Division of Blood and Marrow Transplantation, Department of Medicine, Stanford University, Stanford, California.
Department of Health Research and Policy, Stanford University, Stanford, California.
Biol Blood Marrow Transplant. 2019 Jul;25(7):1293-1303. doi: 10.1016/j.bbmt.2019.03.027. Epub 2019 Apr 3.
Non-myeloablative conditioning, such as with total lymphoid irradiation and antithymocyte globulin (TLI-ATG), has allowed allogeneic hematopoietic cell transplantation (allo-HCT) with curative potential for older patients and those with comorbid medical conditions with myeloid neoplasms. However, early achievement of full donor chimerism (FDC) and relapse remain challenging. Cytokine-induced killer (CIK) cells have been shown to have antitumor cytotoxicity. Infusion of donor-derived CIK cells has been studied for hematologic malignancies relapsed after allo-HCT but has not been evaluated as post-transplant consolidation. In this phase II study, we prospectively studied whether a one-time infusion of 1 × 10/kg CD3 donor-derived CIK cells administered between day +21 and day +35 after TLI-ATG conditioning could improve achievement of FDC by day +90 and 2-year clinical outcomes in patients with myeloid neoplasms. CIK cells, containing predominantly CD3CD8NKG2D cells along with significantly expanded CD3CD56 cells, were infused in 31 of 44 patients. Study outcomes were compared to outcomes of a retrospective historical cohort of 100 patients. We found that this one-time CIK infusion did not increase the rate of FDC by day +90. On an intention-to-treat analysis, 2-year non-relapse mortality (6.8%; 95% confidence interval [CI], 0-14.5%), event-free survival (27.3%; 95% CI, 16.8-44.2%), and overall survival (50.6%; 95% CI, 37.5-68.2%) were similar to the values seen in the historical cohort. The cumulative incidence of grade II-IV acute graft-versus-host disease at 1-year was 25.1% (95% CI, 12-38.2%). On univariate analysis, the presence of monosomal or complex karyotype was adversely associated with relapse-free survival and overall survival. Given the favorable safety profile of CIK cell infusion, strategies such as repeat dosing or genetic modification merit exploration. This trial was registered at ClinicalTrials.gov (NCT01392989).
非清髓性预处理，如全身淋巴照射和抗胸腺细胞球蛋白（TLI-ATG），使具有治愈潜力的异基因造血细胞移植（allo-HCT）能够应用于老年患者和伴有合并症的髓系肿瘤患者。然而，早期实现完全供者嵌合（FDC）和复发仍然具有挑战性。细胞因子诱导的杀伤（CIK）细胞已被证明具有抗肿瘤细胞毒性。输注供体来源的 CIK 细胞已被研究用于 allo-HCT 后复发的血液系统恶性肿瘤，但尚未作为移植后巩固治疗进行评估。在这项 II 期研究中，我们前瞻性研究了在 TLI-ATG 预处理后第 21 天至第 35 天之间单次输注 1×10/kg CD3 供体来源的 CIK 细胞是否可以提高 FDC 的获得率，并改善髓系肿瘤患者的 2 年临床结局。在 44 例患者中，31 例输注了 CIK 细胞，这些细胞主要包含 CD3CD8NKG2D 细胞，同时显著扩增了 CD3CD56 细胞。我们将研究结果与 100 例回顾性历史队列患者的结果进行了比较。我们发现，单次 CIK 输注并不能提高第 90 天的 FDC 率。在意向治疗分析中，2 年无复发死亡率（6.8%；95%置信区间[CI]，0-14.5%）、无事件生存率（27.3%；95%CI，16.8-44.2%）和总生存率（50.6%；95%CI，37.5-68.2%）与历史队列相似。1 年时 II-IV 级急性移植物抗宿主病的累积发生率为 25.1%（95%CI，12-38.2%）。单因素分析显示，单体或复杂核型与无复发生存和总生存不良相关。鉴于 CIK 细胞输注的良好安全性，重复给药或基因修饰等策略值得进一步研究。该试验在 ClinicalTrials.gov 注册（NCT01392989）。
