既往治疗失败后用于淋巴瘤的增强型嵌合抗原受体T细胞疗法

Enhanced CAR T-Cell Therapy for Lymphoma after Previous Failure.

作者信息

Svoboda Jakub, Landsburg Daniel J, Gerson James, Nasta Sunita D, Barta Stefan K, Chong Elise A, Cook Michael, Frey Noelle V, Shea Joanne, Cervini Amanda, Marshall Amy, Four Megan, Davis Megan M, Jadlowsky Julie K, Chew Anne, Pequignot Edward, Gonzalez Vanessa, Noll Julia Han, Paruzzo Luca, Rojas-Levine Juliana, Plesa Gabriela, Scholler John, Siegel Donald L, Levine Bruce L, Porter David L, Ghassemi Saba, Ruella Marco, Rech Andrew, Leskowitz Rachel M, Fraietta Joseph A, Hwang Wei-Ting, Hexner Elizabeth, Schuster Stephen J, June Carl H

机构信息

Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia.

University of Vermont Medical Center, Burlington.

出版信息

N Engl J Med. 2025 May 8;392(18):1824-1835. doi: 10.1056/NEJMoa2408771.

DOI:10.1056/NEJMoa2408771

PMID:40334157

Abstract

BACKGROUND

Chimeric antigen receptor (CAR) T cells targeting CD19 have transformed the treatment of B-cell cancers, but many patients do not have long-term remission. We designed an anti-CD19 enhanced (armored) CAR T-cell product (huCART19-IL18) that secretes interleukin-18 to enhance antitumor activity.

METHODS

In this study, we assessed the safety, feasibility, and preliminary efficacy of huCART19-IL18 in patients with relapsed or refractory lymphoma after previous anti-CD19 CAR T-cell therapy. Using a 3-day manufacturing process, we administered huCART19-IL18-positive cells in doses ranging from 3×10 to 3×10.

RESULTS

A total of 21 patients received huCART19-IL18. Cytokine release syndrome occurred in 62% of the patients (47% with grade 1 or 2), and immune effector-cell-associated neurotoxicity syndrome occurred in 14% (all grade 1 or 2). No unexpected adverse events were observed. Robust CAR T-cell expansion was detected across all dose levels. At 3 months after infusion, a complete or partial response was seen in 81% of the patients (90% confidence interval [CI], 62 to 93) and a complete response in 52% (90% CI, 33 to 71). With a median follow-up of 17.5 months (range, 3 to 34), the median duration of response was 9.6 months (90% CI, 5.5 to not reached).

CONCLUSIONS

In this small study, huCART19-IL18 had a safety profile consistent with other CAR T-cell treatments and showed promising efficacy at low cell doses in patients with lymphoma after the failure of previous anti-CD19 CAR T-cell therapy. (ClinicalTrials.gov number, NCT04684563.).

摘要

背景

靶向CD19的嵌合抗原受体（CAR）T细胞已经改变了B细胞癌症的治疗方式，但许多患者并未实现长期缓解。我们设计了一种抗CD19增强型（武装）CAR T细胞产品（huCART19-IL18），其可分泌白细胞介素-18以增强抗肿瘤活性。

方法

在本研究中，我们评估了huCART19-IL18在先前接受过抗CD19 CAR T细胞治疗的复发或难治性淋巴瘤患者中的安全性、可行性和初步疗效。采用为期3天的生产工艺，我们给予剂量范围为3×10至3×10的huCART19-IL18阳性细胞。

结果

共有21例患者接受了huCART19-IL18治疗。62%的患者发生了细胞因子释放综合征（47%为1级或2级），14%的患者发生了免疫效应细胞相关神经毒性综合征（均为1级或2级）。未观察到意外不良事件。在所有剂量水平均检测到强大的CAR T细胞扩增。输注后3个月，81%的患者出现完全或部分缓解（90%置信区间[CI]，62至93），52%的患者出现完全缓解（90%CI，33至71）。中位随访17.5个月（范围3至34个月），中位缓解持续时间为9.6个月（90%CI，5.5至未达到）。