Chimeric antigen receptor (CAR) T cells targeting CD30 are safe and have promising activity when preceded by lymphodepleting chemotherapy. We aimed to determine the safety of anti-CD30 CAR T cells as consolidation after autologous haematopoietic stem-cell transplantation (HSCT) in patients with CD30 lymphoma at high risk of relapse. This phase 1 dose-escalation study was performed at two sites in the USA. Patients aged 3 years and older, with classical Hodgkin lymphoma or non-Hodgkin lymphoma with CD30 disease documented by immunohistochemistry, and a Karnofsky performance score of more than 60% planned for autologous HSCT were eligible if they were considered high risk for relapse as defined by primary refractory disease or relapse within 12 months of initial therapy or extranodal involvement at the start of pre-transplantation salvage therapy. Patients received a single infusion of CAR T cells (2 × 10 CAR T cells per m, 1 × 10 CAR T cells per m, or 2 × 10 CAR T cells per m) as consolidation after trilineage haematopoietic engraftment (defined as absolute neutrophil count ≥500 cells per μL for 3 days, platelet count ≥25 × 10 platelets per L without transfusion for 5 days, and haemoglobin ≥8 g/dL without transfusion for 5 days) following carmustine, etoposide, cytarabine, and melphalan (BEAM) and HSCT. The primary endpoint was the determination of the maximum tolerated dose, which was based on the rate of dose-limiting toxicity in patients who received CAR T-cell infusion. This study is registered with () and enrolment is complete. Between June 7, 2016, and Nov 30, 2020, 21 patients were enrolled and 18 patients (11 with Hodgkin lymphoma, six with T-cell lymphoma, one with grey zone lymphoma) were infused with anti-CD30 CAR T cells at a median of 22 days (range 16–44) after autologous HSCT. There were no dose-limiting toxicities observed, so the highest dose tested, 2 × 10 CAR T cells per m, was determined to be the maximum tolerated dose. One patient had grade 1 cytokine release syndrome. The most common grade 3–4 adverse events were lymphopenia (two [11%] of 18) and leukopenia (two [11%] of 18). There were no treatment-related deaths. Two patients developed secondary malignancies approximately 2 years and 2·5 years following treatment (one stage 4 non-small cell lung cancer and one testicular cancer), but these were judged unrelated to treatment. At a median follow-up of 48·2 months (IQR 27·5–60·7) post-infusion, the median progression-free survival for all treated patients (n=18) was 32·3 months (95% CI 4·6 months to not estimable) and the median progression-free survival for treated patients with Hodgkin lymphoma (n=11) has not been reached. The median overall survival for all treated patients has not been reached. Anti-CD30 CAR T-cell infusion as consolidation after BEAM and autologous HSCT is safe, with low rates of toxicity and encouraging preliminary activity in patients with Hodgkin lymphoma at high risk of relapse, highlighting the need for larger studies to confirm these findings. National Heart Lung and Blood Institute, University Cancer Research Fund at the Lineberger Comprehensive Cancer Center.

中文翻译：

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抗 CD30 CAR T 细胞作为高危 CD30+ 淋巴瘤患者自体造血干细胞移植后的巩固：一项 1 期研究

靶向 CD30 的嵌合抗原受体 (CAR) T 细胞是安全的，并且在进行淋巴细胞清除化疗之前具有良好的活性。我们的目的是确定抗 CD30 CAR T 细胞作为高复发风险 CD30 淋巴瘤患者自体造血干细胞移植 (HSCT) 后巩固治疗的安全性。这项 1 期剂量递增研究在美国的两个地点进行。年龄 3 岁及以上、患有经典霍奇金淋巴瘤或通过免疫组织化学记录患有 CD30 疾病的非霍奇金淋巴瘤且卡诺夫斯基评分超过 60% 且计划进行自体 HSCT 的患者，如果被认为具有复发高风险（定义如下），则符合计划进行自体 HSCT 的资格：原发性难治性疾病或初始治疗后 12 个月内复发或移植前挽救治疗开始时结外受累。患者接受单次 CAR T 细胞输注（每平方米 2 × 10 个 CAR T 细胞、每平方米 1 × 10 个 CAR T 细胞或每平方米 2 × 10 个 CAR T 细胞）作为三系造血移植后的巩固（定义为绝对中性粒细胞计数）卡莫司汀、依托泊苷、阿糖胞苷和美法仑 (BEAM) 后，连续 3 天≥500 个细胞/μL，血小板计数≥25 × 10 个血小板/L（连续 5 天不输血），血红蛋白≥8 g/dL（连续 5 天不输血）造血干细胞移植。主要终点是根据接受 CAR T 细胞输注的患者的剂量限制毒性发生率确定最大耐受剂量。本研究已注册（），登记已完成。 2016年6月7日至2020年11月30日期间，入组了21名患者，其中18名患者（11名霍奇金淋巴瘤，6名T细胞淋巴瘤，1名灰区淋巴瘤）接受了抗CD30 CAR T细胞的中位输注。自体 HSCT 后 22 天（范围 16-44）。没有观察到剂量限制性毒性，因此测试的最高剂量（每平方米 2 × 10 个 CAR T 细胞）被确定为最大耐受剂量。一名患者患有 1 级细胞因子释放综合征。最常见的 3-4 级不良事件是淋巴细胞减少症（18 例中的 2 例 [11%]）和白细胞减少症（18 例中的 2 例 [11%]）。没有出现与治疗相关的死亡。两名患者在治疗后约 2 年和 2·5 年出现继发性恶性肿瘤（一名 4 期非小细胞肺癌和一名睾丸癌），但这些患者被判断与治疗无关。输注后中位随访 48·2 个月 (IQR 27·5–60·7)，所有治疗患者 (n=18) 的中位无进展生存期为 32·3 个月 (95% CI 4 · 6 个月至不可估计），霍奇金淋巴瘤治疗患者 (n=11) 的中位无进展生存期尚未达到。尚未达到所有接受治疗的患者的中位总生存期。抗 CD30 CAR T 细胞输注作为 BEAM 和自体 HSCT 后的巩固治疗是安全的，毒性发生率低，并且鼓励复发高风险霍奇金淋巴瘤患者进行初步活动，强调需要进行更大规模的研究来证实这些发现。国家心肺和血液研究所、莱恩伯格综合癌症中心大学癌症研究基金。