免疫治疗在急性淋巴细胞白血病中的研究进展

摘要/Abstract

摘要：

急性淋巴细胞白血病（ALL）是一种主要影响儿童和成人的血液恶性肿瘤，源于淋巴样前体细胞的恶性增殖，侵入骨髓并可扩散到髓外部位。虽然近几十年儿童ALL患者的预后得到显著改善，但儿童ALL中的某些亚组预后很差，特别是复发和难治亚组，且在这些预后不良亚组中进一步增加常规化疗强度会带来显著的不良反应。此外，使用了多种细胞毒性药物联合治疗会导致在治愈患儿中出现多种长期并发症，包括多器官功能障碍、继发癌症、精神恶化以及社会和心理问题等。迄今为止，成人ALL患者的存活率仍然较差，复发率高且治愈率不令人满意。因此，需要探索更有效和更安全的治疗方法来改善ALL患者的治疗效果。在过去十年中，免疫疗法和分子疗法的靶向治疗取得了重大进展。美国FDA已批准的基于抗体的治疗（Blinatumomab和Inotuzumab ozogamicin）和基于T细胞的治疗（Tisagenlecleucel）显著提高了复发/难治性B-ALL患者的反应率和预后。将这些免疫疗法纳入ALL治疗中，有望降低常规化疗的强度，减少相关毒性，进一步提高患者的生存率和生活质量。因此，本综述讨论了新的治疗选择，包括双特异性抗体、抗体-药物偶联物、基于嵌合抗原受体（CAR）的疗法，旨在为ALL的治疗提供新的思路和方向。

关键词: 急性淋巴细胞白血病, 免疫治疗, 嵌合抗原受体T细胞疗法, 抗体偶联药物, 双特异性抗体

Abstract:

Acute lymphoblastic leukemia （ALL） is a blood cancer that primarily affects children and adults. ALL is due to the malignant proliferation of lymphoid precursor cells that invade the bone marrow and can spread to extramedullary sites. The prognosis for pediatric ALL patients has significantly improved over the past few decades， however， certain subgroups of pediatric ALL， particularly those with relapsed and refractory disease， still have poor outcomes. Further increasing in the intensity of conventional chemotherapy would be associated with significant adverse effects in these poor prognosis subgroups. In addition， the use of multiple cytotoxic drugs in combination therapy can lead to multiple long-term complications among cured patients， including multi-organ dysfunction， second cancers， mental deterioration， and social and psychological issues. To date， the survival rate in adults continues to be poor， with high relapse rates and unsatisfactory cure rates. Therefore， it is necessary to explore more effective and safer treatment methods to improve the treatment effect of ALL patients. Significant advance has been made in targeted therapy with immunotherapy and molecular therapeutics in the past 10 years. For immunotherapy， the approval of antibody-based therapy （Blinatumomab and Inotuzumab ozogamicin） and T cell-based therapy （Tisagenlecleucel） by the US FDA has significantly improved the response rate and outcomes in patients with relapsed/refractory B-ALL. Incorporating effective immunotherapy into ALL therapy would enable reduce the intensity of conventional chemotherapy， reduce associated toxicity， and further improve the survival rate and quality of life for patients with ALL. In this review， we will discuss novel therapeutic options including bispecific antibodies， antibody-drug conjugates， chimeric antigen receptor （CAR）-based therapies， to provide new ideas and directions for the treatment of ALL patients.

Key words: , Acute lymphoblastic leukemia , （ALL）； , Immunotherapy； , Chimeric antigen receptor T cells therapy； , Antibody-drug conjugates； , Bispecific antibodies

中图分类号:

R733.7

叶家利, 李增政, 何逸凡, 姚翔媚, 王娅婕, .

免疫治疗在急性淋巴细胞白血病中的研究进展 [J]. 中国医药导刊, 2024, 26(5): 455-460.

YE Jiali, LI Zengzheng, HE Yifan, YAO Xiangmei, WANG Yajie, .

Advances in Immunotherapy of Acute Lymphoblastic Leukemia （ALL） [J]. CHINESE JOURNAL OF MEDICINAL GUIDE, 2024, 26(5): 455-460.

参考文献

［1］ Malard F，Mohty M.Acute lymphoblastic leukaemia ［J］.Lancet， 2020， 395（10230）： 1146-1162.

［2］ Pennesi E，Michels N，Brivio E，et al.Inotuzumab ozogamicin as single agent in pediatric patients with relapsed and refractory acute lymphoblastic leukemia： results from a phase II trial［J］. Leukemia，2022，36（6）： 1516-1524.

［3］ Shah BD，Ghobadi A，Oluwole OO，et al. KTE-X19 for relapsed or refractory adult B-cell acute lymphoblastic leukaemia：phase 2 results of the single-arm， open-label， multicentre ZUMA-3 study ［J］.Lancet，2021，398（10299）： 491-502.

［4］ Brivio E，Locatelli F，Lopez-Yurda M，et al.A phase 1 study of inotuzumab ozogamicin in pediatric relapsed/refractory acute lymphoblastic leukemia（ITCC-059 study）［J］.Blood，2021， 137（12）： 1582-1590.

［5］ Pasvolsky O，Kebriaei P，Shah BD，et al.Chimeric antigen receptor T-cell therapy for adult B-cell acute lymphoblastic leukemia： state-of-the-（C）ART and the road ahead ［J］.Blood Adv， 2023，7（14）： 3350-3360.

［6］ Aureli A，Marziani B，Venditti A，et al. Acute lymphoblastic leukemia Immunotherapy treatment： now， next， and beyond ［J］.Cancers （Basel），2023， 15（13）：33-46.

［7］ Zhai Y，Hong J，Wang J，et al.Comparison of blinatumomab and CAR T-cell therapy in relapsed/refractory acute lymphoblastic leukemia： a systematic review and meta-analysis［J］. Expert Rev Hematol，2024，17（1-3）： 67-76.

［8］ Kantarjian H，Stein A，Gökbuget N，et al.Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia ［J］. N Engl J Med，2017， 376（9）： 836-847.

［9］ 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］.J Clin Oncol，2017，35（16）：1795-1802.

［10］ Gökbuget N，Dombret H，Bonifacio M，et al.Blinatumomab for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukemia ［J］. Blood，2018，131（14）：1522-1531.

［11］ 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 ［J］.JAMA， 2021， 325（9）： 843-854.

［12］ Brown PA，Ji L，Xu X，et al.Effect of postreinduction therapy consolidation with blinatumomab vs chemotherapy on disease-free survival in children， adolescents， and young adults with first relapse of B-cell acute lymphoblastic leukemia：a randomized clinical trial ［J］.JAMA，2021，325（9）： 833-842.

［13］ Kantarjian HM，Stock W，Cassaday RD，et al.Inotuzumab ozogamicin for relapsed/refractory acute lymphoblastic leukemia in the INO-VATE Trial： CD22 Pharmacodynamics， efficacy， and safety by baseline CD22 ［J］.Clin Cancer Res，2021，27（10）： 2742-2754.

［14］ Meckler JF，Levis DJ，Vang DP，et al.A novel bispecific T-cell engager （BiTE） targeting CD22 and CD3 has both in vitro and in vivo activity and synergizes with blinatumomab in an acute lymphoblastic leukemia （ALL） tumor model ［J］. Cancer Immunol Immunother，2023，72（9）： 2939-2948.

［15］ Samantasinghar A，Sunildutt NP，Ahmed F，et al. A comprehensive review of key factors affecting the efficacy of antibody drug conjugate ［J］.Biomed Pharmacother，2023，161：114408.

［16］ Jain N，Stock W，Zeidan A，et al.Loncastuximab tesirine， an anti-CD19 antibody-drug conjugate， in relapsed/refractory B-cell acute lymphoblastic leukemia ［J］. Blood Adv，2020，4（3）：449-457.

［17］ Kantarjian HM，Deangelo DJ，Stelljes M，et al. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia ［J］.N Engl J Med，2016，375（8）：740-753.

［18］ O'brien MM，Ji L，Shah NN，et al.Phase II Trial of inotuzumab ozogamicin in children and adolescents with relapsed or refractory B-cell acute lymphoblastic leukemia：children's oncology group protocol AALL1621 ［J］.J Clin Oncol，2022，40（9）： 956-967.

［19］ Pennesi E，Brivio E，Ammerlaan ACJ，et al.Inotuzumab ozogamicin combined with chemotherapy in pediatric B-cell precursor CD22⁺ acute lymphoblastic leukemia： results of the phase IB ITCC-059 trial ［J］.Haematologica， 2024. doi：10.3324/haematol.2023.284409.

［20］ Stelljes M， Raffel S， Alakel N， et al. Inotuzumab ozogamicin as induction therapy for patients older than 55 years with philadelphia chromosome-negative B-precursor ALL［J］.J Clin Oncol， 2024， 42（3）： 273-282.

［21］ Chevallier P， Leguay T， Doubek M， et al. Fractionated inotuzumab ozogamicin combined with low-Intensity chemotherapy provides very good outcome in older patients with newly diagnosed CD22⁺ philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukemia： first results from the EWALL-INO study ［J］. Blood，2021，138（Supplement 1）： 511.

［22］ 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 ［J］. Lancet Oncol， 2018， 19（2）： 240-248.

［23］ Jain N，Jabbour E，Aldoss I，et al.Adct-602， a CD22 targeting antibody drug conjugate bound to PBD toxin in adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia： a phase 1 trial ［J］. Blood， 2022， 140（Supplement 1）： 521-522.

［24］ Zammarchi F， Havenith KE， Sachini N， et al. ADCT-602， a Novel PBD dimer-containing antibody-drug conjugate for treating CD22-positive hematologic malignancies ［J］. Mol Cancer Ther， 2024， 23（4）： 520-531.

［25］ Shah NN， Bhojwani D， August K， et al. Results from an international phase 2 study of the anti-CD22 immunotoxin moxetumomab pasudotox in relapsed or refractory childhood B-lineage acute lymphoblastic leukemia ［J］. Pediatr Blood Cancer，2020，67（5）： 1545-5009.

［26］ Flynn MJ， Hartley JA. The emerging role of anti-CD25 directed therapies as both immune modulators and targeted agents in cancer ［J］. Br J Haematol，2017，179（1）： 20-35.

［27］ Goldberg AD，Atallah E，Rizzieri D，et al. Camidanlumab tesirine， an antibody-drug conjugate， in relapsed/refractory CD25-positive acute myeloid leukemia or acute lymphoblastic leukemia：a phase I study ［J］.Leuk Res，2020，95： 0145-2126.

［28］ Maude SL，Laetsch TW，Buechner J，et al.Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia ［J］. N Engl J Med，2018，378（5）： 439-448.

［29］ Maude SL，Teachey DT，Rheingold SR，et al. Sustained remissions with CD19-specific chimeric antigen receptor （CAR）-modified T cells in children with relapsed/refractory ALL［J］. Jo Clin Oncol， 2016， 34（15_suppl）： 3011.

［30］ Myers RM，Li Y，Barz Leahy A，et al.Humanized CD19-targeted chimeric antigen receptor （CAR） T cells in CAR-naive and CAR-exposed children and young zdults with relapsed or refractory acute lymphoblastic leukemia［J］. J Clin Oncol， 2021， 39（27）： 3044-3055.

［31］ Laetsch TW，Maude SL，Rives S，et al.Three-year update of tisagenlecleucel in pediatric and young adult patients with relapsed/refractory acute lymphoblastic leukemia in the ELIANA trial ［J］.J Clin Oncol，2023，41（9）： 1664-1669.

［32］ Rives S，Maude SL，Hiramatsu H，et al.S112：Tisagenlecleucel in pediatric and young adult patients （pts） with relapsed/refractory （r/r） b-cell acute lymphoblastic leukemia （b-all）： final analyses from the eliana study ［J］.HemaSphere， 2022， 6（S3）： 13-14.

［33］ Shah BD，Ghobadi A，Oluwole OO，et al.Two-year follow-up of KTE-X19 in patients with relapsed or refractory adult B-cell acute lymphoblastic leukemia in ZUMA-3 and its contextualization with SCHOLAR-3， an external historical control study［J］.J Hematol Oncol， 2022， 15（1）： 1756-8722.

［34］ Roddie C，Dias J，O'reilly MA，et al.Durable responses and low toxicity after fast off-rate CD19 chimeric antigen receptor-T therapy in adults with relapsed or refractory B-cell acute lymphoblastic leukemia［J］.J Clin Oncol，2021， 39（30）： 3352-3363.

［35］ Roloff G，Faramand R，Aldoss I，et al.Outcomes following brexucabtagene autoleucel administered as an FDA-approved therapy for adults with relapsed/refractory B-ALL［J］. J Clin Oncol， 2023， 41（16_suppl）： 7001.

［36］ Pan J，Niu Q，Deng B，et al.CD22 CAR T-cell therapy in refractory or relapsed B acute lymphoblastic leukemia［J］.Leukemia，2019，33（12）： 2854-2866.

［37］ 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［J］.Nat Med，2018， 24（1）： 20-28.

［38］ Lamble AJ，Myers RM，Taraseviciute A，et al.Preinfusion factors impacting relapse immunophenotype following CD19 CAR T cells［J］. Blood Adv， 2023，7（4）： 575-585.

［39］ Pan J，Tang K，Luo Y，et al.Sequential CD19 and CD22 chimeric antigen receptor T-cell therapy for childhood refractory or relapsed B-cell acute lymphocytic leukaemia： a single-arm， phase 2 study［J］.Lancet Oncol，2023， 24（11）： 1229-1241.

［40］ Liu S，Deng B，Yin Z，et al. Combination of CD19 and CD22 CAR-T cell therapy in relapsed B-cell acute lymphoblastic leukemia after allogeneic transplantation［J］.Am J Hematol，2021， 96（6）： 671-679.

［41］ 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［J］.Clin Cancer Res，2021，27（10）： 2764-2772.

［42］ Spiegel JY，Patel S，Muffly L，et al.CAR T cells with dual targeting of CD19 and CD22 in adult patients with recurrent or refractory B cell malignancies： a phase 1 trial［J］.Nat Med，2021，27（8）： 1419-1431.

［43］ Cordoba S，Onuoha S，Thomas S，et al.CAR T cells with dual targeting of CD19 and CD22 in pediatric and young adult patients with relapsed or refractory B cell acute lymphoblastic leukemia： a phase 1 trial［J］.Nat Med，2021，27（10）：1797-1805.

［44］ Cappell KM，Kochenderfer JN.Long-term outcomes following CAR T cell therapy：what we know so far［J］.Nat Rev Clin Oncol，2023，20（6）： 359-371.

［45］ Xiao X，Huang S，Chen S，et al. Mechanisms of cytokine release syndrome and neurotoxicity of CAR T-cell therapy and associated prevention and management strategies［J］.J Exp Clin Cancer Res，2021，40（1）： 367.

［46］ Rubinstein JD，O'brien MM.Inotuzumab ozogamicin in B-cell precursor acute lymphoblastic leukemia： efficacy， toxicity， and practical considerations［J］.Front Immunol，2023，14：1664-3224.

[1]	朱鸿斌, 林晓燕, 何玉卓, 郭学军. 急性白血病首次诱导缓解后合并脑梗死报告分析#br#[J]. 中国医药导刊, 2023, 25(9): 971-974.
[2]	单鹄声. 瘤内免疫治疗临床研究组织实施推荐与建议[J]. 中国医药导刊, 2023, 25(3): 249-255.
[3]	马瑞, 刘欣童, 常英军. 成人急性淋巴细胞患者的异基因造血干细胞移植适应证变迁[J]. 中国医药导刊, 2022, 24(10): 983-987.
[4]	冯淑仙, 褚玉会, 张智风. 安脱达尘螨疫苗与低温等离子治疗变应性鼻炎的疗效比较[J]. 中国医药导刊, 2021, 23(4): 261-263.
[5]	何玲,郭成龙,王兰. 铂类耐药的非小细胞肺癌的治疗策略[J]. , 2018, 20(8): 472-476.

快速检索引用检索图表检索高级检索