奥贝卡基因自体淋巴细胞疗法治疗成人B细胞急性淋巴细胞白血病

Obecabtagene Autoleucel in Adults with B-Cell Acute Lymphoblastic Leukemia.

作者信息

Roddie Claire, Sandhu Karamjeet S, Tholouli Eleni, Logan Aaron C, Shaughnessy Paul, Barba Pere, Ghobadi Armin, Guerreiro Manuel, Yallop Deborah, Abedi Mehrdad, Pantin Jeremy M, Yared Jean A, Beitinjaneh Amer M, Chaganti Sridhar, Hodby Katharine, Menne Tobias, Arellano Martha L, Malladi Ram, Shah Bijal D, Mountjoy Luke, O'Dwyer Kristen M, Peggs Karl S, Lao-Sirieix Pierre, Zhang Yiyun, Brugger Wolfram, Braendle Edgar, Pule Martin, Bishop Michael R, DeAngelo Daniel J, Park Jae H, Jabbour Elias

机构信息

From the Cancer Institute, University College London (C.R., K.S.P., M.P.), University College London Hospitals NHS Foundation Trust (C.R.), King's College Hospital NHS Foundation Trust (D.Y.), and Autolus Therapeutics (P.L.-S., Y.Z., W.B., E.B., M.P.), London, Manchester Royal Infirmary, Manchester (E.T.), University Hospitals Birmingham NHS Foundation Trust, Birmingham (S.C.), University Hospitals Bristol NHS Foundation Trust, Bristol (K.H.), Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle (T.M.), and Cambridge University Hospitals NHS Foundation Trust, Cambridge (R.M.) - all in the United Kingdom; City of Hope National Medical Center, Duarte (K.S.S.), the Hematology, Blood and Marrow Transplant, and Cellular Therapy Program, University of California, San Francisco, San Francisco (A.C.L.), and UC Davis Medical Center, Sacramento (M.A.) - all in California; the Sarah Cannon Transplant and Cellular Therapy Program, Methodist Hospital, San Antonio (P.S.), and the University of Texas M.D. Anderson Cancer Center, Houston (E.J.) - both in Texas; Hospital Universitari Vall d'Hebron-Universitat Autónoma de Barcelona, Barcelona (P.B.), and Hospital Universitari i Politècnic La Fe, Valencia (M.G.) - both in Spain; Washington University School of Medicine, St. Louis (A.G.); the Sarah Cannon Transplant and Cellular Therapy Program, TriStar Centennial Medical Center, Nashville (J.M.P.); the University of Maryland Medical Center, Baltimore (J.A.Y.); Miller School of Medicine, University of Miami, Miami (A.M.B.), and Moffitt Cancer Center, Tampa (B.D.S.) - both in Florida; Winship Cancer Institute of Emory University, Atlanta (M.L.A.); Colorado Blood Cancer Institute, Denver (L.M.); the University of Rochester Medical Center, Rochester (K.M.O.), and Memorial Sloan Kettering Cancer Center, New York (J.H.P.) - both in New York; the David and Etta Jonas Center for Cellular Therapy, University of Chicago, Chicago (M.R.B.); and Dana-Farber Cancer Institute, Boston (D.J.D.).

出版信息

N Engl J Med. 2024 Dec 12;391(23):2219-2230. doi: 10.1056/NEJMoa2406526. Epub 2024 Nov 27.

DOI:10.1056/NEJMoa2406526

PMID:39602653

Abstract

BACKGROUND

Obecabtagene autoleucel (obe-cel) is an autologous 41BB-ζ anti-CD19 chimeric antigen receptor (CAR) T-cell therapy which uses an intermediate-affinity CAR to reduce toxic effects and improve persistence.

METHODS

We conducted a phase 1b-2 multicenter study of obe-cel in adults (≥18 years of age) with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL). The main cohort, cohort 2A, included patients with morphologic disease; patients in cohort 2B had measurable residual disease. The primary end point was overall remission (complete remission or complete remission with incomplete hematologic recovery) in cohort 2A. Secondary end points included event-free survival, overall survival, and safety.

RESULTS

Of the 153 enrolled patients, 127 (83.0%) received at least one infusion of obe-cel and were evaluable. In cohort 2A (94 patients; median follow-up, 20.3 months), overall remission occurred in 77% (95% confidence interval [CI], 67 to 85), with complete remission in 55% (95% CI, 45 to 66) and complete remission with incomplete hematologic recovery in 21% (95% CI, 14 to 31). The prespecified null hypotheses of overall remission (≤40%) and complete remission (≤20%) were rejected (P<0.001). In the 127 patients who received at least one obe-cel infusion (median follow-up, 21.5 months), the median event-free survival was 11.9 months (95% CI, 8.0 to 22.1); estimated 6- and 12-month event-free survival was 65.4% and 49.5%, respectively. The median overall survival was 15.6 months (95% CI, 12.9 to not evaluable); estimated 6- and 12-month overall survival was 80.3% and 61.1%, respectively. Grade 3 or higher cytokine release syndrome developed in 2.4% of the patients, and grade 3 or higher immune effector cell-associated neurotoxicity syndrome developed in 7.1% of the patients.

CONCLUSIONS

Obe-cel resulted in a high incidence of durable response among adults with relapsed or refractory B-cell ALL, with a low incidence of grade 3 or higher immune-related toxic effects. (Funded by Autolus Therapeutics; FELIX ClinicalTrials.gov number, NCT04404660.).

摘要

背景

奥贝卡他基因自体白细胞介素（obe-cel）是一种自体4-1BB-ζ抗CD19嵌合抗原受体（CAR）T细胞疗法，它使用中等亲和力的CAR来降低毒性作用并提高持久性。

方法

我们对obe-cel在复发或难治性B细胞急性淋巴细胞白血病（ALL）的成人（≥18岁）患者中进行了1b-2期多中心研究。主要队列，即队列2A，包括有形态学疾病的患者；队列2B中的患者有可测量的残留疾病。主要终点是队列2A中的总体缓解（完全缓解或伴有不完全血液学恢复的完全缓解）。次要终点包括无事件生存期、总生存期和安全性。

结果

在153名入组患者中，127名（83.0%）接受了至少一次obe-cel输注并可进行评估。在队列2A（94名患者；中位随访时间为20.3个月）中，总体缓解率为77%（95%置信区间[CI]，67%至85%），完全缓解率为55%（95%CI，45%至66%），伴有不完全血液学恢复的完全缓解率为21%（95%CI，14%至31%）。总体缓解（≤40%）和完全缓解（≤20%）的预先设定的无效假设被拒绝（P<0.001）。在接受至少一次obe-cel输注的127名患者（中位随访时间为21.5个月）中，中位无事件生存期为11.9个月（95%CI，8.0至22.1）；估计的6个月和12个月无事件生存率分别为65.4%和49.5%。中位总生存期为15.6个月（95%CI，12.9至不可评估）；估计的6个月和12个月总生存率分别为80.3%和61.1%。2.4%的患者发生了3级或更高等级的细胞因子释放综合征，7.1%的患者发生了3级或更高等级的免疫效应细胞相关神经毒性综合征。