Klinikum Nürnberg, Medizinische Klinik 5, Prof-Ernst-Nathan-Str, 1, D-90340 Nuernberg, Germany.
J Transl Med. 2014 Feb 15;12:45. doi: 10.1186/1479-5876-12-45.
The primary aim of this pilot study was to determine the feasibility and safety of an adoptive transfer and in vivo expansion of human haploidentical γδ T lymphocytes.
Patients with advanced haematological malignancies who are not eligible for allogeneic transplantation received peripheral blood mononuclear cells from half-matched family donors. For that, a single unstimulated leukapheresis product was incubated with both the anti-CD4 and anti-CD8 antibodies conjugated to paramagnetic particles. The depletion procedure was performed on a fully automated CliniMACS device according to the manufacturer's instructions. On average, patients received 2.17 × 10⁶/kg (range 0.9-3.48) γδ T cells with <1% CD4- or CD8-positive cells remaining in the product. All patients received prior lymphopenia-inducing chemotherapy (fludarabine 20-25 mg/m² day -6 until day -2 and cyclophosphamide 30-60 mg/kg day -6 and -5) and were treated with 4 mg zoledronate on day 0 and 1.0 x 10⁶ IU/m² IL-2 on day +1 until day +6 for the induction of γδ T cell proliferation in vivo.
This resulted in a marked in vivo expansion of donor γδ T cells and, to a lower extent, natural killer cells and double-negative αβ T cells (mean 68-fold, eight-fold, and eight-fold, respectively). Proliferation peaked by around day +8 and donor cells persisted up to 28 days. Although refractory to all prior therapies, three out of four patients achieved a complete remission, which lasted for 8 months in a patient with plasma cell leukaemia. One patient died from an infection 6 weeks after treatment.
This pilot study shows that adoptive transfer and in vivo expansion of haploidentical γδ T lymphocytes is feasible and suggests a potential role of these cells in the treatment of haematological diseases.
本初步研究的主要目的是确定同种异体人γδ T 淋巴细胞过继转移和体内扩增的可行性和安全性。
不适合进行同种异体移植的晚期血液恶性肿瘤患者接受来自半匹配家族供者的外周血单个核细胞。为此，将单个未刺激的白细胞分离产物与连接到顺磁颗粒上的抗 CD4 和抗 CD8 抗体一起孵育。根据制造商的说明，在全自动 CliniMACS 设备上进行耗竭程序。平均而言，每位患者接受 2.17×10⁶/kg（范围 0.9-3.48）γδ T 细胞，产品中剩余的 <1% CD4-或 CD8-阳性细胞。所有患者均接受先前的淋巴细胞减少诱导化疗（氟达拉滨 20-25mg/m²，从第 -6 天至第 -2 天，环磷酰胺 30-60mg/kg，从第 -6 天至第 -5 天），并在第 0 天和第 1 天接受 4mg唑来膦酸和 1.0x10⁶IU/m²IL-2，以诱导体内 γδ T 细胞增殖。
这导致供体 γδ T 细胞明显的体内扩增，并且在较低程度上导致自然杀伤细胞和双阴性 αβ T 细胞扩增（分别平均 68 倍、8 倍和 8 倍）。增殖在第 +8 天左右达到峰值，供体细胞持续至第 28 天。尽管所有先前的治疗均无效，但 4 名患者中的 3 名获得完全缓解，其中一名浆细胞白血病患者的缓解持续了 8 个月。一名患者在治疗后 6 周死于感染。
本初步研究表明，同种异体人γδ T 淋巴细胞过继转移和体内扩增是可行的，并提示这些细胞在治疗血液疾病方面具有潜在作用。
