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/m² and cyclophosphamide 500 mg/m² (intravenously daily for 3 days), followed by intravenous CTX130 infusion at dose levels ranging from 3 × 10⁷ CAR+ T cells (dose level 1) to 9 × 10⁸ 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.

中文翻译：

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CTX130 是一种靶向 CD70 的同种异体 CRISPR-Cas9 工程 CAR T 细胞疗法，在复发或难治性 T 细胞恶性肿瘤 （COBALT-LYM） 患者中的安全性和活性：一项单臂、开放标签、1 期、剂量递增研究

 背景

复发或难治性 T 细胞淋巴瘤的有效治疗选择很少。本研究评估了 CTX130 （volamcabtagene durzigedleucel） 的安全性和活性，CTX130 （volamcabtagene durzigedleucel） 是一种由健康供体 T 细胞制造的 CD70 导向的同种异体嵌合抗原受体 （CAR） 免疫疗法，用于复发或难治性 T 细胞淋巴瘤患者。

 方法

这项单臂、开放标签、1 期研究在美国、澳大利亚和加拿大的 10 个医疗中心进行，对象为复发或难治性外周 T 细胞淋巴瘤或皮肤 T 细胞淋巴瘤患者（≥18 岁），这些患者分别接受过至少一种或至少两种既往全身治疗线，并且东部肿瘤合作组 （ECOG） 体能状态为 0-1。患者接受氟达拉滨 30 mg/m² 和环磷酰胺 500 mg/m² 淋巴细胞清除（静脉注射每天，持续 3 天），然后静脉输注 CTX130，剂量水平从 3 × 10⁷ 个 CAR+ T 细胞（剂量水平 1）到 9 ×^{10 8} 个 CAR+ T 细胞（剂量水平 4）。主要终点是不良事件的发生率，定义为输注后 28 天内发生的剂量限制性毒性。次要终点包括客观缓解率。对所有接受 CTX130 的患者的数据进行安全性和活性分析。该试验已在 ClinicalTrials.gov （NCT04502446） 和 EudraCT （2019-004526-25） 注册，并已停止注册。

 发现

在 2020 年 8 月 28 日至 2023 年 5 月 30 日期间，共入组 41 例患者，其中 39 例 （95%） 接受了 CTX130。中位患者随访时间为 7·4 个月 （IQR 3·1–12·2）。39 例患者中有 21 例 （54%） 为女性，18 例 （46%） 为男性。24 名 （62%） 患者为白人，8 名 （21%） 为黑人，3 名 （8%） 为亚裔，3 名 （8%） 来自其他种族或族裔群体，1 名 （3%） 未报告。外周 T 细胞淋巴瘤患者的既往抗癌治疗的中位数为 2·5 （IQR 1·3–4·0），皮肤 T 细胞淋巴瘤患者的中位数为 5·0 （IQR 5·0–7·0）。细胞因子释放综合征是最常见的不良事件，39 例患者中有 26 例 （67%） 发生 （23 例为 1-2 级，2 例为 3 级，1 例为剂量水平 4 的 4 级剂量限制性毒性）。在 39 例患者中有 4 例 （10%） 观察到 1-2 级神经毒性事件。最常见的 3-4 级不良事件是中性粒细胞减少症 （14 [36%]）、贫血 （11 [28%]）和血小板减少症 （6 [15%]）。25 例 （64%） 患者发生严重不良事件，14 例 （36%） 患者发生 CTX130 相关严重不良事件，最常见的相关严重不良事件是细胞因子释放综合征 11 例 （28%） 患者。21 例患者死亡，其中 16 例死于疾病进展，5 例死于被认为与 CTX130 治疗无关的不良事件。39 名患者中有 18 名 （46·2% [95% CI 30·1–62·8] 有客观反应。在剂量水平 3 及更高剂量水平的患者中，31 名患者中有 16 名 （51·6% [33·1–69·8]）有客观反应，其中 6 例 （19·4% [7·5–37·5]） 完全缓解，10 例 （32·3% [16·7–51·4]） 部分缓解。

 解释

在既往接受过大量治疗的 T 细胞淋巴瘤患者中，CTX130 显示出可控的安全性和有希望的客观缓解率。这项研究表明，同种异体、现成的 CAR T 细胞可以安全地给予复发或难治性 T 细胞淋巴瘤患者。包含额外效力基因编辑 （CTX131） 的下一代 CAR T 细胞疗法正在临床开发中。

 资金

 CRISPR 疗法。