同種異體抗CD19 CAR-T細胞治療B細胞急性淋巴細胞白血病安全有效
作者：
小柯機器人發布時間：2020/12/15 16:12:39
英國倫敦國王學院Reuben Benjamin團隊研究了基因組編輯、供者來源的同種異體抗CD19嵌合抗原受體T細胞治療兒童和成人B細胞急性淋巴細胞白血病的療效。2020年12月12日，該研究發表在《柳葉刀》雜誌上。
基因組編輯的供體來源的同種異體抗CD19嵌合抗原受體（CAR）T細胞提供了一種新型的CAR-T細胞產品，可立即用於臨床，從而擴大了其使用範圍和適用性。UCART19就是研究復發或難治性B細胞急性淋巴細胞白血病的兒童和成人的此類產品之一。
研究組進行了兩項多中心臨床1期研究，旨在研究UCART19治療復發性或難治性B細胞急性淋巴細胞白血病兒童和成人的可行性、安全性和抗白血病活性。所有患者均接受氟達拉濱和環磷醯胺加或不加阿侖單抗的淋巴清除，然後兒童接受1.1-2.3×10 6個細胞/kg劑量的UCART19，成人在劑量遞增研究中分別接受6×10 6個細胞，6-8×10 7個細胞，或1.8–2.4×10 8個細胞劑量的UCART19。主要結局是首次輸注至數據截止之間的不良事件。
2016年6月3日至2018年10月23日，共有7名兒童和14名成人參加了兩項研究，並接受了UCART19。細胞因子釋放症候群是最常見的不良事件，共有19例患者發生（91％）； 3名（14％）患有3–4級細胞因子釋放症候群。其他不良事件包括8例患者（38％）的1或2級神經毒性，2例患者（10％）的1級急性皮膚移植物抗宿主病和6例患者（32％）的4級持續性血細胞減少。
共發生兩起與治療有關的死亡：一起因並發細胞因子釋放症候群患者的中性粒細胞減少引起，另一起因持續性血細胞減少症患者的肺出血引起。輸注後28天，21例患者中有14例（67％）出現完全緩解或血液學不完全恢復。未接受阿侖單抗的4例患者未顯示UCART19擴增或抗白血病活性。中位緩解持續時間為4.1個月，其中14位緩解者中有10位（71％）接受了隨後的同種異體幹細胞移植。6個月無進展生存率為27％，總生存率為55％。
這兩項研究首次顯示了使用經基因組編輯的異基因CAR-T細胞治療侵襲性白血病的可行性。UCART19治療經過大量預處理的兒童和成人復發或難治性B細胞急性淋巴細胞白血病患者中表現出體內擴增和抗白血病活性，並具有可控的安全性。這項研究結果為同種異體CAR-T細胞領域的發展邁出了令人鼓舞的一步。
附：英文原文
Title: Genome-edited, donor-derived allogeneic anti-CD19 chimeric antigen receptor T cells in paediatric and adult B-cell acute lymphoblastic leukaemia: results of two phase 1 studies
Author: Reuben Benjamin, Charlotte Graham, Deborah Yallop, Agnieszka Jozwik, Oana C Mirci-Danicar, Giovanna Lucchini, Danielle Pinner, Nitin Jain, Hagop Kantarjian, Nicolas Boissel, Marcela V Maus, Matthew J Frigault, André Baruchel, Mohamad Mohty, Athos Gianella-Borradori, Florence Binlich, Svetlana Balandraud, Fabien Vitry, Elisabeth Thomas, Anne Philippe, Sylvain Fouliard, Sandra Dupouy, Ibtissam Marchiq, Maria Almena-Carrasco, Nicolas Ferry, Sylvain Arnould, Cyril Konto, Paul Veys, Waseem Qasim, Reuben Benjamin, Charlotte Graham, Deborah Yallop, Agnieszka Jozwik, Antonio Pagliuca, Ghulam Mufti, Piers Patten, Shireen Kassam, Stephen Devereux, Majid Kazmi, Kirsty Cuthill, Victoria Potter, Andrea Kuhnl, Victoria Metaxa, Laarni Bonganay, Orla Stewart, Rose Ellard, Lorraine Catt, Jen Lewis, Farzin Farzaneh, Jackie Chappell, Alice Mason, Vicky Chu, Alan Dunlop, Adeel Saleem, Gary Cheung, Helena Munro, Elka Giemza, Waseem Qasim, Paul Veys, Oana Ciocarlie, Giovanna Lucchini, Danielle Pinner, Jan Chu, Persis Amrolia, Kanchan Rao, Robert Chiesa, Juliana Silva, Annette Hill, Maria Finch, Lindsey Young, Harvinder Hara, Sujith Samarasinghe, Anupama Rao, Ajay Vora, Kimberley Gilmour, Christine Rivat, Clare Murphy, Gulrukh Ahsan, Rasha Said Shamsah, Jesmina James, Sarah Inglott, Gary Wright, Stuart Adams, Natalia Izotova, Nitin Jain, Marina Konopleva, William Wierda, Elias Jabbour, Hagop Kantarjian, Partow Kebrieai, Emily Jones, Kara McGee, Marcela Maus, Matthew Frigault, Jami Brown, Vesselina Toncheva, Keagan Casey, Hanno Hock, Meaghan A McKeown, Richard Mathews, Thomas Spitzer, Nicolas Boissel, Emmanuel Raffoux, Etienne Lengliné, Raphael Itzykson, Florence Rabian, Jérme Larghero, Isabelle Madelaine, Elie Azoulay, Emmanuelle Clappier, Sophie Caillat-Zucman, Martine Meunier, Karine Celli-Lebras, Marie-Thérèse Tremorin, André Baruchel
Issue&Volume: 2020/12/12
Abstract:
Background
Genome-edited donor-derived allogeneic anti-CD19 chimeric antigen receptor (CAR) T cells offer a novel form of CAR-T-cell product that is available for immediate clinical use, thereby broadening access and applicability. UCART19 is one such product investigated in children and adults with relapsed or refractory B-cell acute lymphoblastic leukaemia. Two multicentre phase 1 studies aimed to investigate the feasibility, safety, and antileukaemic activity of UCART19 in children and adults with relapsed or refractory B-cell acute lymphoblastic leukaemia.
Methods
We enrolled paediatric or adult patients in two ongoing, multicentre, phase 1 clinical trials to evaluate the safety and antileukaemic activity of UCART19. All patients underwent lymphodepletion with fludarabine and cyclophosphamide with or without alemtuzumab, then children received UCART19 at 1·1–2·3×10 6 cells per kg and adults received UCART19 doses of 6×10 6 cells, 6–8×10 7 cells, or 1·8–2·4×10 8 cells in a dose-escalation study. The primary outcome measure was adverse events in the period between first infusion and data cutoff. These studies were registered at ClinicalTrials.gov, NCT02808442 and NCT02746952.
Findings
Between June 3, 2016, and Oct 23, 2018, seven children and 14 adults were enrolled in the two studies and received UCART19. Cytokine release syndrome was the most common adverse event and was observed in 19 patients (91%); three (14%) had grade 3–4 cytokine release syndrome. Other adverse events were grade 1 or 2 neurotoxicity in eight patients (38%), grade 1 acute skin graft-versus-host disease in two patients (10%), and grade 4 prolonged cytopenia in six patients (32%). Two treatment-related deaths occurred; one caused by neutropenic sepsis in a patient with concurrent cytokine release syndrome and one from pulmonary haemorrhage in a patient with persistent cytopenia. 14 (67%) of 21 patients had a complete response or complete response with incomplete haematological recovery 28 days after infusion. Patients not receiving alemtuzumab (n=4) showed no UCART19 expansion or antileukaemic activity. The median duration of response was 4·1 months with ten (71%) of 14 responders proceeding to a subsequent allogeneic stem-cell transplant. Progression-free survival at 6 months was 27%, and overall survival was 55%.
Interpretation
These two studies show, for the first time, the feasibility of using allogeneic, genome-edited CAR T cells to treat patients with aggressive leukaemia. UCART19 exhibited in-vivo expansion and antileukaemic activity with a manageable safety profile in heavily pretreated paediatric and adult patients with relapsed or refractory B-cell acute lymphoblastic leukaemia. The results this study are an encouraging step forward for the field of allogeneic CAR T cells, and UCART19 offers the opportunity to treat patients with rapidly progressive disease and where autologous CAR-T-cell therapy is unavailable.
DOI: 10.1016/S0140-6736(20)32334-5
Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)32334-5/fulltext