Preliminary Results of UCART19, an Allogeneic Anti-CD19 CAR T-Cell Product, in a First-in-Human Trial (CALM) in Adult Patients with CD19+ Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia-猫眼课题宝

DOI：

10.1182/blood.v130.suppl_1.887.887

发表时间：

2017-12

期刊：

Blood

影响因子：

20.3

通讯作者：

中科院分区：

医学1区

文献类型：

作者：

C. Graham;D. Yallop;A. Jóźwik;P. Patten;A. Dunlop;R. Ellard;Orla Stewart;V. Potter;V. Metaxa;S. Kassam;F. Farzaneh;S. Devereux;A. Pagliuca;A. Zinai;F. Binlich;S. Dupouy;Anne Philippe;S. Balandraud;F. Dubois;C. Konto;Premal H. Patel;G. Mufti;R. Benjamin

背景UCART19是一种由非人类白细胞抗原相合的健康供体细胞制成的转基因T细胞产品。慢病毒转导的CAR T细胞表达(1)抗CD19CAR(抗CD19scFv-41BB-CD3ζ)和(2)RQR8“安全开关”，旨在允许利妥昔单抗靶向清除RQR8+细胞。UCART19已被额外修改，以破坏T细胞受体α常数(TRAC)和CD52基因。描述了UCART19在CD19+R/R B-ALL成人患者(PTS)中进行的I期UCART19同种异体CAR T细胞治疗的初步结果。方法本研究的主要目的是通过在不同的序贯队列中调查最多四个剂量水平(DL)来确定UCART19的最大耐受量。患有≥+R/R B的成人PTS(年龄16岁)-所有用尽可用的治疗方案的人都有资格。疾病负担必须在形态上是可量化的，或者在最后一次抗白血病治疗结束时具有最低残留疾病负荷≥1x10-3。淋巴净化方案结合环磷酰胺和氟达拉滨，加或不加阿仑珠单抗(FC或FCA)。在第0天给予单剂量UCART19，并密切监测PTS的安全性和抗白血病活性，直到研究结束，即UCART19给药后3个月。然后，PTS被滚动到为期15年的长期跟踪研究中。剂量递增遵循修改的毒性概率区间(MTPI)设计，该设计基于在UCART19(D28)后28天评估期结束时评估的剂量限制毒性(DLT)的发生。结果截至2017年6月24日，获得第一个DL(DL1=6x106个CAR+细胞)的2个首批队列(每个队列3分)已经完成。中位年龄22.5岁(18-42岁)。PTS接受了1至5个以前的治疗方案，其中5个患者接受了异基因干细胞移植(allo-SCT)。其中4人在移植后4-6个月内复发。在UCART19输注前，4例患者的疾病负担较低(所有患者均经历了细胞因子释放综合征(CRS)：1例G1、4例G2和1例G4)。CRS G1和G2可通过支持治疗±tocilizumab进行治疗。CRS G4被评估为DLT，发生在中性粒细胞减少的败血症环境中，并被认为是患者在D15死于多器官衰竭的一个促成因素。首次出现CRS症状的时间从D5到D10不等。CRS与血清细胞因子(IL-6、IL-10、干扰素γ)升高及血中UCART19扩大率相关。据报道，一名患者可能患有皮肤GvHD G1。1例仅观察到G1期神经毒性事件。3例出现无症状病毒再激活(CMV和/或腺病毒)，经抗病毒治疗后缓解。在6例患者中，4例在28天获得CRI且MRD阴性(MRD-Ve定义为肿瘤负担)所有4例获得MRD-Ve缓解的患者均接受了随后的allo-SCT，其中3例在UCART19输注后3个月内，1例在再次接受FC淋巴清除术和相同剂量的UCART19治疗后，该患者在首次输注UCART19后2个月复发。移植后100天CD19+1例复发，1例死于感染，2例完全缓解。3例患者在UCART19治疗后分别存活2.4、5.3和10.2个月。UCART19(细胞和转基因水平)在血液中的D12和D17之间达到峰值(分别为流式细胞术[图1]和定量聚合酶链式反应)。在D10至D28的血液中可检测到UCART19(1例患者可达D42)，在D14和D28进行的骨髓抽吸物中可检测到UCART19。除难治性患者外，所有患者的骨髓内细胞都发生了体内扩增。结论UCART19治疗在高危R/R B-ALL成人人群中的首次人体试验的初步结果显示没有意外的毒性。无症状淋巴衰竭相关病毒重新激活和可能的皮肤移植物抗宿主病G1。在达到D28的5例患者中，有4例获得了CRI和MRD-VE。在DL1治疗的2个首批队列已经完成，现在将对DL2进行调查，可能会提出进一步的结果。这项研究在英国很活跃，并将扩展到其他欧盟国家和美国(NCT 02746952)。披露格雷厄姆：瑟维尔：研究资金；辉瑞：其他：教育会议出席；吉利德：其他：教育会议出席；赛诺菲：其他：教育会议出席。雅乐普：爵士制药：Honoraria；安进：Honoraria；辉瑞：其他：顾问委员会。Jozwik：Servier：研究资金。Patten：Gilead Inc：Honoraria，Research Funding；罗氏：Honoraria；Abbvie：Honoraria。Ellard：Moldmed：荣誉。波特：辉瑞：其他：顾问委员会；爵士：荣誉。Devereux：AbbVie：咨询，酬金；MSD：咨询，酬金；罗氏：咨询，其他：差旅费用；GSK：咨询；吉列德：咨询，酬金，发言人局；扬森：咨询，酬金，其他：差旅费用，发言人局；Servier：其他：顾问委员会。Pagliuca：Jazz：Honoraria；Merck：Honoraria，Research Funding；Bluebird：Honoraria；Pfizer：Honoraria；Basilea：Honoraria；Astellas：咨询，发言人局；Gilead：HonorariaZinai：Servier：就业。宾利希：瑟维尔：就业。Dupouy：Servier：就业。菲利普：瑟维尔：就业。Balandraud：Servier：就业。杜布瓦：塞维耶：就业。Konto：百时美施贵宝：就业，股权；辉瑞：就业，股权。帕特尔：辉瑞：就业，股权。本杰明：辉瑞：其他：参加广告董事会会议，研究资助；Servier：研究资助；Celgene：酬金。

Background UCART19 is a genetically modified T-cell product manufactured from non-HLA matched healthy donor cells. Lentiviral-transduced CAR T-cells express (1) an anti-CD19 CAR (anti-CD19 scFv- 41BB- CD3ζ) and (2) an RQR8 "safety switch" that is intended to allow targeted elimination of RQR8+ cells by rituximab. UCART19 has been additionally modified to disrupt the T-cell receptor alpha constant (TRAC) and CD52 genes. The preliminary results of this "off-the-shelf" allogeneic CAR T-cell therapy in a phase I, dose-escalation trial of UCART19 in CD19+ R/R B-ALL adult patients (pts) are described. Methods The primary objective of this study is to determine the maximum tolerated dose of UCART19 by investigating up to four dose levels (DL) in separate sequential cohorts. Adult pts (age ≥16 years) with CD19+ R/R B-ALL who have exhausted available treatment options are eligible. Disease burden must be quantifiable morphologically or with a minimal residual disease (MRD) load ≥1x10-3 at the end of the last anti-leukemic treatment. The lymphodepletion regimen combines cyclophosphamide and fludarabine, with or without alemtuzumab (FC or FCA). A single dose of UCART19 is administered on Day 0, and pts are closely monitored for safety and anti-leukemic activity until the end of study, 3 months after UCART19 administration. Pts are then rolled-over into a 15-years long-term follow-up study. The dose escalation follows a modified Toxicity Probability Interval (mTPI) design based on the occurrence of dose-limiting toxicity (DLT) assessed at the end of the 28-day evaluation period post UCART19 (D28). Results As of 24 June 2017, the 2 first cohorts (3 pts each) who received the first DL (DL1=6x106 total CAR+ cells) have been completed. Median age was 22.5 years (range 18-42). Pts received 1 to 5 previous lines of treatment with 5 out of 6 pts having undergone an allogeneic stem cell transplant (allo-SCT). Four of them had relapsed within 4-6 months post-transplant. Prior to UCART19 infusion, 4 pts had low disease burden ( All pts experienced cytokine release syndrome (CRS): 1 G1, 4 G2 and 1 G4. CRS G1 and G2 were manageable by supportive care ± tocilizumab. CRS G4, assessed as a DLT, occurred in the context of neutropenic sepsis, and was considered to be a contributory factor in the patient9s death from multiple organ failure at D15. Time to onset of first CRS symptoms ranged between D5 and D10. CRS correlated with serum cytokine increase (IL-6; IL-10 and INFγ) and UCART19 expansion in the blood. One patient was reported to have probable skin GvHD G1. Only G1 neurotoxic events were observed in 1 patient. Asymptomatic viral reactivations (CMV and/or adenovirus) were seen in 3 pts and resolved with antiviral therapy. Among the 6 pts, 4 achieved a CRi with MRD negativity at D28 (MRD-ve, defined as a tumor burden All 4 pts achieving MRD-ve remission underwent a subsequent allo-SCT, 3 of them within 3 months of UCART19 infusion and 1 following retreatment with FC lymphodepletion and the same dose of UCART19, this patient having relapsed with CD19+ disease 2 months post initial UCART19 infusion. Post allo-SCT, 1 patient relapsed at 100 days with CD19+ disease, 1 died from infection and 2 remain in complete remission. Three pts remain alive at 2.4, 5.3 and 10.2 months respectively post UCART19 treatment. UCART19 (both cells and transgene levels) peaked between D12 and D17 in blood (flow cytometry [figure 1] and qPCR, respectively). UCART19 was detectable in blood from D10 to D28 (up to D42 in 1 patient) and in BM aspirates performed at D14 and D28. In-vivo cell expansion in BM occurred in all but the refractory patient. Conclusion Preliminary results of this first-in-human trial of UCART19 treatment in a high risk R/R B-ALL adult population revealed no unexpected toxicities. Asymptomatic lymphodepletion-related viral reactivations and a probable skin GvHD G1 were encountered. CRi with MRD-ve was achieved in 4 out of 5 pts who reached D28. The 2 first cohorts treated at DL1 have been completed and DL2 will now be investigated on which further results may be presented. The study is active in the UK and will be expanded to other EU countries and the US (NCT 02746952). Disclosures Graham: Servier: Research Funding; Pfizer: Other: Educational meeting attendance; Gilead: Other: Educational meeting attendance; Sanofi: Other: Educational meeting attendance. Yallop: Jazz Pharmaceuticals: Honoraria; Amgen: Honoraria; Pfizer: Other: Advisory board. Jozwik: Servier: Research Funding. Patten: Gilead Inc: Honoraria, Research Funding; Roche: Honoraria; Abbvie: Honoraria. Ellard: Moldmed: Honoraria. Potter: Pfizer: Other: Advisory board; Jazz: Honoraria. Devereux: AbbVie: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Roche: Consultancy, Other: travel expenses; GSK: Consultancy; Gilead: Consultancy, Honoraria, Other: travel expenses, Speakers Bureau; Janssen: Consultancy, Honoraria, Other: travel expenses, Speakers Bureau; Servier: Other: Advisory board. Pagliuca: Jazz: Honoraria; Merck: Honoraria, Research Funding; Bluebird: Honoraria; Pfizer: Honoraria; Basilea: Honoraria; Astellas: Consultancy, Speakers Bureau; Gilead: Honoraria. Zinai: Servier: Employment. Binlich: Servier: Employment. Dupouy: Servier: Employment. Philippe: Servier: Employment. Balandraud: Servier: Employment. Dubois: Servier: Employment. Konto: Bristol-Myers Squibb: Employment, Equity Ownership; Pfizer: Employment, Equity Ownership. Patel: Pfizer: Employment, Equity Ownership. Benjamin: Pfizer: Other: Participated in Adboard meeting, Research Funding; Servier: Research Funding; Celgene: Honoraria.

Preliminary Results of UCART19, an Allogeneic Anti-CD19 CAR T-Cell Product, in a First-in-Human Trial (CALM) in Adult Patients with CD19+ Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia

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