嵌合抗原受体基因修饰T细胞早期临床试验的探讨

中国药物警戒 ›› 2017, Vol. 14 ›› Issue (10): 611-614.

嵌合抗原受体基因修饰T细胞早期临床试验的探讨

高建超, 高晨燕^*

国家食品药品监督管理总局药品审评中心，北京100038

收稿日期:2017-08-08 修回日期:2017-11-30 出版日期:2017-10-20 发布日期:2017-11-30
通讯作者: 高晨燕，女，主任药师，生物制品技术审评。E-mail: gaocy@cde.org.cn
作者简介:高建超，男，主管药师，生物制品技术审评。

General Considerations for Early-phase Clinical Trials of Chimeric Antigen Receptor T Cell Therapy

GAO Jian-chao，GAO Chen-yan^*

Center for Drug Evaluation, CFDA, Beijing 100038, China

Received:2017-08-08 Revised:2017-11-30 Online:2017-10-20 Published:2017-11-30

摘要/Abstract

摘要： 目的对影响早期临床试验设计的因素进行探讨，并深入分析早期临床试验的设计原则和方法。方法从产品特征、临床前研究、安全性风险等方面分析CAR-T细胞临床试验的影响因素，并从试验目的、研究对象、试验设计等角度总结CAR-T细胞早期临床试验的考虑要点。结果 CAR-T细胞的产品特征、临床前研究方法和安全性风险与其它药物有显著差异，对早期临床试验有重要影响。结论在早期临床试验中探索CAR-T细胞的有效剂量、不良反应、初步的有效性非常重要，此外，还应在早期临床试验中验证CAR-T细胞的临床可及性及工艺稳定性。

关键词: 嵌合抗原受体基因修饰T细胞, 早期临床试验, 临床前研究, 安全性, 试验设计

Abstract: Objective To discuss the factors that affect the design of early-phase clinical trials and analyze the designing principles and methods of early-phase clinical trials. Methods The influencing factors of the clinical trials of CAR-T cells including the product characteristics, preclinical study and safety risk were analyzed, and the important considerations for the early clinical trials were summarized in terms of study objectives, subject and trial design, etc. Results The product characteristics, pre-clinical studies and safety risks of CAR-T cells are significantly different from other drugs, all of which have significant influences on early clinical trials. Conclusion It is important to explore the effective dose, side effects, and initial effectiveness of CAR-T cells in early clinical trials, and furthermore, the clinical applicability and process stability of CAR-T cells should also be validated in early clinical trials.

Key words: chimeric antigen receptor T cells, early-phase clinical trial, pre-clinical study, safety, trial design

中图分类号:

R969

高建超, 高晨燕. 嵌合抗原受体基因修饰T细胞早期临床试验的探讨[J]. 中国药物警戒, 2017, 14(10): 611-614.

GAO Jian-chao，GAO Chen-yan . General Considerations for Early-phase Clinical Trials of Chimeric Antigen Receptor T Cell Therapy[J]. Chinese Journal of Pharmacovigilance, 2017, 14(10): 611-614.

参考文献

[1] FDA. Considerations for the Design of Early-Phase Clinical Trials of Cellular and Gene Therapy Products[EB/OL].(2015-06)[2017-
07-01]. https://www.fda.gov/downloads/BiologicsBloodVaccines/
GuidanceComplianceRegulatoryInformation/Guidances/CellularandGeneTherapy/UCM564952.pdf.
[2] Kakarla S, Gottschalk S. CAR T cells for solid tumors: armed and ready to go?[J]. Cancer Journal, 2014, 20(2):151.
[3] 张敬伟, 段冬梅, 袁小笋, 等. 沙利度胺联合化疗治疗老年晚期非小细胞肺癌的临床观察[J]. 中国药物警戒, 2017, 14(8):460-
463，469.
[4] 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.
[5] Davila M L, Riviere I, Wang X, et al. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia[J]. Science Translational Medicine, 2014, 6(224):224.
[6] Maude S L, Barrett D, Teachey D T, et al. Managing Cytokine Release Syndrome Associated With Novel T Cell-Engaging Therapies[J]. Cancer Journal, 2014, 20(2):119.
[7] Lee D W, Kochenderfer J N, Stetlerstevenson M, et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial[J]. Lancet, 2015, 385(9967):517.
[8] Maus M V, Grupp S A, Porter D L, et al. Antibody-modified T cells: CARs take the front seat for hematologic malignancies[J]. Blood, 2014, 123(17):2625-2635.
[9] Maus M V, Grupp S A, Porter D L, et al. Antibody-modified T cells: CARs take the front seat for hematologic malignancies[J]. Blood, 2014, 123(17):2625-2635.
[10] Fisher D T, Chen Q, Skitzki J J, et al. IL-6 trans-signaling licenses mouse and human tumor microvascular gateways for trafficking of cytotoxic T cells[J]. Journal of Clinical Investigation, 2011, 121(10):3846-3859.
[11] Kochenderfer J N, Dudley M E, Carpenter R O, et al. Donor-derived CD19-targeted T cells cause regression of malignancy persisting after allogeneic hematopoietic stem cell transplantation[J]. Blood, 2013, 122(25):4129-4139.
[12] Miao Y Q, Qu X Y, Wang L, et al. Tumor lysis syndrome in patients with chronic lymphocytic leukemia: two case reports and review of the literature[J]. Int J Clin Exp Pathol 2017;10(2):2446-2450.
[13] Morgan R A, Yang J C, 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[J]. Molecular Therapy the Journal of the American Society of Gene Therapy, 2010, 18(4):843.
[14] Porter D L, Hwang W T, Frey N V, et al. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia[J]. Science Translational Medicine, 2015, 7(303):303ra139.
[15] Brudno J N, Somerville R P T, 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]. Journal of Clinical Oncology Official Journal of the American Society of Clinical Oncology, 2016, 34(10):1112.
[16] Therese L, Noemi P J, David E. Lentiviral Vectors for Cancer Immunotherapy and Clinical Applications[J]. Cancers, 2013, 5(3):815-37.
[17] Lee D W, Kochenderfer J N, Stetlerstevenson M, et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial[J]. Lancet, 2015, 385(9967):517.
[18] Ji Y, Wang S J. Modified toxicity probability interval design: a safer and more reliable method than the 3+3 design for practical phase I trials[J]. Journal of Clinical Oncology Official Journal of the American Society of Clinical Oncology, 2013, 31(14):1785.
[19] FDA. Guidance for Industry: Gene Therapy Clinical Trials-Observing Subjects for Delayed Adverse Events[EB/OL].(2006-11)[2017-07-19].https://www.fda.gov/downloads/BiologicsBloodVaccines/Guidance-ComplianceRegulatoryInformation/Guidances/CellularandGeneTherapy/UCM564952.pdf