncol.2019.5909.
  31. Zhu F, Wei G, Zhang M, et al. Factors Associated with Costs in Chimeric Antigen Receptor T-Cell Therapy for Patients with Relapsed/Refractory B-Cell Malignancies. Cell Transplant. 2020;29:963689720919434. doi: 10.1177/0963689720919434.
  32. Heine R, Thielen FW, Koopmanschap M, et al. Health Economic Aspects of Chimeric Antigen Receptor T-cell Therapies for Hematological Cancers: Present and Future. Hemasphere. 2021;5(2):e524. doi: 10.1097/HS9.0000000000000524.
  33. Zhang LN, Song Y, Liu D. CD19 CAR-T cell therapy for relapsed/refractory acute lymphoblastic leukemia: factors affecting toxicities and long-term efficacies. J Hematol Oncol. 2018;11(1):41. doi: 10.1186/s13045-018-0593-5.
  34. Brudno JN, Kochenderfer JN. Toxicities of chimeric antigen receptor T cells: recognition and management. Blood. 2016;127(26):3321–30. doi: 10.1182/blood-2016-04-703751.
  35. Kochenderfer JN, Somerville RPT, Lu T, et al. Lymphoma remissions caused by anti-CD19 chimeric antigen receptor T cells are associated with high serum interleukin-15 levels. J Clin Oncol. 2017;35(16):1803–13. doi: 10.1200/JCO.2016.71.3024.
  36. Lee DW, Gardner R, Porter DL, et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood. 2014;124(2):188–95. doi: 10.1182/blood-2014-05-552729.
  37. Ran T, Eichmuller SB, Schmidt P, Schlander M. Cost of decentralized CAR T-cell production in an academic nonprofit setting. Int J Cancer. 2020;147(12):3438–45. doi: 10.1002/ijc.33156.
  38. Abramson JS, Palomba ML, Gordon LI, et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Lancet. 2020;396(10254):839–52. doi: 10.1016/S0140-6736(20)31366-0.
  39. Benjamin R, Graham C, Yallop D, et al. Genome-edited, donor-derived allogeneic anti-CD19 chimeric antigen receptor T cells in paediatric and adult B-cell acute lymphoblastic leukaemia: results of two phase 1 studies. Lancet. 2020;396(10266):1885–94. doi: 10.1016/S0140-6736(20)32334-5.
  40. Pfeiffer A, Thalheimer FB, Hartmann S, et al. In vivo generation of human CD19-CAR T cells results in B-cell depletion and signs of cytokine release syndrome. EMBO Mol Med. 2018;10(11):e9158. doi: 10.15252/emmm.201809158.
  41. Jones BS, Lamb LS, Goldman F, Di Stasi A. Improving the safety of cell therapy products by suicide gene transfer. Front Pharmacol. 2014;5:254. doi: 10.3389/fphar.2014.00254.
  42. Wu CY, Roybal KT, Puchner EM, et al. Remote control of therapeutic T cells through a small molecule-gated chimeric receptor. Science. 2015;350(6258):aab4077. doi: 10.1126/science.aab4077.
  43. Mikkilineni L, Kochenderfer JN. CAR T cell therapies for patients with multiple myeloma. Nat Rev Clin Oncol. 2021;18(2):71–84. doi: 10.1038/s41571-020-0427-6.
  44. Strati P, Ahmed S, Furqan F, et al. Prognostic impact of corticosteroids on efficacy of chimeric antigen receptor T-cell therapy in large B-cell lymphoma. Blood. 2021;137(23):3272–6. doi: 10.1182/blood.2020008865.
  45. Gauthier J, Hirayama AV, Hay KA, et al. Comparison of efficacy and toxicity of CD19-specific chimeric antigen receptor T-cells alone or in combination with ibrutinib for relapsed and/or refractory CLL. Blood. 2018;132(Suppl 1):299. doi: 10.1182/blood-2018-99-111061.
  46. Gill SI, Vides V, Frey NV, et al. Prospective clinical trial of anti-CD19 CAR T cells in combination with ibrutinib for the treatment of chronic lymphocytic leukemia shows a high response rate. Blood. 2018;132(Suppl 1):298. doi: 10.1182/blood-2018-99-115418.

CAR Т-клетки для лечения хронического лимфоцитарного лейкоза: обзор литературы

И.В. Грибкова, А.А. Завьялов

ГБУ «НИИ организации здравоохранения и медицинского менеджмента ДЗМ», ул. Шарикоподшипниковская, д. 9, Москва, Российская Федерация, 115088

Для переписки: Ирина Владимировна Грибкова, канд. биол. наук, ул. Шарикоподшипниковская, д. 9, Москва, Российская Федерация, 115088; тел.: +7(916)078-73-90; e-mail: igribkova@yandex.ru

Для цитирования: Грибкова И.В., Завьялов А.А. CAR Т-клетки для лечения хронического лимфоцитарного лейкоза: обзор литературы. Клиническая онкогематология. 2021;14(2):225–30.

DOI: 10.21320/2500-2139-2021-14-2-225-230


РЕФЕРАТ

Хронический лимфоцитарный лейкоз (ХЛЛ) является наиболее распространенным злокачественным лимфоидным заболеванием взрослых. Несмотря на появление новых высокоэффективных таргетных препаратов, прогноз у больных с рецидивами и резистентной формой заболевания остается неблагоприятным. CAR Т-клеточная терапия, предполагающая использование Т-лимфоцитов с химерным антигенным рецептором (CAR), продемонстрировала свою эффективность в лечении ряда онкогематологических заболеваний, таких как В-клеточные неходжкинские лимфомы и острый лимфобластный лейкоз. В настоящем обзоре литературы рассматривается опыт применения CAR Т-клеток для лечения ХЛЛ. Представлены преимущества и недостатки данной технологии, а также проблемы, которые еще предстоит решить для внедрения метода в широкую клиническую практику.

Ключевые слова: хронический лимфоцитарный лейкоз, CAR T-клеточная терапия, химерный антигенный рецептор, адоптивная терапия, иммунотерапия.

Получено: 15 декабря 2020 г.

Принято в печать: 10 марта 2021 г.

Читать статью в PDF

Статистика Plumx русский

ЛИТЕРАТУРА

  1. Hallek M. Chronic lymphocytic leukemia: 2017 update on diagnosis, risk stratification, and treatment. Am J Hematol. 2017;92(9):946–65. doi: 10.1002/ajh.24826.
  2. Fernandez-Martinez JL, de Andres-Galiana EJ, Sonis ST. Genomic data integration in chronic lymphocytic leukemia. J Gene Med. 2017;19(1–2):e2936. doi: 10.1002/jgm.2936.
  3. Kipps TJ, Stevenson FK, Wu CJ, et al. Chronic lymphocytic leukaemia. Nat Rev Dis Primers. 2017;3(1):16096. doi: 10.1038/nrdp.2016.96.
  4. Byrd JC, Brown JR, O’Brien S, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371(3):213–23. doi: 10.1056/NEJMoa1400376.
  5. Roberts AW, Davids MS, Pagel JM, et al. Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia. N Engl J Med. 2016;374(4):311–22. doi: 10.1056/NEJMoa1513257.
  6. Bottcher S, Ritgen M, Fischer K, et al. Minimal residual disease quantification is an independent predictor of progression-free and overall survival in chronic lymphocytic leukemia: a multivariate analysis from the randomized GCLLSG CLL8 trial. J Clin Oncol. 2012;30(9):980–8. doi: 10.1200/JCO.2011.36.9348.
  7. Strati P, Keating MJ, O’Brien SM, et al. Outcomes of first-line treatment for chronic lymphocytic leukemia with 17p deletion. Haematologica. 2014;99(8):1350–5. doi: 10.3324/haematol.2014.104661.
  8. Mato AR, Nabhan C, Barr PM, et al. Outcomes of CLL patients treated with sequential kinase inhibitor therapy: a real world experience. Blood. 2016;128(18):2199–205. doi: 10.1182/blood-2016-05-716977.
  9. Anderson MA, Tam C, Lew TE, et al. Clinicopathological features and outcomes of progression of CLL on the BCL2 inhibitor venetoclax. Blood. 2017;129(25):3362–70. doi: 10.1182/blood-2017-01-763003.
  10. Dreger P, Schetelig J, Andersen N, et al. Managing high-risk CLL during transition to a new treatment era: Stem cell transplantation or novel agents? 2014;124(26):3841–9. doi: 10.1182/blood-2014-07-586826.
  11. June CH, O’Connor RS, Kawalekar OU, et al. CAR T cell immunotherapy for human cancer. 2018;359(6382):1361–5. doi: 10.1126/science.aar6711.
  12. Грибкова И.В., Завьялов А.А. Терапия Т-лимфоцитами с химерным антигенным рецептором (CAR) В-клеточной неходжкинской лимфомы: возможности и проблемы. Вопросы онкологии. 2021. В печати.
    [Gribkova IV, Zav’yalov AA. Chimeric antigen receptor T‑cell therapy of B-cell non-Hodgkin’s lymphoma: opportunities and challenges. Voprosy onkologii. 2021. In print. (In Russ)]
  13. Porter DL, Levine BL, Kalos M, et al. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med. 2011;365(8):725–33. doi: 10.1056/NEJMoa1103849.
  14. Forconi F, Moss P. Perturbation of the normal immune system in patients with CLL. Blood. 2015;126(5):573–81. doi: 10.1182/blood-2015-03-567388.
  15. Pourgheysari B, Bruton R, Parry H, et al. The number of cytomegalovirus-specific CD4+ T cells is markedly expanded in patients with B-cell chronic lymphocytic leukemia and determines the total CD4+ T-cell repertoire. 2010;116(16):2968–74. doi: 10.1182/blood-2009-12-257147.
  16. Palma M, Gentilcore G, Heimersson K, et al. T cells in chronic lymphocytic leukemia display dysregulated expression of immune checkpoints and activation markers. 2017;102(3):562–72. doi: 10.3324/haematol.2016.151100.
  17. Riches JC, Davies JK, McClanahan F, et al. T cells from CLL patients exhibit features of T-cell exhaustion but retain capacity for cytokine production. Blood. 2013;121(9):1612–21. doi: 10.1182/blood-2012-09-457531.
  18. Ramsay AG, Clear AJ, Fatah R, Gribben JG. Multiple inhibitory ligands induce impaired T-cell immunologic synapse function in chronic lymphocytic leukemia that can be blocked with lenalidomide: Establishing a reversible immune evasion mechanism in human cancer. Blood. 2012;120(7):1412–21. doi: 10.1182/blood-2012-02-411678.
  19. D’Arena G, Laurenti L, Minervini MM, et al. Regulatory T-cell number is increased in chronic lymphocytic leukemia patients and correlates with progressive disease. Leuk Res. 2011;35(3):363–8. doi: 10.1016/j.leukres.2010.08.010.
  20. Gorgun G, Holderried TA, Zahrieh D, et al. Chronic lymphocytic leukemia cells induce changes in gene expression of CD4 and CD8 T cells. J Clin Invest. 2005;115(7):1797–805. doi: 10.1172/JCI24176.
  21. Piper KP, Karanth M, McLarnon A, et al. Chronic lymphocytic leukaemia cells drive the global CD4+ T cell repertoire towards a regulatory phenotype and leads to the accumulation of CD4+ forkhead box P3+ T cells. Clin Exp Immunol. 2011;166(2):154–63. doi: 10.1111/j.1365-2249.2011.04466.x.
  22. Brentjens RJ, Riviere I, Park JH, et al. Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias. Blood. 2011;118(18):4817–28. doi: 10.1182/blood-2011-04-348540.
  23. Kalos M, Levine BL, Porter DL, et al. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med. 2011;3(95):95ra73. doi: 10.1126/scitranslmed.3002842.
  24. Kochenderfer JN, Dudley ME, Feldman SA, et al. B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor-transduced T cells. 2012;119(12):2709–20. doi: 10.1182/blood-2011-10-384388.
  25. Cruz CRY, Micklethwaite KP, Savoldo B, et al. Infusion of donor-derived CD19-redirected virus-specific T cells for B-cell malignancies relapsed after allogeneic stem cell transplant: a phase 1 study. Blood. 2013;122(17):2965–73. doi: 10.1182/blood-2013-06-506741.
  26. Kochenderfer JN, Dudley ME, Kassim SH, et al. Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. J Clin Oncol. 2015;33(6):540–9. doi: 10.1200/JCO.2014.56.2025.
  27. Porter DL, Hwang W-T, Frey NV, et al. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med. 2015;7(303):303ra139. doi: 10.1126/scitranslmed.aac5415.
  28. Fraietta JA, Beckwith KA, Patel PR, et al. Ibrutinib enhances chimeric antigen receptor T-cell engraftment and efficacy in leukemia. 2016;127(9):1117–27. doi: 10.1182/blood-2015-11-679134.
  29. Brudno JN, Somerville RPT, Shi V, et al. Allogeneic T cells that express an anti-CD19 chimeric antigen receptor induce remissions of B-cell malignancies that progress after allogeneic hematopoietic stem-cell transplantation without causing graft-versus-host disease. J Clin Oncol. 2016;34(10):1112–21. doi: 10.1200/JCO.2015.64.5929.
  30. Ramos CA, Savoldo B, Torrano V, et al. Clinical responses with T lymphocytes targeting malignancy-associated κ light chains. J Clin Invest. 2016;126(7):2588–96. doi: 10.1172/JCI86000.
  31. Turtle CJ, Hay KA, Hanafi L-A, et al. Durable molecular remissions in chronic lymphocytic leukemia treated with CD19-specific chimeric antigen receptor-modified T cells after failure of ibrutinib. J Clin Oncol. 2017;35(26):3010–20. doi: 10.1200/JCO.2017.72.8519.
  32. Geyer MB, Riviere I, Senechal B, et al. Autologous CD19-targeted CAR T cells in patients with residual CLL following initial purine analog-based therapy. Mol Ther J Am Soc Gene Ther. 2018;26(8):1896–905. doi: 10.1016/j.ymthe.2018.05.018.
  33. Gauthier J, Hirayama AV, Hay KA, et al. Comparison of efficacy and toxicity of CD19-specific chimeric antigen receptor T-cells alone or in combination with ibrutinib for relapsed and/or refractory CLL. Blood. 2018;132(Suppl 1):299. doi: 1182/blood-2018-99-111061.
  34. Gill SI, Vides V, Frey NV, et al. Prospective clinical trial of anti-CD19 CAR T cells in combination with ibrutinib for the treatment of chronic lymphocytic leukemia shows a high response rate. Blood. 2018;132(Suppl 1):298. doi: 10.1182/blood-2018-99-115418.
  35. Siddiqi T, Soumerai JD, Wierda WG, et al. Rapid MRD-negative responses in patients with relapsed/refractory CLL treated with Liso-Cel, a CD19-directed CAR T-cell product: preliminary results from transcend CLL 004, a phase 1/2 study including patients with high-risk disease previously treated with ibrutinib. Blood. 2018;132(Suppl 1):300. doi: 10.1182/blood-2018-99-110462.
  36. Geyer MB, Riviere I, Senechal B, et al. Safety and tolerability of conditioning chemotherapy followed by CD19-targeted CAR T cells for relapsed/refractory CLL. JCI Insight. 2019;4(9):e122627. doi: 10.1172/jci.insight.122627.
  37. Fraietta JA, Lacey SF, Orlando EJ, et al. Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia. Nat Med. 2018;24(5):563–71. doi: 10.1038/s41591-018-0010-1.
  38. Porter DL, Frey NV, Melenhorst JJ, et al. Randomized, phase II dose optimization study of chimeric antigen receptor modified T cells directed against CD19 (CTL019) in patients with relapsed, refractory CLL. Blood. 2014;124(21):1982. doi: 10.1182/blood.V124.21.1982.1982.
  39. Porter DL, Frey NV, Melenhorst JJ, et al. Randomized, phase II dose optimization study of chimeric antigen receptor (CAR) modified T cells directed against CD19 in patients (pts) with relapsed, refractory (R/R) CLL. J Clin Oncol. 2016;34(15_Suppl):3009. doi: 10.1200/JCO.2016.34.15_suppl.3009.
  40. Hofland T, Eldering E, Kater AP, Tonino SH. Engaging Cytotoxic T and NK Cells for Immunotherapy in Chronic Lymphocytic Leukemia. Int J Mol Sci. 2019;20(17):4315. doi: 10.3390/ijms20174315.
  41. Zou Y, Xu W, Li J. Chimeric antigen receptor-modified T cell therapy in chronic lymphocytic leukemia. J Hematol Oncol. 2018;11(1):130. doi: 10.1186/s13045-018-0676-3.
  42. Bair SM, Porter DL. Accelerating chimeric antigen receptor therapy in chronic lymphocytic leukemia: The development and challenges of chimeric antigen receptor T-cell therapy for chronic lymphocytic leukemia. Am J Hematol. 2019;94(Suppl 1):S10–S17. doi: 10.1002/ajh.25457.
  43. Gattinoni L, Finkelstein SE, Klebanoff CA, et al. Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells. J Exp Med. 2005;202(7):907–12. doi: 10.1084/jem.20050732.
  44. Dudley ME, Wunderlich JR, Yang JC, et al. Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin Oncol. 2005;23(10):2346–57. doi: 10.1200/JCO.2005.00.240.
  45. Yin Q, Sivina M, Robins H, et al. Ibrutinib therapy increases T cell repertoire diversity in patients with chronic lymphocytic leukemia. J Immunol. 2017;198(4):1740–7. doi: 10.4049/jimmunol.1601190.
  46. Geyer MB, Park JH, Riviere I, et al. Implications of concurrent ibrutinib therapy on CAR T cell manufacturing and phenotype and on clinical outcomes following CD19-targeted CAR T cell administration in adults with relapsed/refractory CLL. Blood. 2016;128(22):58. doi: 10.1182/blood.V128.22.58.58.
  47. Golubovskaya V, Wu L. Different subsets of T cells, memory, effector functions, and CAR-T immunotherapy. Cancers (Basel). 2016;8(3):36. doi: 10.3390/cancers8030036.
  48. Hoffmann JM, Schubert ML, Wang L, et al. Differences in expansion potential of naive chimeric antigen receptor T cells from healthy donors and untreated chronic lymphocytic leukemia patients. Front Immunol. 2018;8: doi: 10.3389/fimmu.2017.01956.
  49. Sommermeyer D, Hudecek M, Kosasih PL, et al. Chimeric antigen receptor-modified T cells derived from defined CD8+ and CD4+ subsets confer superior antitumor reactivity in vivo. Leukemia. 2016;30(2):492–500. doi: 10.1038/leu.2015.247.
  50. Hill JA, Li D, Hay KA, et al. Infectious complications of CD19-targeted chimeric antigen receptor-modified T-cell immunotherapy. Blood. 2018;131(1):121–30. doi: 10.1182/blood-2017-07-793760.
  51. Hay KA, Hanafi LA, Li D, et al. Kinetics and biomarkers of severe cytokine release syndrome after CD19 chimeric antigen receptor-modified T-cell therapy. Blood. 2017;130(21):2295–306. doi: 10.1182/blood-2017-06-793141.
  52. Gust J, Hay KA, Hanafi LA, et al. Endothelial activation and blood-brain barrier disruption in neurotoxicity after adoptive immunotherapy with CD19 CAR-T cells. Cancer Discov. 2017;7(12):1404–19. doi: 10.1158/2159-8290.CD-17-0698.
  53. Davila ML, Riviere I, Wang X, et al. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med. 2014;6(224):224ra25. doi: 10.1126/scitranslmed.3008226.
  54. Maude SL, Frey N, Shaw PA, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371(16):1507–17. doi: 10.1056/NEJMoa1407222.
  55. Neelapu SS, Tummala S, Kebriaei P, et al. Chimeric antigen receptor T-cell therapy – assessment and management of toxicities. Nat Rev Clin Oncol. 2018;15(1):47–62. doi: 10.1038/nrclinonc.2017.148.

Клеточный препарат с химерным антигенным рецептором NKG2D в CAR T-терапии рецидивов/рефрактерных острых миелоидных лейкозов и миелодиспластического синдрома

К.A. Левчук1, Е.В. Белоцерковская1,2, Д.Ю. Поздняков1, Л.Л. Гиршова1, А.Ю. Зарицкий1, А.В. Петухов1,2,3

1 ФГБУ «НМИЦ им. В.А. Алмазова» Минздрава России, ул. Аккуратова, д. 2, Санкт-Петербург, Российская Федерация, 197341

2 ФГБУН «Институт цитологии РАН», Тихорецкий пр-т, д. 4, Санкт-Петербург, Российская Федерация, 194064

3 НТУ «Сириус», Олимпийский пр-т, д. 1, Сочи, Российская Федерация, 354340

Для переписки: Ксения Александровна Левчук, ул. Аккуратова, д. 2, Санкт-Петербург, Российская Федерация, 197341; e-mail: levchuk_ka@almazovcentre.ru

Для цитирования: Левчук К.A., Белоцерковская Е.В., Поздняков Д.Ю. и др. Клеточный препарат с химерным антигенным рецептором NKG2D в CAR T-терапии рецидивов/рефрактерных острых миелоидных лейкозов и миелодиспластического синдрома. Клиническая онкогематология. 2021;14(1):138–48.

DOI: 10.21320/2500-2139-2021-14-1-138-148 


РЕФЕРАТ

NK-клетки как элементы врожденного иммунитета реализуют ключевые реакции противоопухолевого иммунного ответа. NKG2D — активационный трансмембранный рецептор NK-клеток, ответственный за инициацию цитотоксичности в ответ на связывание специфичных лигандов генетически модифицированных клеток. Селективная экспрессия лигандов NKG2D открывает уникальные перспективы для терапии широкого спектра опухолей. Острые миелоидные лейкозы (ОМЛ) — это злокачественные опухоли системы крови, характеризующиеся высоким риском развития рецидивов. Сложность терапевтической стратегии при ОМЛ создает необходимость поиска новых подходов к элиминации опухоли с применением инновационных генетических конструкций. Имеющиеся к настоящему времени CAR T-клеточные препараты, несущие рецептор NKG2D, успешно изучаются в клинических исследованиях у пациентов с ОМЛ, доказывая свой высокий терапевтический потенциал.

Ключевые слова: острые миелоидные лейкозы, химерный антигенный рецептор, адоптивная терапия, NKG2D, NK-клетки.

Получено: 22 августа 2020 г.

Принято в печать: 5 декабря 2020 г.

Читать статью в PDF

Статистика Plumx русский

ЛИТЕРАТУРА

  1. Arber D, Orazi A, Hasserjian R. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391–405. doi: 10.1182/blood-2016-03-643544.
  2. Bullinger L, Dohner K, Dohner H. Genomics of Acute Myeloid Leukemia Diagnosis and Pathways. J Clin Oncol. 2017;35(9):934–46. doi: 10.1200/JCO.2016.71.2208.
  3. The Leukemia & Lymphoma Society Updated data on blood cancers. Facts 2018–2019. Available from: https://www.lls.org/facts-and-statistics/facts-and-statistics-overview/facts-and-statistics (accessed 30.11.2020).
  4. Dohner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. 2017;129(4):424–47. doi: 10.1182/blood-2016-08-733196.
  5. Herold T, Rothenberg-Thurley M, Grunwald VV, et al. Validation and refinement of the revised 2017 European LeukemiaNet genetic risk stratification of acute myeloid leukemia Leukemia. [published online ahead of print, 2020 Mar 30] doi: 10.1038/s41375-020-0806-0.
  6. Estey EH, Schrier SL. Prognosis of the myelodysplastic syndromes in adults. UpToDate. 2017. Available from: https://www.uptodate.com/contents/prognosis-of-the-myelodysplastic-syndromes-in-adults (accessed 28.11.2020).
  7. Tallman MS, Gilliland DG, Rowe JM. Drug therapy for acute myeloid leukemia. 2005;106(4):1154–63. doi: 10.1182/blood-2005-01-0178.
  8. Burnett AK, Milligan D, Goldstone A, et al. The impact of dose escalation and resistance modulation in older patients with acute myeloid leukemia and high risk myelodysplastic syndrome: the results of the LRF AML14 trial. Br J Haematol. 2009;145(3):318–32. doi: 10.1111/j.1365-2141.2009.07604.x.
  9. Lowenberg G. Strategies in the treatment of acute myeloid leukemia. Haematologica. 2004;89(9):1029–32.
  10. Burnett AK. Acute myeloid leukemia: Treatment of adults under 60 years. Rev Clin Exp Hematol. 2002;6(1):26–45. doi: 10.1046/j.1468-0734.2002.00058.x.
  11. Estey EH. Treatment of relapsed and refractory acute myelogenous leukemia. 2000;14(3):476–9. doi: 10.1038/sj.leu.2401568.
  12. Giles F, O’Brien S, Cortes J, et al. Outcome of patients with acute myelogenous leukemia after second salvage therapy. 2005;104(3):547–54. doi: 10.1002/cncr.21187.
  13. Leopold LH, Willemze R. The treatment of acute myeloid leukemia in first relapse: A comprehensive review of the literature. Leuk Lymphoma. 2002;43(9):1715–27. doi: 10.1080/1042819021000006529.
  14. Lee S, Tallman MS, Oken MM, et al. Duration of second complete remission compared with first complete remission in patients with acute myeloid leukemia. 2000;14(8):1345–8. doi: 10.1038/sj.leu.2401853.
  15. Patel SA, Gerber JM. A User’s Guide to Novel Therapies for Acute Myeloid Leukemia. Clin Lymphoma Myel Leuk. 2020;20(5):277–88. doi: 10.1016/j.clml.2020.01.011.
  16. Kucukyurt S, Eskazan AE. New drugs approved for acute myeloid leukemia in 2018. Br J Clin Pharmacol. 2018;85(12):2689–93. doi: 10.1111/bcp.14105.
  17. Spear P, Wu MR, Sentman ML, Sentman CL. NKG2D ligands as therapeutic targets. Cancer Immun. 2013;13:8.
  18. Greenberg PL, Tuechler H, Schanz J, et al. Revised international prognostic scoring system for myelodysplastic syndromes. 2012;120(12):2454–65. doi: 10.1016/s0145-2126(13)70009-2.
  19. Blum WG. Hypomethylating agents in myelodysplastic syndromes. Clin Adv Hematol Oncol. 2011;9(2):123–8.
  20. Семочкин С.В., Толстых Т.Н., Иванова В.Л. и др. Азацитидин в лечении миелодиспластических синдромов: клиническое наблюдение и обзор литературы. Клиническая онкогематология. 2012;5(3):233–8.
    [Semochkin SV, Tolstykh TN, Ivanova VL, et al. Azacitidine in the treatment of myelodysplastic syndromes: case report and literature review. Klinicheskaya onkogematologiya. 2012;5(3):233–8. (In Russ)]
  21. Ширин А.Д., Баранова О.Ю. Гипометилирующие препараты в онкогематологии. Клиническая онкогематология. 2016;9(4):369–82. doi: 10.21320/2500-2139-2016-9-4-369-382.
    [Shirin AD, Baranova OYu. Hypomethylating Agents in Oncohematology. Clinical oncohematology. 2016;9(4):369–82. doi: 10.21320/2500-2139-2016-9-4-369-382. (In Russ)]
  22. Richard-Carpentier G, DeZern AE, Takahashi K, et al. Preliminary Results from the Phase II Study of the IDH2-Inhibitor Enasidenib in Patients with High-Risk IDH2-Mutated Myelodysplastic Syndromes (MDS). 2019;134(1):678. doi: 10.1182/blood-2019-130501.
  23. Foran JM, DiNardo CD, Watts JM, et al. Ivosidenib (AG-120) in Patients with IDH1-Mutant Relapsed/Refractory Myelodysplastic Syndrome: Updated Enrollment of a Phase 1 Dose Escalation and Expansion Study. 2019;134(1):4254. doi: 10.1182/blood-2019-123946.
  24. Garcia JS. Prospects for Venetoclax in Myelodysplastic Syndromes. Hematol Oncol Clin N Am. 2020;34(2):441–8. doi: 10.1016/j.hoc.2019.10.005.
  25. Germing U, Schroeder T, Kaivers J, et al. Novel therapies in low- and high-risk myelodysplastic syndrome. Exp Rev Hematol. 2019;12(10):893–908. doi: 10.1080/17474086.2019.1647778.
  26. Platzbecker U. Treatment of MDS. 2019;133(10):1096–107. doi: 10.1182/blood-2018-10-844696.
  27. Swoboda DM, Sallman DA. Mutation-Driven Therapy in MDS. Curr Hematol Malig Rep. 2019;14(6):550–60. doi: 10.1007/s11899-019-00554-4.
  28. Миелодиспластические синдромы. Интервью с С.В. Грицаевым. Клиническая онкогематология. 2018;11(2):125–37.
    [Myelodysplastic syndromes. Interview with SV Gritsaev. Clinical oncohematology. 2018;11(2):125–37. (In Russ)]
  29. Manley PW, Weisberg E, Sattler M, et al. Midostaurin, a Natural Product-Derived Kinase Inhibitor Recently Approved for the Treatment of Hematological Malignancies. 2018;57(5):477–8. doi: 10.1021/acs.biochem.7b01126.
  30. Liu X, Gong Y. Isocitrate dehydrogenase inhibitors in acute myeloid leukemia. Biomark Res. 2019;7(1):22. doi: 10.1186/s40364-019-0173-z.
  31. Kim ES. Enasidenib: First Global Approval. 2017;77(15):1705–11. doi: 10.1007/s40265-017-0813-2.
  32. Garcia-Aranda M, Perez-Ruiz E, Redondo M. Bcl-2 Inhibition to Overcome Resistance to Chemo- and Immunotherapy. Int J Mol Sci. 2018;19(12):3950. doi: 10.3390/ijms19123950.
  33. Davids MS, Kim HT, Bachireddy P, et al. Ipilimumab for patients with relapse after allogeneic transplantation. Leukemia and Lymphoma Society Blood Cancer Research Partnership. N Engl J Med. 2016;375(2):143–53. doi: 10.1056/NEJMoa1601202.
  34. Li F, Sutherland MK, Yu C, et al. Characterization of SGN-CD123A, A Potent CD123-Directed Antibody-Drug Conjugate for Acute Myeloid Leukemia. Mol Cancer Ther. 2018;17(2):554–64. doi: 10.1158/1535-7163.MCT-17-0742.
  35. Mawad R, Gooley TA, Rajendran JG, et al. Radiolabeled AntiCD45 Antibody with Reduced-Intensity Conditioning and Allogeneic Transplantation for Younger Patients with Advanced Acute Myeloid Leukemia or Myelodysplastic Syndrome. Biol Blood Marrow Transplant. 2014;20(9):1363–8. doi: 10.1016/j.bbmt.2014.05.014.
  36. Guy DG, Uy GL. Bispecific Antibodies for the Treatment of Acute Myeloid Leukemia. Curr Hematol Malig Rep. 2018;13(6):417– doi: 10.1007/s11899-018-0472-8.
  37. Di Stasi A, Jimenez AM, Minagawa K, et al. Review of the Results of WT1 Peptide Vaccination Strategies for Myelodysplastic Syndromes and Acute Myeloid Leukemia from Nine Different Studies. Front Immunol. 2015;6:36. doi: 10.3389/fimmu.2015.00036.
  38. Van Acker HH, Versteven M, Lichtenegger FS, et al. Dendritic Cell-Based Immunotherapy of Acute Myeloid Leukemia. J Clin Med. 2019;8(5):579. doi: 10.3390/jcm8050579.
  39. Yabe T, McSherry C, Bach FH, et al. A multigene family on human chromosome 12 encodes natural killer-cell lectins. 1993;37(6):455–60. doi: 10.1007/bf00222470.
  40. Houchins JP, Yabe T, McSherry C, Bach FH. DNA sequence analysis of NKG2, a family of related cDNA clones encoding type II integral membrane proteins on human natural killer cells. J Exp Med. 1991;173(4):1017–20. doi: 10.1084/jem.173.4.1017.
  41. Upshaw JL, Arneson LN, Schoon RA, et al. NKG2D-mediated signaling requires a DAP10-bound Grb2-Vav1 intermediate and phosphatidylinositol-3-kinase in human natural killer cells. Nat Immunol. 2006;7(5):524–32. doi: 10.1038/ni1325.
  42. Diefenbach A, Tomasello E, Lucas M, et al. Selective associations with signaling proteins determine stimulatory versus costimulatory activity of NKG2D. Nat Immunol. 2002;3(12):1142–9. doi: 10.1038/ni858.
  43. Duan S, Guo W, Xu Z, et al. Natural killer group 2D receptor and its ligands in cancer immune escape. Mol Cancer. 2019;18(1):29. doi: 10.1186/s12943-019-0956-8.
  44. Wu J, Song Y, Bakker AB, et al. An activating immunoreceptor complex formed by NKG2D and DAP10. 1999;285(5428):730–2. doi: 10.1126/science.285.5428.730.
  45. Ogasawara K, Lanier LL. NKG2D in NK and T cell-mediated immunity. J Clin Immunol. 2005;25(6):534–40. doi: 10.1007/s10875-005-8786-4.
  46. Gilfillan S, Ho EL, Cella M, et al. NKG2D recruits two distinct adapters to trigger NK cell activation and costimulation. Nat Immunol. 2002;3(12):1150–5. doi: 10.1038/ni857.
  47. Groh V, Rhinehart R, Randolph-Habecker J, et al. Costimulation of CD8alphabeta T cells by NKG2D via engagement by MIC induced on virus-infected cells. Nat Immunol. 2001;2(3):255–60. doi: 10.1038/85321.
  48. Jamieson AM, Diefenbach A, McMahon CW, et al. The role of the NKG2D immunoreceptor in immune cell activation and natural killing. 2002;17(1):19–29. doi: 10.1016/s1074-7613(02)00333-3.
  49. Raulet DH. Roles of the NKG2D immunoreceptor and its ligands. Nat Rev Immunol. 2003;3(10):781–90. doi: 10.1038/nri1199.
  50. Roberts AI, Lee L, Schwarz E, et al. NKG2D receptors induced by IL-15 costimulate CD28-negative effector CTL in the tissue microenvironment. J Immunol. 2001;167(10):5527–30. doi: 10.4049/jimmunol.167.10.5527.
  51. Lanier LL. NK cell recognition. Annu Rev Immunol. 2005;23(1):225–74. doi: 10.1146/annurev.immunol.23.021704.115526.
  52. Raulet DH, Gasser S, Gowen BG, et al. Regulation of ligands for the NKG2D activating receptor. Annu Rev Immunol. 2013;31(1):413–41. doi: 10.1146/annurev-immunol-032712-095951.
  53. Stephens HA. MICA and MICB genes: can the enigma of their polymorphism be resolved?. Trends Immunol. 2001;22(7):378–85. doi: 10.1016/s1471-4906(01)01960-3.
  54. Carapito R, Bahram S. Genetics, genomics, and evolutionary biology of NKG2D ligands. Immunol Rev. 2015;267(1):88–116. doi: 10.1111/imr.12328.
  55. Bartkova J, Horejsi Z, Koed K, et al. DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. 2005;434(7035):864–70. doi: 10.1038/nature03482.
  56. Gorgoulis VG, Vassiliou LV, Karakaidos P, et al. Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions. 2005;434(7035):907–13. doi: 10.1038/nature03485.
  57. Maeda T, Towatari M, Kosugi H, Saito H. Up-regulation of costimulatory/adhesion molecules by histone deacetylase inhibitors in acute myeloid leukemia cells. Blood. 2000;96(12):3847–56. doi: 1182/blood.v96.12.3847.
  58. Diermayr S, Himmelreich H, Durovic B, et al. NKG2D ligand expression in AML increases in response to HDAC inhibitor valproic acid and contributes to allorecognition by NK-cell lines with single KIR-HLA class I specificities. 2008;111(3):1428–36. doi: 10.1182/blood-2007-07-101311.
  59. Chang YH, Connolly J, Shimasaki N, et al. A chimeric receptor with NKG2D specificity enhances natural killer cell activation and killing of tumor cells. Cancer Res. 2013;73(6):1777–86. doi: 10.1158/0008-5472.CAN-12-3558.
  60. Hamerman JA, Ogasawara K, Lanier LL. Cutting edge: Toll-like receptor signaling in macrophages induces ligands for the NKG2D receptor. J Immunol. 2004;172(4):2001–5. doi: 10.4049/jimmunol.172.4.2001.
  61. Carlsten M, Bjorkstrom NK, Norell H, et al. DNAX accessory molecule-1 mediated recognition of freshly isolated ovarian carcinoma by resting natural killer cells. Cancer Res. 2007;67(3):1317–25. doi: 10.1158/0008-5472.CAN-06-2264.
  62. McGilvray RW, Eagle RA, Rolland P, et al. ULBP2 and RAET1E NKG2D ligands are independent predictors of poor prognosis in ovarian cancer patients. Int J Cancer. 2010;127(6):1412–20. doi: 10.1002/ijc.25156.
  63. Cathro HP, Smolkin ME, Theodorescu D, et al. Relationship between HLA class I antigen processing machinery component expression and the clinicopathologic characteristics of bladder carcinomas. Cancer Immunol Immunother. 2010;59(3):465–72. doi: 10.1007/s00262-009-0765-9.
  64. Seitz S, Hohla F, Schally AV, et al. Inhibition of estrogen receptor positive and negative breast cancer cell lines with a growth hormone-releasing hormone antagonist. Oncol Rep. 2008;20(5):1289–94.
  65. Mamessier E, Sylvain A, Thibult ML, et al. Human breast cancer cells enhance self tolerance by promoting evasion from NK cell antitumor immunity. J Clin Invest. 2011;121(9):3609–22. doi: 10.1172/JCI45816.
  66. Busche A, Goldmann T, Naumann U, et al. Natural killer cell-mediated rejection of experimental human lung cancer by genetic overexpression of major histocompatibility complex class I chain-related gene A. Hum Gene Ther. 2006;17(2):135–46. doi: 10.1089/hum.2006.17.135.
  67. Platonova S, Cherfils-Vicini J, Damotte D, et al. Profound coordinated alterations of intratumoral NK cell phenotype and function in lung carcinoma. Cancer Res. 2011;71(16):5412–22. doi: 10.1158/0008-5472.CAN-10-4179.
  68. Jinushi M, Takehara T, Tatsumi T, et al. Expression and role of MICA and MICB in human hepatocellular carcinomas and their regulation by retinoic acid. Int J Cancer. 2003;104(3):354–61. doi: 10.1002/ijc.10966.
  69. Watson NF, Spendlove I, Madjd Z, et al. Expression of the stress-related MHC class I chain-related protein MICA is an indicator of good prognosis in colorectal cancer patients. Int J Cancer. 2006;118(6):1445–52. doi: 10.1002/ijc.21510.
  70. Sconocchia G, Spagnoli GC, Del Principe D, et al. Defective infiltration of natural killer cells in MICA/B-positive renal cell carcinoma involves beta(2)-integrin-mediated interaction. 2009;11(7):662–71. doi: 10.1593/neo.09296.
  71. Wu JD, Higgins LM, Steinle A, et al. Prevalent expression of the immunostimulatory MHC class I chain-related molecule is counteracted by shedding in prostate cancer. J Clin Invest. 2004;114(4):560–8. doi: 10.1172/JCI22206.
  72. Salih HR, Antropius H, Gieseke F, et al. Functional expression and release of ligands for the activating immunoreceptor NKG2D in leukemia. 2003;102(4):1389–96. doi: 10.1182/blood-2003-01-0019.
  73. Diermayr S, Himmelreich H, Durovic B, et al. NKG2D ligand expression in AML increases in response to HDAC inhibitor valproic acid and contributes to allorecognition by NK-cell lines with single KIR-HLA class I specificities. 2008;111(3):1428–36. doi: 10.1182/blood-2007-07-101311.
  74. Sconocchia G, Lau M, Provenzano M, et al. The antileukemia effect of HLA-matched NK and NK-T cells in chronic myelogenous leukemia involves NKG2D-target-cell interactions. 2005;106(10):3666–72. doi: 10.1182/blood-2005-02-0479.
  75. Nuckel H, Switala M, Sellmann L, et al. The prognostic significance of soluble NKG2D ligands in B-cell chronic lymphocytic leukemia. 2010;24(6):1152–9. doi: 10.1038/leu.2010.74.
  76. Zhang B, Kracker S, Yasuda T, et al. Immune surveillance and therapy of lymphomas driven by Epstein-Barr virus protein LMP1 in a mouse model. 2012;148(4):739–51. doi: 10.1016/j.cell.2011.12.031.
  77. Girlanda S, Fortis C, Belloni D, et al. MICA expressed by multiple myeloma and monoclonal gammopathy of undetermined significance plasma cells costimulates pamidronate-activated gammadelta lymphocytes. Cancer Res. 2005;65(16):7502–8. doi: 10.1158/0008-5472.CAN-05-0731.
  78. Paschen A, Sucker A, Hill B, et al. Differential clinical significance of individual NKG2D ligands in melanoma: soluble ULBP2 as an indicator of poor prognosis superior to S100B. Clin Cancer Res. 2009;15(16):5208–15. doi: 10.1158/1078-0432.CCR-09-0886.
  79. Verhoeven DH, de Hooge AS, Mooiman EC, et al. NK cells recognize and lyse Ewing sarcoma cells through NKG2D and DNAM-1 receptor dependent pathways. Mol Immunol. 2008;45(15):3917–25. doi: 10.1016/j.molimm.2008.06.016.
  80. Friese MA, Platten M, Lutz SZ, et al. MICA/NKG2D-mediated immunogene therapy of experimental gliomas. Cancer Res. 2003;63(24):8996–9006.
  81. Raffaghello L, Prigione I, Airoldi I, et al. Downregulation and/or release of NKG2D ligands as immune evasion strategy of human neuroblastoma. 2004;6(5):558–68. doi: 10.1593/neo.04316.
  82. Chitadze G, Lettau M, Bhat J, et al. Shedding of endogenous MHC class I-related chain molecules A and B from different human tumor entities: heterogeneous involvement of the “a disintegrin and metalloproteases” 10 and 17. Int J Cancer. 2013;133(7):1557–66. doi: 10.1002/ijc.28174.
  83. Zhang T, Lemoi BA, Sentman CL. Chimeric NK-receptor-bearing T cells mediate antitumor immunotherapy. 2005;106(5):1544–51. doi: 10.1182/blood-2004-11-4365.
  84. Zhang T, Barber A, Sentman CL. Generation of antitumor responses by genetic modification of primary human T cells with a chimeric NKG2D receptor. Cancer Res. 2006;66(11):5927–33. doi: 10.1158/0008-5472.CAN-06-0130.
  85. Barber A, Zhang T, DeMars LR, et al. Chimeric NKG2D receptor-bearing T cells as immunotherapy for ovarian cancer. Cancer Res. 2007;67(10):5003–8. doi: 10.1158/0008-5472.CAN-06-4047.
  86. Barber A, Zhang T, Megli CJ, et al. Chimeric NKG2D receptor-expressing T cells as an immunotherapy for multiple myeloma. Exp Hematol. 2008;36(10):1318–28. doi: 10.1016/j.exphem.2008.04.010.
  87. Barber A, Meehan KR, Sentman CL. Treatment of multiple myeloma with adoptively transferred chimeric NKG2D receptor-expressing T cells. Gene Ther. 2011;18(5):509–16. doi: 10.1038/gt.2010.174.
  88. Barber A, Rynda A, Sentman CL. Chimeric NKG2D expressing T cells eliminate immunosuppression and activate immunity within the ovarian tumor microenvironment. J Immunol. 2009;183(11):6939–47. doi: 10.4049/jimmunol.0902000.
  89. Zhang T, Sentman CL. Cancer immunotherapy using a bispecific NK receptor fusion protein that engages both T cells and tumor cells. Cancer Res. 2011;71(6):2066–76. doi: 10.1158/0008-5472.CAN-10-3200.
  90. Zhang T, Sentman CL. Mouse tumor vasculature expresses NKG2D ligands and can be targeted by chimeric NKG2D-modified T cells. J Immunol. 2013;190(5):2455–63. doi: 10.4049/jimmunol.1201314.
  91. Lehner M, Gotz G, Proff J, et al. Redirecting T cells to Ewing’s sarcoma family of tumors by a chimeric NKG2D receptor expressed by lentiviral transduction or mRNA transfection. PLoS One. 2012;7(2):e31210. doi: 10.1371/journal.pone.0031210.
  92. Song DG, Ye Q, Santoro S, et al. Chimeric NKG2D CAR-expressing T cell-mediated attack of human ovarian cancer is enhanced by histone deacetylase inhibition. Hum Gene Ther. 2013;24(3):295–305. doi: 10.1089/hum.2012.143.
  93. Kalos M, Levine BL, Porter DL, et al. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med. 2011;3(95):95ra73. doi: 10.1126/scitranslmed.3002842.
  94. Brentjens RJ, Davila ML, Riviere I, et al. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med. 2013;5(177):177ra38. doi: 10.1126/scitranslmed.3005930.
  95. Meehan KR, Talebian L, Tosteson TD, et al. Adoptive cellular therapy using cells enriched for NKG2D+CD3+CD8+ T cells after autologous transplantation for myeloma. Biol Blood Marrow Transplant. 2013;19(1):129–37. doi: 10.1016/j.bbmt.2012.08.018.
  96. Nakajima J, Murakawa T, Fukami T, et al. A phase I study of adoptive immunotherapy for recurrent non-small-cell lung cancer patients with autologous gammadelta T cells. Eur J Cardiothorac Surg. 2010;37(5):1191–7. doi: 10.1016/j.ejcts.2009.11.051.
  97. Abe Y, Muto M, Nieda M, et al. Clinical and immunological evaluation of zoledronate-activated Vgamma9gammadelta T-cell-based immunotherapy for patients with multiple myeloma. Exp Hematol. 2009;37(8):956–68. doi: 10.1016/j.exphem.2009.04.008.
  98. Gattinoni L, Powell DJ Jr, Rosenberg SA, Restifo NP. Adoptive immunotherapy for cancer: building on success. Nat Rev Immunol. 2006;6(5):383–93. doi: 10.1038/nri1842.
  99. June CH. Principles of adoptive T cell cancer therapy. J Clin Invest. 2007;117(5):1204–12. doi: 10.1172/JCI31446.
  100. Morgan RA, Chinnasamy N, Abate-Daga D, et al. Cancer regression and neurological toxicity following anti-MAGE-A3 TCR gene therapy. J Immunother. 2013;36(2):133–51. doi: 10.1097/CJI.0b013e3182829903.
  101. Morgan RA, Yang JC, Kitano M, et al. Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Mol Ther. 2010;18(4):843–51. doi: 10.1038/mt.2010.24.
  102. Miller JS, Soignier Y, Panoskaltsis-Mortari A, et al. Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer. 2005;105(8):3051–7. doi: 10.1182/blood-2004-07-2974.
  103. Sentman CL, Meehan KR. NKG2D CARs as cell therapy for cancer. Cancer J. 2014;20(2):156–9. doi: 10.1097/PPO.0000000000000029.
  104. Lonez C, Hendlisz A, Shaza L, et al. Celyad’s novel CAR T-cell therapy for solid malignancies. Curr Res Transl Med. 2018;66(2):53–6. doi: 10.1016/j.retram.2018.03.001.
  105. Baumeister SH, Murad J, Werner L, et al. Phase I Trial of Autologous CAR T Cells Targeting NKG2D Ligands in Patients with AML/MDS and Multiple Myeloma. Cancer Immunol Res. 2019;7(1):100–12. doi: 10.1158/2326-6066.CIR-18-0307.
  106. Al-Homsi S, Purev E, Lewalle P, et al. Interim Results from the Phase I Deplethink Trial Evaluating the Infusion of a NKG2D CAR T-Cell Therapy Post a Non-Myeloablative Conditioning in Relapse or Refractory Acute Myeloid Leukemia and Myelodysplastic Syndrome Patients. 2019;134(Suppl_1):3844. doi: 10.1182/blood-2019-128267.
  107. Liu H, Wang S, Xin J, et al. Role of NKG2D and its ligands in cancer immunotherapy. Am J Cancer Res. 2019;9(10):2064–78.