美国华盛顿大学医学院Armin Ghobadi团队研究了诱导多能干细胞衍生的，CD19导向的嵌合抗原受体自然杀伤细胞，在B细胞淋巴瘤中的应用疗效。相关论文发表在2025年1月11日出版的《柳叶刀》杂志上。

FT596是一种诱导多能干细胞（iPSC）衍生的嵌合抗原受体（CAR）自然杀伤（NK）细胞疗法，具有三种抗肿瘤方式：CD19 CAR；高亲和力、不可切割的CD16-Fc受体；白细胞介素-15受体融合。该研究旨在确定推荐的2期剂量（RP2D），并评估FT596作为单一疗法和与利妥昔单抗联合使用的安全性和耐受性。该研究还旨在评估FT596作为单一疗法和与利妥昔单抗联合使用的抗肿瘤活性，并分析其药代动力学。

在这项临床1期的首次人体试验中，研究组在美国的9个地点评估了复发或难治性B细胞淋巴瘤患者的FT596疗效。接受过至少一次全身治疗且没有治愈性治疗选择的患者有资格入选。FT596在不使用利妥昔单抗（方案A）或联合利妥昔单抗（方案B）的条件化疗后给药。该研究包括一个采用3+3设计的剂量递增阶段，剂量递增从第1天的3×10⁷个活细胞开始，作为单次剂量，并针对单个方案独立进行。治疗周期包括在提前5至3天静脉注射环磷酰胺（500 mg/m²）和氟达拉滨（30 mg/m²）进行预处理化疗，然后提前4天静脉注射不同剂量和时间表的FT596，以及不注射（方案A）或单剂量利妥昔单抗（375 mg/m²）。

支持性护理由治疗研究者决定。观察患者28天的剂量限制性不良事件。耐受治疗并获得临床益处的患者可以接受后续的研究治疗周期，如果临床需要，可以修改条件化疗剂量。剂量扩大阶段评估了选定剂量和给药方案下可耐受的额外患者。该研究的主要终点是每个剂量递增队列中剂量限制性毒性的发生率和性质，以确定建立RP2D的最大耐受剂量或最大评估剂量，以及不良事件的发生率、性质和严重程度，严重程度根据国家癌症研究所常见毒性标准和不良事件5.0版确定。

2020年3月19日至2023年1月12日，86名B细胞淋巴瘤患者接受了方案A（n=18）或方案B（n=68）的FT596治疗。在86名患者中，有22名（26%）为女性，72名（84%）为白人。患者接受过先前疗法的中位数为四种（范围1-11），86名患者中有33名（38%）接受过CAR T细胞疗法。未达到最大耐受剂量。在方案A的18名患者中，有1名（6%）报告了细胞因子释放综合征（最高1级），在方案B的68名患者中有9名（13%）（6名最高1级，3名最高2级）。未观察到神经毒性。

研究结果表明，FT596作为单一疗法或与利妥昔单抗联用具有良好的耐受性，并在惰性和侵袭性淋巴瘤患者中诱导了深度和持久的缓解，初步确定RP2D为1.8×10⁹个细胞，每个周期输注三剂。这项研究支持使用iPSC-衍生的基因修饰的NK细胞的细胞治疗是癌症治疗的有效平台，并表明这种平台可能会解决目前可用的免疫细胞治疗的局限性，包括制造时间、异质性、可及性和成本。

附：英文原文

Title: Induced pluripotent stem-cell-derived CD19-directed chimeric antigen receptor natural killer cells in B-cell lymphoma: a phase 1, first-in-human trial

Author: Armin Ghobadi, Veronika Bachanova, Krish Patel, Jae H Park, Ian Flinn, Peter A Riedell, Carlos Bachier, Catherine S Diefenbach, Carol Wong, Cara Bickers, Lilly Wong, Deepa Patel, Jode Goodridge, Matthew Denholt, Bahram Valamehr, Rebecca L Elstrom, Paolo Strati

Issue&Volume: 2025/01/11

Abstract:

Background

FT596 is an induced pluripotent stem-cell (iPSC)-derived chimeric antigen receptor (CAR) natural killer (NK) cell therapy with three antitumour modalities: a CD19 CAR; a high-affinity, non-cleavable CD16 Fc receptor; and interleukin-15-interleukin-15 receptor fusion. In this study, we aimed to determine the recommended phase 2 dose (RP2D) and evaluate the safety and tolerability of FT596 as monotherapy and in combination with rituximab. We also aimed to evaluate the antitumour activity and characterise the pharmacokinetics of FT596 as monotherapy and in combination with rituximab.

Methods

In this phase 1, first-in-human trial, we evaluated FT596 in patients with relapsed or refractory B-cell lymphoma at nine sites in the USA. Patients who had received at least one previous systemic therapy and had no curative treatment options were eligible for inclusion. FT596 was administered after conditioning chemotherapy without rituximab (regimen A) or combined with rituximab (regimen B). The study consisted of a dose-escalation phase using a 3+3 design, with dose escalation commencing at 3×107 viable cells as a single dose on day 1 and done independently for individual regimens. A treatment cycle consisted of conditioning chemotherapy with cyclophosphamide (500 mg/m2) and fludarabine (30 mg/m2) intravenously on days –5 to –3, followed by FT596 administered at various doses and schedules, without (regimen A) or with (regimen B) a single dose of rituximab (375 mg/m2) intravenously on day –4. Supportive care was determined by the treating investigator. Patients were observed for dose-limiting adverse events for 28 days. Patients who tolerated therapy and derived clinical benefit could receive subsequent cycles of study treatment, with modification of conditioning chemotherapy dose if clinically indicated. The dose-expansion phase evaluated additional patients at selected doses and dosing schedules that had been found to be tolerable. The primary endpoints of the study were the incidence and nature of dose-limiting toxicities within each dose-escalation cohort to determine the maximum tolerated dose or maximum assessed dose to establish the RP2D and the incidence, nature, and severity of adverse events, with severity determined according to National Cancer Institute Common Toxicity Criteria and Adverse Events version 5·0. The trial was registered with ClinicalTrials.gov, NCT04245722.

Findings

Between March 19, 2020, and Jan 12, 2023, 86 patients with B-cell lymphoma received FT596 on regimen A (n=18) or regimen B (n=68). 22 (26%) of 86 patients were female and 72 (84%) of 86 patients were White. Patients had received a median of four previous lines of therapy (range 1–11) and 33 (38%) of 86 patients had received previous CAR T-cell therapy. The maximum tolerated dose was not reached. Cytokine release syndrome was reported in one (6%) of 18 patients (maximum grade 1) on regimen A and nine (13%) of 68 patients on regimen B (six with maximum grade 1 and three with grade 2). Neurotoxicity was not observed.

Interpretation

FT596 was well tolerated as monotherapy or with rituximab and induced deep and durable responses in patients with indolent and aggressive lymphomas and the RP2D was preliminarily identified to be 1·8×109 cells for three doses per cycle. This study supports that cell therapy using iPSC-derived, gene-modified NK cells is a potent platform for cancer treatment and suggests that such a platform might address limitations of currently available immune cell therapies, including manufacturing time, heterogeneity, access, and cost.

DOI: 10.1016/S0140-6736(24)02462-0

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(24)02462-0/abstract