Strati Paolo, Castro Januario, Goodman Aaron, Bachanova Veronika, Kamdar Manali, Awan Farrukh T, Solomon Scott R, Wong Lilly, Wong Carol, Patel Deepa, Bickers Cara, Zhao Wei, Bashir Zahid, Valamehr Bahram, Elstrom Rebecca L, Patel Krish
Department of Lymphoma and Myeloma and Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Mayo Clinic, Phoenix, AZ, USA.
Lancet Haematol. 2025 Jul;12(7):e505-e515. doi: 10.1016/S2352-3026(25)00142-5.
Natural killer-cell therapies are limited by donor cell sourcing and dose-to-dose variability. FT516 is an induced pluripotent stem cell (iPSC)-derived natural killer-cell therapy expressing high-affinity, non-cleavable CD16 to optimise antibody-dependent cellular cytotoxicity in combination with therapeutic monoclonal antibody. We aimed to assess the safety of FT516 in patients with relapsed or refractory B-cell lymphoma.
This multicentre, open-label, phase 1 study was conducted at eight research centres in the USA. Eligible patients were aged 18 years or older, had B-cell lymphoma expected to express CD20, with relapsed or refractory disease following at least one previous systemic therapy including anti-CD20 antibody, had measurable disease, and had no treatment options expected to improve survival. Participants received fludarabine (30 mg/m for 3 days on days -5 to -3) and cyclophosphamide (500 mg/m for 3 days on days -5 to -3) or bendamustine (90 mg/m for 2 days on days -4 and -3) combined with rituximab at 375 mg/m on day -4 or obinutuzumab 1000 mg replaced rituximab in patients with follicular lymphoma during dose expansion. FT516 was administered intravenously at escalating doses, ranging from 3 × 10 to 9 × 10 cells per dose on days 1, 8, and 15, with IL-2 (6 million units) administered subcutaneously 2-4 h after each FT516 dose. The primary endpoint was safety, including dose-limiting toxicity and maximum tolerated dose. Safety was analysed in all patients who received at least one dose of FT516. Patients with acute myeloid leukaemia were also enrolled and will be reported elsewhere. This study was registered with ClinicalTrials.gov, NCT04023071, and is completed.
From Oct 11, 2019, to Nov 28, 2022, 56 patients were enrolled, 55 of whom received FT516. 32 (58%) patients were male, 23 (42%) were female, and 43 (78%) were White. The maximum FT516 cell dose (9 × 10 cells per dose for three doses per 28-day cycle) was tolerated and identified as the recommended phase 2 dose. No dose-limiting toxicities were reported. Cytokine release syndrome was reported in one (2%) patient and was grade 1; neurotoxicity was not observed. Most common adverse events grade 3 or worse were neutropenia (in 46 [84%] patients), thrombocytopenia (20 [36%]), and anaemia (15 [27%]). There were no treatment-related deaths. Objective response was observed in 32 (58%) of 55 patients.
Our findings suggest that cell therapy using iPSC-derived, gene-modified natural killer cells in combination with monoclonal antibody and IL-2 is safe and active in B-cell malignancies and might address limitations of currently available immune-cell therapies, including manufacturing time, heterogeneity, access, and cost.
Fate Therapeutics.
自然杀伤细胞疗法受到供体细胞来源和剂量间变异性的限制。FT516是一种诱导多能干细胞（iPSC）衍生的自然杀伤细胞疗法，表达高亲和力、不可裂解的CD16，以优化与治疗性单克隆抗体联合使用时的抗体依赖性细胞毒性。我们旨在评估FT516在复发或难治性B细胞淋巴瘤患者中的安全性。
这项多中心、开放标签的1期研究在美国的八个研究中心进行。符合条件的患者年龄在18岁及以上，患有预计表达CD20的B细胞淋巴瘤，在至少接受过包括抗CD20抗体在内的一种先前全身治疗后疾病复发或难治，有可测量的疾病，且没有预期能改善生存的治疗选择。参与者接受氟达拉滨（-5至-3天，30mg/m²，共3天）和环磷酰胺（-5至-3天，500mg/m²，共3天）或苯达莫司汀（-4和-3天，90mg/m²，共2天），并在-4天联合使用375mg/m²的利妥昔单抗，或在剂量扩展期间，滤泡性淋巴瘤患者用1000mg的奥妥珠单抗替代利妥昔单抗。FT516以递增剂量静脉给药，每剂量范围为3×10⁷至9×10⁷个细胞，于第1、8和15天给药，每次FT516给药后2 - 4小时皮下注射IL-2（600万单位）。主要终点是安全性，包括剂量限制性毒性和最大耐受剂量。对所有接受至少一剂FT516的患者进行安全性分析。急性髓系白血病患者也被纳入研究，相关结果将在其他地方报告。本研究已在ClinicalTrials.gov注册，编号为NCT04023071，现已完成。
从2019年10月11日至2022年11月28日，共纳入56例患者，其中55例接受了FT516治疗。32例（58%）患者为男性，23例（42%）为女性，43例（78%）为白人。FT516的最大细胞剂量（每28天周期三剂，每剂9×10⁷个细胞）可耐受，并被确定为推荐的2期剂量。未报告剂量限制性毒性。1例（2%）患者报告发生细胞因子释放综合征，为1级；未观察到神经毒性。3级或更严重的最常见不良事件为中性粒细胞减少（46例[84%]患者）、血小板减少（20例[36%]）和贫血（15例[27%]）。没有与治疗相关的死亡。55例患者中有32例（58%）观察到客观缓解。
我们的研究结果表明，使用iPSC衍生的、基因修饰的自然杀伤细胞联合单克隆抗体和IL-2进行细胞治疗在B细胞恶性肿瘤中是安全且有效的，可能解决目前可用免疫细胞疗法的局限性，包括生产时间、异质性、可及性和成本。
命运治疗公司。
