CAR-T细胞免疫疗法副作用的优化策略
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摘要
CAR-T细胞免疫疗法(chimeric antigen receptor T-cell immunotherapy)即嵌合抗原受体T细胞免疫疗法已在血液恶性肿瘤治疗中取得了明显效果。然而,CAR T细胞的抗肿瘤活性需要进一步改善以增强其在肿瘤临床治疗中的应用。实体瘤由于缺乏肿瘤特异性抗原难以有效区分肿瘤相关抗原和正常组织或器官,导致脱靶效应。另外CAR T细胞治疗可以引发一系列毒副作用,例如细胞因子释放综合征及神经毒性等。本文针对CAR-T细胞疗法中几个重大的安全性问题的优化方案进行总结。
Chimeric antigen receptor(CAR) T cell therapy can be used to effectively treat hematological malignancies. However,there is necessary to enhance the anti-tumor activity of CAR T cells to improve the clinical application. It is difficult to effectively distinguish between tumor-associated antigens and normal tissues or organs due to the lack of tumor specific antigens,leading to off-target effects. In addition,CAR T cell therapy can trigger a series of toxic side effects,such as cytokine release syndrome and neurotoxicity. This article summarizes the optimization schemes for several major safety issues of CAR T cell therapy.
Chimeric antigen receptor(CAR) T cell therapy can be used to effectively treat hematological malignancies. However,there is necessary to enhance the anti-tumor activity of CAR T cells to improve the clinical application. It is difficult to effectively distinguish between tumor-associated antigens and normal tissues or organs due to the lack of tumor specific antigens,leading to off-target effects. In addition,CAR T cell therapy can trigger a series of toxic side effects,such as cytokine release syndrome and neurotoxicity. This article summarizes the optimization schemes for several major safety issues of CAR T cell therapy.
引文
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[2] ZHANG Tengfei,CAO Ling,XIE Jing,et al. Efficiency of CD19 chimeric antigen receptor-modified T cells for treatment of B cell malignancies in phase I clinical trials:a meta-analysis[J]. Oncotarget,2015,6 (32):33961-33971.
[3] GHORASHIAN S,PULE M,AMROLIA P,et al.CD19 chimeric antigen receptor T cell therapy for haematological malignancies[J]. Br J Haematol. 2015,169(4):463-478.
[4] MARCO L D,ISABELLE R,WANG Xiuyan,et al. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia[J]. Sci Transl Med,2014,6:224.
[5] MAUDE S L,TEACHEY D T,RHEINGOLD S R,et al. Sustained remissions with CD19-specific chimeric antigen receptor (CAR)-modified T cells in children with relapsed/refractory ALL[J]. ASCO Meeting Abstracts,2016,34(15 suppl):3011.
[6] FEDOROV V D,THEMELI M,SADELAIN M. PD-1 and CTLA-4-based inhibitory chimeric antigen receptors (iCARs) divert off-target immunotherapy responses[J]. Sci Transl Med,2013,5(215):ra172
[7] WILKIE S,van SCHALKWYK M C,HOBBS S,et al. Dual targeting of ErbB2 and MUC1 in breast cancer using chimeric antigen receptors engineered to provide complementary signaling[J]. J Clin Immunol,2012,32(5):1059-1070.
[8] KLOSSCC,CONDOMINESM,CARTELLIERIM,et al.Combinatorial antigen recognition with balanced signaling promotes selective tumor eradication by engineered T cells[J]. Nat Biotechnol,2013,31(1):7175.
[9] HEGDE M,MUKHERJEE M. Tandem CAR T cells targeting HER2 and IL13Rα2 mitigate tumor antigen escape[J]. J Clin Investig,2016,126(8):3036-3052.
[10] DAVILA M L,SADELAIN M. Biology and clinical application of CAR T cells for B cell malignancies[J]. Int J Hematol,2016,104(1):6-17.
[11] BONINI C,FERRARI G,VERZELETTI S,et al. HSV-TK gene transfer into donor lymphocytes for control of allogeneic graftversus-leukemia[J]. Science,1997,276(5319):1719-1724.
[12] STRAATHOF K C,PULè M A,YOTNDA P,et al. An inducible caspase 9 safety switch for T-cell therapy[J]. Blood,2005,105(11):4247-4254.
[13] KERKAR S P,MURANSKI P,KAISER A,et al. Tumor-specific CD8+ T cells expressing interleukin-12 eradicate established cancers in lymphodepleted hosts[J]. Cancer Res,2010,70(17):6725-6734.
[14] HEGDE M,MUKHERJEE M,GRADA Z,et al. Tandem CAR T cells targeting HER2 and IL13Rα2 mitigate tumor antigen escape[J]. J Clin Invest,2016 126(8):3036-3052.
[15] LAMERS C H,SLEIJFER S,van STEENBERGEN S,et al. Treatment of metastatic renal cell carcinoma with CAIX CAR engineered T cells:clinical evaluation and management of ontarget toxicity[J]. Mol Ther,2013,21(4):904-912.
[16] HAWKES N. US regulator stops leukemia treatment trial after three patients die[J]. BMJ,2016,354:i3893.
[17] MCGONIGLE A M,TOBIAN A A R,ZINK J L,et al. Perfect storm:therapeutic plasma exchange for a patient with thyroid storm[J]. J Clin Apher,2017,66:113-116.
[18] KOPECKY K,MORELAND A,HEBERT C,et al. Plasmapheresis for recurrent acute pancreatitis from hypertriglyceridemia[J]. Proceedings,2017,30(3):358-359.
[19] NEWRZELA S,CORNILS K,LI Zhixiong,et al. Resistance of mature T cells to oncogene transformation[J]. Blood,2008,112(6):2278-2286.
[20] FRAIETTA J A,NOBLES C L,SAMMONS M A,et al. Disruption of TET2 promotes the therapeutic efficacy of CD19-targeted T cells[J]. Nature,2018,558(7709):307-312.
[21] RUELLA M,XU Jun,BARRETT D M,et al. Induction of resistance to chimeric antigen receptor T cell therapy by transduction of a single leukemic B cell[J]. Nat Med,2018,24(10):1499-1503.
[22] ZHANG Zhang,QIU Shunfang,ZHANG Xiaopeng,et al. Optimized DNA electroporation for primary human T cell engineering[J]. BMC Biotechnol,2018,3018(1):4-12.
[23] SMITH T T,STEPHAN S B,MOFFETT H F,et al. In situ programming of leukaemia-specific T cells using synthetic DNA nanocarriers[J]. Nat Nanotechnol,2017,12(8):813-820.