CAR-T细胞疗法引起细胞因子释放综合征的研究进展
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摘要
嵌合抗原受体修饰T细胞疗法是目前最具应用前景的靶向免疫治疗,在治疗难治复发性急性淋巴细胞白血病中取得突破性进展,但与之相关的不良反应限制其在临床中的应用。细胞因子释放综合征(cytokine release syndrome,CRS)是常见且严重的不良反应,强化监测、准确分级并及时处理不良反应对减少CRS发病率和病死率有重要作用。本文就CRS的病理生理学机制、CRS分级、CRS严重程度的影响因素及CRS的药物治疗作一综述。
Chimeric angtigen receptor T cell therapy has been regarded as the most promising application targeted immunotherapy,which has achieved a breakthrough progress in treating relapsed refractory acute lymphocytic leukemia,but its related adverse reactions restrict its further clinical application.Cytokine release syndrome(CRS)is the most common and serious adverse reaction,therefore the intensive monitoring,accurate grading and timely treatment of adverse reactions is essential for reducing the incidence and mortality of CRS.This paper reviews the pathophysiological mechanism,grading,influencing factors and drug treatment of CRS.
Chimeric angtigen receptor T cell therapy has been regarded as the most promising application targeted immunotherapy,which has achieved a breakthrough progress in treating relapsed refractory acute lymphocytic leukemia,but its related adverse reactions restrict its further clinical application.Cytokine release syndrome(CRS)is the most common and serious adverse reaction,therefore the intensive monitoring,accurate grading and timely treatment of adverse reactions is essential for reducing the incidence and mortality of CRS.This paper reviews the pathophysiological mechanism,grading,influencing factors and drug treatment of CRS.
引文
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[12] PORTER D,FREY N,WOOD P A,et al.Grading of cytokine release syndrome associated with the CAR T cell therapy tisagenlecleucel[J].J Hematol Oncol,2018,11(1):81-92.
[13] DAVILA M L,RIVIERE I,WANG X,et al.Efficacy and toxicity management of 19-28zCAR T cell therapy in B cell acute lymphoblastic leukemia[J].Sci Transl Med,2014,6(224):224-225.
[14] TEACHEY D T, LACEY S F, SHAW P A,et al.Identification of predictive biomarkers for cytokine release syndrome after chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia[J].Cancer Discov,2016,6(6):664-679.
[15]MAUDE S L,PULSIPHER M A,BOYER M W,et al.Efficacy and safety of CTL019 in the first US phaseⅡmulticenter trialinpediatricrelapsed/refractoryacute lymphoblastic leukemia:results of an interim analysis[J].Blood,2016,128(22):2801-2806.
[16] PARK J H,RIVIERE I,GONEN M,et al.Long-term followup of CD19CAR therapy in acute lymphoblastic leukemia[J].N Engl J Med,2018,378(5):449-459.
[17] STEGEN V D,HAMIEH M,SADELAIN M,et al.The pharmacology of second-generation chimeric antigen receptors[J].Nat Rev Drug Discov,2015,14(7):499-509.
[18] BRUDNO J N,KOCHENDERFER J N.Toxicities of chimeric antigen receptor T cells:recognition and management[J].Blood,2016,127(26):3321-3330.
[19]王琪,张坦,苏凤,等.细胞因子释放综合征的不良反应研究现状[J].中国临床药理学杂志,2018,34(7):906-909.
[20]吴晨,蒋敬庭.CAR-T细胞免疫治疗肿瘤的毒副反应及临床对策[J].中国肿瘤生物治疗杂志,2016,23(6):745-749.
[21] BONIFANT C L,JACKSON H J,BRENTJENS R J,et al.Toxicity and management in CAR T-cell therapy[J].Mol Ther Oncolyt,2016,20(3):16011-16017.
[2]张曼泽,宋秀军,李伟,等.嵌合抗原受体修饰的T细胞在实体肿瘤治疗中的研究进展[J].免疫学杂志,2017,33(3):251-255.
[3]王海涛,李丽敏,付玥玥,等.复发难治性急性淋巴细胞白血病CD19CAR-T治疗后复发相关因素的研究进展[J].中华实用诊断与治疗杂志,2018,32(3):301-302.
[4] NISHIMOTO N,TERAO K,MIMA T,et al.Mechanisms and pathologic significances in increase in serum interleukin-6(IL-6)and soluble IL-6receptor after administration of an anti-IL-6receptor antibody,tocilizumab,in patients with rheumatoid arthritis and Castleman disease[J].Blood,2008,112(10):3959-3964.
[5] HAY K A,HANAFI L A,LI D,et al.Kinetics and biomarkers of severe cytokine release syndrome after CD19chimeric antigen receptor-modified T cell therapy[J].Blood,2017,130(21):2296-2306.
[6] NEELAPU S S,TUMMALA S,KEBRIAEI P,et al.Chimeric antigen receptor T-cell therapy-assessment and management of toxicities[J].Nat Rev Clin Oncol,2018,15(1):47-62.
[7]刘永军,于雪蕾,张军华,等.CAR-T治疗恶性肿瘤的研究进展及趋势分析[J].免疫学杂志,2016,32(11):992-996.
[8]ALEXANDER S V,GODEL P,SUBKLEWE M,et al.Cytokine release syndrome[J].J Immunother Cancer,2018,6(1):56-69.
[9]TANAKA T, NARAZAKI M, KISHIMOTO T,et al.Immunotherapeutic implications of IL-6 blockade for cytokine storm[J].Immunotherapy,2016,8(8):959-970.
[10] OBSTFELD A E,FREY N V,MANSFIELD K,et al.Cytokine release syndrome associated with chimeric-antigen receptor T-cell therapy:clinicopathological insights[J].Blood,2017,130(23):2569-2572.
[11] LEE D W,GARDNER R,PORTER D L,et al.Current concepts in the diagnosis and management of cytokine release syndrome[J].Blood,2014,124(2):188-195.
[12] PORTER D,FREY N,WOOD P A,et al.Grading of cytokine release syndrome associated with the CAR T cell therapy tisagenlecleucel[J].J Hematol Oncol,2018,11(1):81-92.
[13] DAVILA M L,RIVIERE I,WANG X,et al.Efficacy and toxicity management of 19-28zCAR T cell therapy in B cell acute lymphoblastic leukemia[J].Sci Transl Med,2014,6(224):224-225.
[14] TEACHEY D T, LACEY S F, SHAW P A,et al.Identification of predictive biomarkers for cytokine release syndrome after chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia[J].Cancer Discov,2016,6(6):664-679.
[15]MAUDE S L,PULSIPHER M A,BOYER M W,et al.Efficacy and safety of CTL019 in the first US phaseⅡmulticenter trialinpediatricrelapsed/refractoryacute lymphoblastic leukemia:results of an interim analysis[J].Blood,2016,128(22):2801-2806.
[16] PARK J H,RIVIERE I,GONEN M,et al.Long-term followup of CD19CAR therapy in acute lymphoblastic leukemia[J].N Engl J Med,2018,378(5):449-459.
[17] STEGEN V D,HAMIEH M,SADELAIN M,et al.The pharmacology of second-generation chimeric antigen receptors[J].Nat Rev Drug Discov,2015,14(7):499-509.
[18] BRUDNO J N,KOCHENDERFER J N.Toxicities of chimeric antigen receptor T cells:recognition and management[J].Blood,2016,127(26):3321-3330.
[19]王琪,张坦,苏凤,等.细胞因子释放综合征的不良反应研究现状[J].中国临床药理学杂志,2018,34(7):906-909.
[20]吴晨,蒋敬庭.CAR-T细胞免疫治疗肿瘤的毒副反应及临床对策[J].中国肿瘤生物治疗杂志,2016,23(6):745-749.
[21] BONIFANT C L,JACKSON H J,BRENTJENS R J,et al.Toxicity and management in CAR T-cell therapy[J].Mol Ther Oncolyt,2016,20(3):16011-16017.