肿瘤细胞治疗研究
英文原题：Enhancement of High-Dose Chemotherapy and Autologous SCT with the PARP Inhibitor Olaparib for Refractory Lymphoma.
在这项首次将 PARP 抑制剂与 HDC 联合的试验中，olaparib/vorinostat/GemBuMel 是安全的，并在难治性淋巴瘤中显示出有前景的活性，包括 CAR-T 治疗后复发者。
难治性淋巴瘤的自体干细胞移植（ASCT）需要更有效的高剂量化疗（HDC）方案。为寻求用 PARP 抑制剂增强 HDC，我们观察到 olaparib 与 vorinostat/gemcitabine/busulfan/melphalan（GemBuMel）对淋巴瘤细胞系具有显著协同作用，该作用由 DNA 损伤修复抑制所介导。我们的临床前工作促使我们开展 olaparib/vorinostat/GemBuMel 联合 ASCT 的临床研究。
年龄15至65岁、患有难治性淋巴瘤且终末器官功能足够的患者符合本项I期试验的入选条件。olaparib剂量从25 mg口服、每日两次（第-11天至第-3天）开始递增，并联合vorinostat（1,000 mg口服/天，第-10天至第-3天）、gemcitabine（2,475 mg/m2/天 i.v.，第-8天和第-3天）、busulfan（目标 AUC 4,000 mol/L.minute-1/day i.v.，第-8天至第-5天）、melphalan（60 mg/m2/天 i.v.，第-3天和第-2天）和rituximab（CD20+肿瘤；375 mg/m2，第-10天），同时进行ASCT。
共入组 50 例患者（23 例霍奇金淋巴瘤、18 例弥漫性大 B 细胞淋巴瘤和 9 例 T 细胞非霍奇金淋巴瘤）；中位年龄为 35 岁（范围 20-61）；患者既往接受过中位 3 线治疗（范围 2-7）；17 例患者既往在CAR-T 细胞治疗或其他细胞免疫治疗后复发；23 例患者在 HDC 时为 PET 阳性肿瘤（9 例处于进展）。olaparib 150 mg 口服、每日两次的剂量被确定为推荐的 II 期剂量。主要髓外毒性为黏膜炎。总缓解率和完全缓解率分别为 100% 和 90%。在中位随访 30 个月（范围 12-56 个月）时，所有患者的无事件生存率和总生存率分别为 72% 和 82%，既往 CAR T 细胞治疗失败患者的分别为 71% 和 88%。
PURPOSE: More active high-dose chemotherapy (HDC) regimens are needed for autologous stem cell transplantation (ASCT) for refractory lymphomas. Seeking HDC enhancement with a PARP inhibitor, we observed marked synergy between olaparib and vorinostat/gemcitabine/busulfan/melphalan (GemBuMel) against lymphoma cell lines, mediated by the inhibition of DNA damage repair. Our preclinical work led us to clinically study olaparib/vorinostat/GemBuMel with ASCT. PATIENTS AND METHODS: Patients ages 15 to 65 years with refractory lymphoma and adequate end-organ function were eligible for this phase I trial. The olaparib dosage was escalated from 25 mg orally twice a day on days -11 to -3, plus vorinostat (1,000 mg orally/day, days -10 to -3), gemcitabine (2,475 mg/m2/day i.v., days -8 and -3), busulfan (target AUC 4,000 mol/L.minute-1/day i.v., days -8 to -5), melphalan (60 mg/m2/day i.v., days -3 and -2), and rituximab (CD20+ tumors; 375 mg/m2, day -10), with ASCT. RESULTS: Fifty patients were enrolled (23 with Hodgkin lymphoma, 18 with diffuse large B-cell lymphoma, and 9 with T-cell non-Hodgkin lymphoma); the median age was 35 years (range, 20-61); patients received a median of three prior lines of therapy (range, 2-7); 17 patients had previously relapsed after chimeric antigen receptor T-cell therapy or other cellular immunotherapies; 23 patients had PET-positive tumors at HDC (9 in progression). An olaparib dosage of 150 mg orally twice a day was identified as the recommended phase II dosage. The main extramedullary toxicity was mucositis. The overall response rate and complete response rate were 100% and 90%, respectively. At the median follow-up of 30 (range, 12-56) months, the event-free survival and overall survival rates were 72% and 82% in all patients and 71% and 88% in patients with prior CAR T-cell failure, respectively. CONCLUSIONS: In this first trial combining a PARP inhibitor with HDC, olaparib/vorinostat/GemBuMel was safe and showed promising activity in refractory lymphomas, including post-CAR-T relapses.
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