Терапия Т-лимфоцитами с химерным антигенным рецептором (CAR) В-клеточной неходжкинской лимфомы: возможности и проблемы
pdf

Ключевые слова

В-клеточная неходжкинская лимфома
CAR T-клеточная терапия
химерный антигенный рецептор
тисагенлеклейсел
аксикабтаген силолейсел
лизокабтаген маралейсел

Как цитировать

Грибкова, И., & Завьялов, А. (2021). Терапия Т-лимфоцитами с химерным антигенным рецептором (CAR) В-клеточной неходжкинской лимфомы: возможности и проблемы. Вопросы онкологии, 67(3), 350–360. https://doi.org/10.37469/0507-3758-2021-67-3-350-360

Аннотация

В-клеточная неходжкинская лимфома (НХЛ) является наиболее распространённым гематологическим злокачественным новообразованием. Несмотря на усовершенствование иммунохимиотерапии, значительное количество пациентов имеют рефрактерную форму заболевания. CAR Т-клеточная терапия (терапия Т-лимфоцитами с химерным антигенным рецептором (CAR)) считается наиболее перспективной и эффективной терапией для преодоления хеморефрактерной В-клеточной НХЛ. На основании многообещающих результатов, полученных в ходе основных исследований, Управление по санитарному надзору за качеством пищевых продуктов и медикаментов США (FDA) и Европейское агентство по лекарственным средствам (EMA) одобрили анти-CD19 CAR Т-клеточную терапию при рецидивирующей/рефрактерной диффузной В-клеточной лимфоме. Тем не менее, остается несколько спорных вопросов и проблем, ожидающих решения, включая оптимальное управление токсичностью, преодоление рецидивов заболевания, возникающих после CAR Т-клеточной терапии и улучшение производственной платформы CAR T-клеток. В этом обзоре описаны результаты последних клинических исследований и разработок, а также перспективы развития CAR Т-клеточной терапии B-клеточной НХЛ.

https://doi.org/10.37469/0507-3758-2021-67-3-350-360
pdf

Библиографические ссылки

Makita S, Imaizumi K, Kurosawa S, Tobinai K. Chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma: opportunities and challenges // Drugs in Context 2019;8:212567. https: // doi: org/10.7573/dic.212567

Brudno JN, Kochenderfer JN. Chimeric Antigen Receptor T-cell Therapies for Lymphoma // Nat Rev Clin Oncol. 2018 Jan;15(1):31–46. https: // doi: org/10.1038/nrclinonc.2017.128

Martelli M, Ferreri AJ, Agostinelli C et al. Diffuse large B‑cell lymphoma // Crit. Rev. Oncol. Hematol. 2013;87:146–171. https: // doi: org/10.1016/j.critrevonc.2012.12.009

Feugier P, Van Hoof A, Sebban C et al. Long-term results of the R‑CHOP study in the treatment of elderly patients with diffuse large B‑cell lymphoma: a study by the Groupe d’Etude des Lymphomes de l’Adulte // J. Clin. Oncol. 2005;23:4117–4126. https: // doi: org/10.1200/JCO.2005.09.131

Elstrom RL, Martin P, Ostrow K et al. Response to second-line therapy defines the potential for cure in patients with recurrent diffuse large B‑cell lymphoma: implications for the development of novel therapeutic strategies // Clin. Lymphoma Myeloma Leuk. 2010;10:192–196. https: // doi: org/10.3816/CLML.2010.n.030. PMID:20511164

Seshadri T, Stakiw J, Pintilie M et al. Utility of subsequent conventional dose chemotherapy in relapsed/refractory transplanteligible patients with diffuse large B‑cell lymphoma failing platinum-based salvage chemotherapy // Hematology 2008;13:261–266. https: // doi: org/10.1179/102453308X343527

Van Den Neste E, Schmitz N, Mounier N et al.Outcomes of diffuse large B‑cell lymphoma patients relapsing after autologous stem cell transplantation: an analysis of patients included in the CORAL study // Bone Marrow Transplant. 2017;52:216–221. https: // doi: org/10.1038/bmt.2016.213

Emtage PC, Lo AS, Gomes EM et al. Second-generation anti-carcinoembryonic antigen designer T cells resist activation-induced cell death, proliferate on tumor contact, secrete cytokines, and exhibit superior antitumor activity in vivo: a preclinical evaluation // Clin Cancer Res. 2008;14(24):8112–8122. https: // doi: org/10.1158/1078-0432.CCR-07-4910

Штыров Е.М., Зотов Р.А., Лапштаева А.В. CAR T клеточная терапия как современный метод лечения онкологических заболеваний // Бюллетень науки и практики. 2019;5(5):121–127. https: //doi.org/10.33619/2414 2948/42/16./ [Shtyro E., Zotov R., Lapshtaeva, A. (2019). CAR T cell Therapy as a Modern Method for the Treatment of Oncological Diseases // Bulletin of Science and Practice, 2019;5(5):121–127. https: // doi: org/10.33619/2414 2948/42/16. (in Russian)].

Klebanoff CA, Khong HT, Antony PA et al. Sinks, suppressors and antigen presenters: how lymphodepletion enhances T cellmediated tumor immunotherapy // Trends Immunol. 2005;26:111–117. https: // doi: org/10.1016/j.it.2004.12.003

Turtle CJ, Hanafi LA, Berger C et al. Immunotherapy of non-Hodgkin’s lymphoma with a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen receptor-modified T cells // Sci Transl Med. 2016;8:355ra116. https: // doi: org/10.1126/scitranslmed.aaf8621

Павлова А.А, Масчан М.А., Пономарев В.Б. Адоптивная иммунотерапия генетически модифицированными Т-лимфоцитами, экспрессирующими химерные антигенные рецепторы // Онкогематология 2017;12(1):17–32. https: // doi: org/10.17650/1818-8346-2017-12-1-17-32/ [Pavlova A.А., Maschan M.А., Ponomarev V.B. Adoptitive immunotherapy with genetically engineered T lymphocytes modified to express chimeric antigen receptors // Oncohematology 2017;12(1):17–32. https: // doi: org/10.17650/1818-8346-2017-12-1-17-32 (in Russian)].

Makita S, Yoshimura K, Tobinai K. Clinical development of anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma // Cancer Sci. 2017;108:1109–1118. https: // doi: org/10.1111/cas.13239

Schuster SJ, Bishop MR, Tam CS et al. JULIET Investigators. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma // N Engl J Med. 2019;380:45–56. https: // doi: org/10.1056/NEJMoa1804980

Schuster SJ, Bishop MR, Tam C et al. Global pivotal phase 2 trial of the CD19-targeted therapy CTL019 in adult patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) — An interim analysis // Hematol. Oncol. 2017;35:27. https: // doi: org/10.1002/hon.2437_6

Neelapu SS, Locke FL, Bartlett NL et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma // N Engl J Med. 2017;377:2531–2544. https: // doi: org/10.1056/NEJMoa1707447

FDA approves axicabtagene ciloleucel for large B-cell lymphoma. Approved drugs. U.S. Food and Drug Administration. https: //www.fda.gov/drugs/informationondrugs/approveddrugs/ucm581296.htm. Accessed September 30, 2018.

Schuster SJ, Svoboda J, Chong EA et al. Chimeric antigen receptor T cells in refractory B-cell lymphomas // N Engl J Med. 2017;377:2545–2554. https: // doi: org/10.1056/NEJMoa1708566

Borchmann P, Tam CS, Jäger U et al. An updated analysis of JULIET, a global pivotal phase 2 trial of tisagenlecleucel in adult patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL). Abstract S799. The 23rd Congress of European Hematology Association (EHA), Stockholm, Sweden. https: //learningcenter.ehaweb.org/eha/2018/stockholm/214521/peter. borchmann.an.updated.analysis.of.juliet.a.global.pivotal.phase.2.trial.html. Accessed September 30, 2018.

Schuster SJ, Bishop MR, Tam C et al. Sustained disease control for adult patients with relapsed or refractory diffuse large B-cell lymphoma: an updated analysis of Juliet, a global pivotal phase 2 trial of tisagenlecleucel. ASH annual meeting; San Diego 2018; Dec 1–4 [abstract #1684]. https: //ash.confex.com/ash/2018/webprogram/Paper115252.html. Accessed January 8, 2019.

Locke FL, Neelapu SS, Bartlett NL et al. Phase 1 results of ZUMA-1: a multicenter study of KTE-C19 anti-CD19 CAR T cell therapy in refractory aggressive lymphoma // Mol Ther. 2017;25:285–295. https: // doi: org/10.1016/j.ymthe.2016.10.020

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. https: // doi: org/10.1016/S1470-2045(18)30864-7

Nastoupil LJ, Jain MD, Spiegel JY et al. Axicabtagene ciloleucel (axi-cel) CD19 chimeric antigen receptor (CAR) T-cell therapy for relapsed/refractory large B-cell lymphoma: Real world experience // Blood 2018;132:91. https: // doi: org/10.1182/BLOOD-2018-99-114152

Jacobson CA, Hunter B, Armand P et al. Axicabtagene ciloleucel in the real world: Outcomes and predictors of response, resistance and toxicity // Blood 2018;132:92. https: // doi: org/10.1182/blood-2018-99-117199

Abramson JS, Palomba ML, Gordon LI et al. Pivotal safety and effcacy results from Transcend NHL 001, a multicenter phase 1 study of lisocabtagene maraleucel (liso-cel) in relapsed/refractory (R/R) large B cell lymphomas // Blood 2019;134:241. https: // doi: org/10.1182/blood-2019-127508

Abramson JS, Palomba ML, Gordon LI et al. CR rates in relapsed/refractory (R/R) aggressive B-NHL treated with the CD19-directed CAR T-cell product JCAR017 (TRANSCEND NHL001) // J. Clin. Oncol. 2017;35:7513. https: // doi: org/10.1200/JCO.2017.35.15_suppl.7513

Abramson J, Palomba ML, Gordon L et al. High CR rates in relapsed/refractory (R/R) aggressive B-NHL treated with the CD19-directed CAR T cell product JCAR017 (TRANSCEND NHL 001) // Hematol. Oncol. 2017;35:138. https: // doi: org/10.1200/JCO.2017.35.15_suppl.7513

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. Published 2020 Feb 24. https: // doi: org/10.3390/pharmaceutics12020194

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. https: // doi: org/10.1126/scitranslmed.3008226

Hay KA, Hanafi LA, Li D et al. Kinetics and biomarkers of severe cytokine release syndrome after CD19 chimeric antigen receptormodified T-cell therapy // Blood. 2017;130:2295–2306. https: // doi: org/10.1182/blood-2017-06-793141

Frey N. Cytokine release syndrome: who is at risk and how to treat // Best Pract Res Clin Haematol. 2017;30:336–340. https: // doi: org/10.1016/j.beha.2017.09.002

Lee D, Santomasso B, Locke F, Ghobadi A, Turtle CJ, Brudno JN, Maus MV, Park JH, Mead E, Pavletic S et al. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells // Biol. Blood Marrow Transplant. 2019;25:625–638. https: // doi: org/10.1016/j.bbmt.2018.12.758

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, 47–62. https: // doi: org/10.1038/nrclinonc.2017.148

Lee DW, Gardner R, Porter DL et al. Current concepts in the diagnosis and management of cytokine release syndrome // Blood 2014;124:188–195. https: // doi: org/10.1182/blood-2014-05-552729

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;35:1803–1813. https: // doi: org/10.1200/JCO.2016.71.3024

Norelli M, Camisa B, Barbiera G et al. Monocyte-derived IL-1 and IL-6 are differentially required for cytokine-release syndrome and neurotoxicity due to CAR T cells // Nat. Med. 2018, 24:739–748. https: // doi: org/10.1038/s41591-018-0036-4

Giavridis T, van der Stegen SJC, Eyquem J et al. CAR T cell-induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade // Nat Med. 2018;24:731–738. https: // doi: org/10.1038/s41591-018-0041-7

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. https: // doi: org/10.3389/fphar.2014.00254

Wu CY, Roybal KT, Puchner EM, Onuffer J, Lim WA. Remote control of therapeutic T cells through a small molecule-gated chimeric receptor // Science. 2015;350:aab4077. https: // doi: org/10.1126/science.aab4077

Кулемзин С.В., Кузнецова В.В, Мамонкин М и др. CAR T-клеточная терапия: баланс эффективности и безопасности // Молекулярная биология. 2017;51(2):274–287. https: // doi: org/10.7868/S0026898417020148/ [Kulemzin S.V., Kuznetsova V.V., Mamonkin M. et al. CAR T-cell therapy: a balance of efficacy and safety // Molecular biology. 2017;51 (2):274–287. https: // doi: org/10.7868/S0026898417020148 (in Russian)].

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. https: // doi: org/10.3389/fimmu.2019.02664

Latchman Y, Wood C R, Chernova T. et al. PD–L2 is a second ligand for PD-1 and inhibits T cell activation // Nat Immunol 2001;2(3):261–8. https: // doi: org/10.1038 / 85330

Chong EA, Melenhorst JJ, Lacey SF et al. PD-1 blockade modulates chimeric antigen receptor (CAR)-modified T cells: refueling the CAR // Blood. 2017;129:1039–1041. https: // doi: org/10.1182/blood-2016-09-738245

Ardeshna KM, Marzolini MAV, Norman J et al. Phase 1/2 study of AUTO3 the first bicistronic chimeric antigen receptor (CAR) targeting CD19 and CD22 followed by an anti-PD1 in patients with relapsed/refractory (r/r) diffuse large B cell lymphoma (DLBCL): Results of cohort 1 and 2 of the Alexander study // Blood 2019;134:246. https: // doi: org/10.1182/blood-2019-122724

Hill BT, Roberts ZJ, Xue A et al. Rapid tumor regression from PD-1 inhibition after anti-CD19 chimeric antigen receptor T-cell therapy in refractory diffuse large B-cell lymphoma // Bone Marrow Transplant. 2019;55:1184-1187. https: // doi: org/10.1038/s41409-019-0657-3

Cao Y, Lu W, Sun R et al. Anti-CD19 chimeric antigen receptor T cells in combination with nivolumab are safe and effective against relapsed/refractory B-cell non-hodgkin lymphoma // Front. Oncol. 2019;9:767. https: // doi: org/10.3389/fonc.2019.00767

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;24:20–28. https: // doi: org/10.1038/nm.4441

Shah N, Maatman T, Hari P, Johnson B. Multi targeted CAR-T cell therapies for B-cell malignancies // Front. Oncol. 2019;9:146. https: // doi: org/10.3389/fonc.2019.00146

Hill L, Lulla P, Heslop HE. CAR-T cell therapy for non-Hodgkin lymphomas: A new treatment paradigm // Adv. Cell Gene Ther. 2019, 2, e54

Jacoby E, Shahani SA, Shah NN. Updates on CAR T-cell therapy in B-cell malignancies // Immunol. Rev. 2019;290:39–59. https: // doi: org/10.1002/acg2.54

Turtle CJ, Hanafi LA, Berger C et al. Immunotherapy of non-Hodgkin’s lymphoma with a defined ratio of CD8+ and CD4+ CD19‑specific chimeric antigen receptor-modified T cells. Sci // Transl Med. 2016;8:355ra116. https: // doi: org/10.1126/scitranslmed.aaf8621

Alabanza L, Pegues M, Geldres C et al. Function of novel anti-CD19 chimeric antigen receptors with human variable regions is affected by hinge and transmembrane domains // Mol Ther. 2017;25:2452–2465. https: // doi: org/10.1016/j.ymthe.2017.07.013

Sommermeyer D, Hill T, Shamah SM et al. Fully human CD19-specific chimeric antigen receptors for T-cell therapy // Leukemia. 2017;31:2191–2199. https: // doi: org/10.1038/leu.2017.57

Ruella M, Kenderian SS, Shestova O et al. The addition of the BTK inhibitor ibrutinib to anti‑CD19 chimeric antigen receptor T Cells (CART19) improves responses against mantle cell lymphoma // Clin. Cancer Res. 2016;22:2684–2696. https: // doi: org/10.1158/1078-0432.CCR-15-1527

Lu TL, Pugach O, Somerville R et al. A rapid cell expansion process for production of engineered autologous CAR-T cell therapies // Hum Gene Ther Methods. 2016;27:209–218. https: // doi: org/10.1089/hgtb.2016.120

Mock U, Nickolay L, Philip B et al. Automated manufacturing of chimeric antigen receptor T cells for adoptive immunotherapy using CliniMACS prodigy // Cytotherapy. 2016;18:1002–1011. https: // doi: org/10.1016/j.jcyt.2016.05.009

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(374):pii:eaaj2013. https: // doi: org/10.1126/scitranslmed.aaj2013

Eyquem J, Mansilla-Soto J, Giavridis T. et al. Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection // Nature. 2017;543:113–117. https: // doi: org/10.1038/nature21405

Лицензия Creative Commons

Это произведение доступно по лицензии Creative Commons «Attribution-NonCommercial-NoDerivatives» («Атрибуция — Некоммерческое использование — Без производных произведений») 4.0 Всемирная.

© АННМО «Вопросы онкологии», Copyright (c) 2021