肿瘤细胞治疗研究
英文原题：Safety and efficacy of a novel anti-CD19 chimeric antigen receptor T cell product targeting a membrane-proximal domain of CD19 with fast on- and off-rates against non-Hodgkin lymphoma: a first-in-human study.
我们开发了一种新型、安全且强效的 CART19 产品，其可识别 CD19 的近膜结构域，具有快速的结合与解离速率，并在复发 B 细胞非霍奇金淋巴瘤患者中显示出显著疗效和良好的安全性。
背景：市售抗CD19CAR-T 细胞疗法（CART19）对晚期B细胞非霍奇金淋巴瘤（NHL）有效，但多数患者最终复发。导致治疗失败的机制包括CD19阴性逃逸和CAR-T功能障碍等。所有4种市售CART19产品均采用FMC63单链可变片段（scFv），该片段特异性识别CD19膜远端表位，并具有较慢的结合（on）和解离（off）速率。我们假设，一种新型抗CD19 scFv可独立于FMC63识别另一CD19膜近端表位，且具有更快的结合和解离速率，从而减轻CART19治疗失败并改善临床疗效。 方法：我们利用新型人源化鸡抗体h1218开发了具有4-1BB共刺激的自体CART19产品。该抗体特异性识别CD19膜近端表位，其结合和解离速率均快于FMC63。我们利用FMC63-CART19耐药模型，在体外和体内测试h1218-CART19。随后开展首个人体多中心I期临床试验，在复发或难治性（r/r）NHL患者中评估AT101（临床级h1218-CART19）。 结果：临床前实验中，h1218-CART19而非FMC63-CART19能够有效清除表达CD19点突变（L174V和R163L）的淋巴瘤，以及与FMC63-CAR19共表达的淋巴瘤；后者见于FMC63-CART19治疗后复发患者。此外，与FMC63-CART19相比，h1218-CART19在体外和体内对B细胞恶性肿瘤的杀伤均增强。机制上，由于结合和解离速率更快，h1218-CART19的活化诱导细胞死亡（AICD）减少、扩增增强。基于这些临床前结果，我们按照3+3设计开展I期剂量递增试验，测试AT101（h1218的GMP制剂）的3个剂量水平（DL）。12例接受治疗的患者包括7例DLBCL、3例滤泡性淋巴瘤（FL）、1例套细胞淋巴瘤（MCL）和1例边缘区淋巴瘤（MZL）。AT101安全性特征令人鼓舞，3级CRS发生率为8.3%（n=1），4级ICANS发生率为8.3%（n=1）。全队列总体缓解率为91.7%，完全缓解率为75.0%；DL-2和DL-3的完全缓解率提高至100%。AT101扩增与完全缓解及B细胞缺失相关。 结论：我们开发了一种新型、安全且效力强的CART19产品，可快速结合和解离CD19膜近端结构域，并在复发性B细胞NHL患者中显示出显著疗效和良好安全性。 试验注册：NCT05338931；日期：2022-04-01。
BACKGROUND: Commercial anti-CD19 chimeric antigen receptor T-cell therapies (CART19) are efficacious against advanced B-cell non-Hodgkin lymphoma (NHL); however, most patients ultimately relapse. Several mechanisms contribute to this failure, including CD19-negative escape and CAR T dysfunction. All four commercial CART19 products utilize the FMC63 single-chain variable fragment (scFv) specific to a CD19 membrane-distal epitope and characterized by slow association (on) and dissociation (off) rates. We hypothesized that a novel anti-CD19 scFv that engages an alternative CD19 membrane-proximal epitope independent of FMC63 and that is characterized by faster on- and off-rates could mitigate CART19 failure and improve clinical efficacy. METHODS: We developed an autologous CART19 product with 4-1BB co-stimulation using a novel humanized chicken antibody (h1218). This antibody is specific to a membrane-proximal CD19 epitope and harbors faster on/off rates compared to FMC63. We tested h1218-CART19 in vitro and in vivo using FMC63-CART19-resistant models. We conducted a first-in-human multi-center phase I clinical trial to test AT101 (clinical-grade h1218-CART19) in patients with relapsed or refractory (r/r) NHL. RESULTS: Preclinically, h1218- but not FMC63-CART19 were able to effectively eradicate lymphomas expressing CD19 point mutations (L174V and R163L) or co-expressing FMC63-CAR19 as found in patients relapsing after FMC63-CART19. Furthermore, h1218-CART19 exhibited enhanced killing of B-cell malignancies in vitro and in vivo compared with FMC63-CART19. Mechanistically, we found that h1218-CART19 had reduced activation-induced cell death (AICD) and enhanced expansion compared to FMC63-CART19 owing to faster on- and off-rates. Based on these preclinical results, we performed a phase I dose-escalation trial, testing three dose levels (DL) of AT101 (the GMP version of h1218) using a 3 + 3 design. In 12 treated patients (7 DLBCL, 3 FL, 1 MCL, and 1 MZL), AT101 showed a promising safety profile with 8.3% grade 3 CRS (n = 1) and 8.3% grade 4 ICANS (n = 1). In the whole cohort, the overall response rate was 91.7%, with a complete response rate of 75.0%, which improved to 100% in DL-2 and -3. AT101 expansion correlates with CR and B-cell aplasia. CONCLUSIONS: We developed a novel, safe, and potent CART19 product that recognizes a membrane-proximal domain of CD19 with fast on- and off-rates and showed significant efficacy and promising safety in patients with relapsed B-cell NHL. TRIAL REGISTRATION: NCT05338931; Date: 2022-04-01.
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