Division of Blood and Marrow Transplantation and Cellular Therapy, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University, Stanford, CA, USA.
Division of Lymphoma, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA, USA.
Lancet. 2024 Jul 27;404(10450):353-363. doi: 10.1016/S0140-6736(24)00746-3. Epub 2024 Jul 9.
Outcomes are poor for patients with large B-cell lymphoma who relapse after CD19-directed chimeric antigen receptor (CAR) T-cell therapy (CAR19). CD22 is a nearly universally expressed B-cell surface antigen and the efficacy of a CD22-directed CAR T-cell therapy (CAR22) in large B-cell lymphoma is unknown, which was what we aimed to examine in this study.
In this single centre, open-label, dose-escalation phase 1 trial, we intravenously administered CAR22 at two dose levels (1 million and 3 million CAR22-positive T cells per kg of bodyweight) to adult patients (aged ≥18 years) who relapsed after CAR19 or had CD19-negative large B-cell lymphoma. The primary endpoints were manufacturing feasibility, safety measured by the incidence and severity of adverse events and dose-limiting toxicities, and identification of the maximum tolerated dose (ie, the recommended phase 2 dose). This study is registered with ClinicalTrials.gov (NCT04088890) and is active, but closed for enrolment.
From Oct 17, 2019, to Oct 19, 2022, a total of 41 patients were assessed for eligibility; however, one patient withdrew. 40 patients underwent leukapheresis and 38 (95%) had CAR T-cell products manufactured successfully. The median age was 65 years (range 25-84), 17 (45%) were women, 32 (84%) had elevated pretreatment lactate dehydrogenase, 11 (29%) had refractory disease to all previous therapies, and patients had received a median of four lines of previous therapy (range 3-8). Of the 38 patients treated, 37 (97%) had relapsed after previous CAR19. The identified maximum tolerated dose was 1 million CAR T cells per kg. Of 29 patients who received the maximum tolerated dose, no patients developed a dose-limiting toxicity or grade 3 or higher cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, or immune effector cell-associated haemophagocytic lymphohistiocytosis-like syndrome.
This trial identifies CD22 as an immunotherapeutic target in large B-cell lymphoma and demonstrates the durable clinical activity of CAR22 in patients with disease progression after CAR19 therapy. Although these findings are promising, it is essential to recognise that this is a phase 1 dose-finding study. Further investigations are warranted to establish the long-term efficacy and to delineate the patient subgroups that will derive the most benefit from this therapeutic approach.
National Cancer Institute, National Institutes of Health, Stanford Cancer Institute, Leukemia & Lymphoma Society, Parker Institute for Cancer Immunotherapy, Lymph & Co, and the European Hematology Association.
接受 CD19 导向嵌合抗原受体 (CAR) T 细胞疗法 (CAR19) 后复发的大 B 细胞淋巴瘤患者的预后较差。CD22 是一种几乎普遍表达的 B 细胞表面抗原，CD22 导向的 CAR T 细胞疗法 (CAR22) 在大 B 细胞淋巴瘤中的疗效尚不清楚，这是我们在这项研究中旨在研究的内容。
在这项单中心、开放标签、剂量递增的 1 期试验中，我们静脉输注 CAR22，剂量分别为每公斤体重 100 万和 300 万个 CAR22 阳性 T 细胞，用于接受 CAR19 治疗后复发或患有 CD19 阴性大 B 细胞淋巴瘤的成年患者（年龄≥18 岁）。主要终点是制造可行性、通过不良事件的发生率和严重程度以及确定最大耐受剂量（即推荐的 2 期剂量）来衡量的安全性。这项研究在 ClinicalTrials.gov 上注册（NCT04088890），目前正在进行中，但已关闭入组。
从 2019 年 10 月 17 日至 2022 年 10 月 19 日，共有 41 名患者符合入组条件；然而，有 1 名患者退出。40 名患者接受了白细胞分离术，其中 38 名（95%）成功制造了 CAR T 细胞产品。中位年龄为 65 岁（范围 25-84），17 名（45%）为女性，32 名（84%）乳酸脱氢酶升高，11 名（29%）对所有既往治疗均耐药，患者接受了中位数为 4 线的既往治疗（范围 3-8）。在接受治疗的 38 名患者中，37 名（97%）在接受 CAR19 治疗后复发。确定的最大耐受剂量为每公斤 100 万个 CAR T 细胞。在接受最大耐受剂量的 29 名患者中，没有患者发生剂量限制性毒性或 3 级或更高的细胞因子释放综合征、免疫效应细胞相关神经毒性综合征或免疫效应细胞相关噬血细胞淋巴组织细胞增生症样综合征。
这项试验确定 CD22 是大 B 细胞淋巴瘤的一种免疫治疗靶点，并证明了 CAR22 在接受 CAR19 治疗后疾病进展的患者中的持久临床活性。尽管这些发现很有希望，但必须认识到这是一项 1 期剂量发现研究。需要进一步的研究来确定长期疗效，并阐明将从这种治疗方法中获益最多的患者亚组。
美国国立癌症研究所、美国国立卫生研究院、斯坦福癌症研究所、白血病和淋巴瘤协会、帕克癌症免疫治疗研究所、Lymph & Co.和欧洲血液学协会。
