肿瘤细胞治疗研究
英文原题：Safety and activity of CTX130, a CD70-targeted allogeneic CRISPR-Cas9-engineered CAR T-cell therapy, in patients with relapsed or refractory T-cell malignancies (COBALT-LYM): a single-arm, open-label, phase 1, dose-escalation study.
在经过重度预治疗的 T 细胞淋巴瘤患者中，CTX130 显示出可控的安全性和有前景的客观缓解率。
背景：复发或难治性T细胞淋巴瘤的有效治疗选择有限。本研究评估CTX130（volamcabtagene durzigedleucel）的安全性和活性。这是一种以健康供者T细胞制备、靶向CD70的异基因嵌合抗原受体（CAR）免疫疗法，研究对象为复发或难治性T细胞淋巴瘤患者。 方法：本单臂、开放标签1期研究在美国、澳大利亚和加拿大的10家医疗中心开展。纳入年龄≥18岁的复发或难治性外周T细胞淋巴瘤或皮肤T细胞淋巴瘤患者；前者至少既往接受1线全身治疗，后者至少接受2线，并且ECOG体能状态评分为0–1。患者接受氟达拉滨30 mg/m²和环磷酰胺500 mg/m²静脉给药，每日1次、连续3天进行淋巴细胞清除，随后静脉输注CTX130，剂量从3×10⁷ CAR阳性T细胞（剂量水平1）至9×10⁸ CAR阳性T细胞（剂量水平4）。主要终点是在输注后28天内发生的剂量限制性毒性等不良事件发生率；次要终点包括客观应答率。所有接受CTX130的患者均纳入安全性和活性分析。本试验在ClinicalTrials.gov注册（NCT04502446）及EudraCT注册（2019-004526-25），目前已停止入组。 结果：2020年8月28日至2023年5月30日，共入组41例患者，其中39例（95%）接受CTX130。患者中位随访时间为7.4个月（IQR 3.1–12.2）。39例患者中女性21例（54%），男性18例（46%）；白人24例（62%），黑人8例（21%），亚裔3例（8%），其他种族或族裔3例（8%），另有1例（3%）未报告。外周T细胞淋巴瘤患者既往抗癌治疗线数中位数为2.5线（IQR 1.3–4.0），皮肤T细胞淋巴瘤患者为5.0线（IQR 5.0–7.0）。最常见不良事件是细胞因子释放综合征（CRS），39例中26例（67%）发生CRS，其中23例为1–2级、2例为3级、1例在剂量水平4发生4级剂量限制性毒性。4例（10%）患者出现1–2级神经毒性。最常见的3–4级不良事件为中性粒细胞减少（14例[36%]）、贫血（11例[28%]）和血小板减少（6例[15%]）。25例（64%）患者发生严重不良事件，其中14例（36%）发生与CTX130相关的严重不良事件；最常见的相关严重不良事件为CRS（11例[28%]）。21例患者死亡，其中16例死于疾病进展，5例死于研究者认为与CTX130治疗无关的不良事件。39例中18例（46.2%；95% CI：30.1–62.8）客观应答。接受剂量水平3及以上治疗的患者中，31例有16例（51.6%；95% CI：33.1–69.8）获得客观应答，包括6例（19.4%；95% CI：7.5–37.5）完全缓解和10例（32.3%；95% CI：16.7–51.4）部分缓解。 解释：在既往接受多线治疗的T细胞淋巴瘤患者中，CTX130安全性可控，且客观应答率有前景。本研究显示，可向复发或难治性T细胞淋巴瘤患者安全给予异基因现货型CAR-T细胞。含有额外增强效力基因编辑的下一代CAR-T疗法CTX131正在临床开发中。 经费：CRISPR Therapeutics资助。
BACKGROUND: Effective treatment options are scarce for relapsed or refractory T-cell lymphoma. This study assesses the safety and activity of CTX130 (volamcabtagene durzigedleucel), a CD70-directed, allogeneic chimeric antigen receptor (CAR) immunotherapy manufactured from healthy donor T cells, in patients with relapsed or refractory T-cell lymphoma. METHODS: This single-arm, open-label, phase 1 study was done at ten medical centres across the USA, Australia, and Canada in patients (aged 18 years) with relapsed or refractory peripheral T-cell lymphoma or cutaneous T-cell lymphoma, who had received at least one or at least two previous systemic therapy lines, respectively, and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. Patients underwent lymphodepletion with fludarabine 30 mg/m 2 and cyclophosphamide 500 mg/m 2 (intravenously daily for 3 days), followed by intravenous CTX130 infusion at dose levels ranging from 3 10 7 CAR+ T cells (dose level 1) to 9 10 8 CAR+ T cells (dose level 4). The primary endpoint was the incidence of adverse events, defined as dose-limiting toxicities occurring within 28 days post-infusion. Secondary endpoints included objective response rate. Safety and activity analyses were performed on data from all patients who received CTX130. The trial is registered with ClinicalTrials.gov (NCT04502446) and EudraCT (2019-004526-25) and is closed to enrolment. FINDINGS: Between Aug 28, 2020, and May 30, 2023, 41 patients were enrolled and 39 (95%) received CTX130. The median patient follow-up was 7 4 months (IQR 3 1-12 2). 21 (54%) of 39 patients were female and 18 (46%) were male. 24 (62%) patients were White, eight (21%) were Black, three (8%) were Asian, three (8%) were from other racial or ethnic groups, and one (3%) was not reported. The median number of previous lines of anticancer therapy was 2 5 (IQR 1 3-4 0) for patients with peripheral T-cell lymphoma and 5 0 (IQR 5 0-7 0) for patients with cutaneous T-cell lymphoma. Cytokine release syndrome was the most common adverse event, occurring in 26 (67%) of 39 patients (23 were grade 1-2, two were grade 3, and one was a grade 4 dose-limiting toxicity at dose level 4). Grade 1-2 neurotoxic events were observed in four (10%) of 39 patients. The most common grade 3-4 adverse events were neutropenia (14 [36%]), anaemia (11 [28%]), and thrombocytopenia (six [15%]). Serious adverse events occurred in 25 (64%) patients, with CTX130-related serious adverse events in 14 (36%) patients, the most common related serious adverse event being cytokine release syndrome in 11 (28%) patients. 21 patients died, 16 from progressive disease and five from adverse events considered unrelated to CTX130 treatment. 18 of 39 patients (46 2% [95% CI 30 1-62 8) had an objective response. Of those treated at dose level 3 and higher, 16 of 31 patients (51 6% [33 1-69 8]) had objective responses, including six (19 4% [7 5-37 5]) with complete response and ten (32 3% [16 7-51 4]) with a partial response. INTERPRETATION: In patients with heavily pretreated T-cell lymphoma, CTX130 showed manageable safety and a promising objective response rate. This study shows that allogeneic, readily available CAR T cells can be safely given to patients with relapsed or refractory T-cell lymphoma. A next-generation CAR T-cell therapy containing additional potency gene edits (CTX131) is in clinical development. FUNDING: CRISPR Therapeutics.
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