Lamers Cor H J, Klaver Yarne, Gratama Jan W, Sleijfer Stefan, Debets Reno
Laboratory of Tumor Immunology, Department of Medical Oncology, Erasmus MC-Cancer Institute, 3015 CN Rotterdam, The Netherlands
Laboratory of Tumor Immunology, Department of Medical Oncology, Erasmus MC-Cancer Institute, 3015 CN Rotterdam, The Netherlands.
Biochem Soc Trans. 2016 Jun 15;44(3):951-9. doi: 10.1042/BST20160037.
We studied safety and proof of concept of a phase I/II trial with chimeric antigen receptor (CAR) T-cells in patients with metastatic renal cell carcinoma (mRCC). The CAR was based on the G250 mAb that recognized an epitope of carboxy-anhydrase-IX (CAIX). Twelve patients with CAIX+ mRCC were treated in three cohorts with a maximum of 10 daily infusions of 2×10(7) to 2×10(9) CAR T-cells. Circulating CAR T-cells were transiently detectable in all patients and maintained antigen-specific immune functions following their isolation post-treatment. Blood cytokine profiles mirrored CAR T-cell presence and in vivo activity. Unfortunately, patients developed anti-CAR T-cell antibodies and cellular immune responses. Moreover, CAR T-cell infusions induced liver enzyme disturbances reaching CTC grades 2-4, which necessitated cessation of treatment in four out of eight patients (cohort 1+2). Examination of liver biopsies revealed T-cell infiltration around bile ducts and CAIX expression on bile duct epithelium, adding to the notion of on-target toxicity. No such toxicities were observed in four patients that were pretreated with G250 mAb (cohort 3). The study was stopped due to the advent of competing treatments before reaching therapeutic or maximum tolerated dose in cohort 3. No clinical responses have been recorded. Despite that, from this trial numerous recommendations for future trials and their immune monitoring could be formulated, such as choice of the target antigen, format and immunogenicity of receptor and how the latter relates to peripheral T-cell persistence.
我们研究了嵌合抗原受体（CAR）T细胞用于转移性肾细胞癌（mRCC）患者的I/II期试验的安全性和概念验证。该CAR基于识别碳酸酐酶IX（CAIX）表位的G250单克隆抗体。12例CAIX阳性mRCC患者分三个队列进行治疗，每天最多输注10次，剂量为2×10⁷至2×10⁹个CAR T细胞。所有患者均可短暂检测到循环中的CAR T细胞，且在治疗后分离时仍保持抗原特异性免疫功能。血液细胞因子谱反映了CAR T细胞的存在及体内活性。不幸的是，患者产生了抗CAR T细胞抗体和细胞免疫反应。此外，CAR T细胞输注导致肝酶紊乱，达到癌症治疗毒性标准（CTC）2 - 4级，八名患者中的四名（队列1 + 2）因此需要停止治疗。肝活检检查显示胆管周围有T细胞浸润，胆管上皮有CAIX表达，这进一步说明了靶向毒性的概念。在四名接受G250单克隆抗体预处理的患者（队列3）中未观察到此类毒性。由于在队列3中尚未达到治疗剂量或最大耐受剂量时出现了竞争性治疗方法，该研究提前终止。目前尚未记录到临床反应。尽管如此，从该试验中可以为未来试验及其免疫监测制定许多建议，例如靶抗原的选择、受体的形式和免疫原性以及后者与外周T细胞持久性的关系。
