Antitumor effects of HSV-TK-engineered donor lymphocytes after allogeneic stem-cell transplantation
Antitumor effects of HSV-TK-engineered donor lymphocytes after allogeneic stem-cell transplantation
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DOI：
10.1182/blood-2006-05-023416
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发表时间：
2007-06-01
期刊：
影响因子：
20.3
通讯作者：
Bordignon, Claudio
中科院分区：
文献类型：
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作者：
Ciceri, Fabio;Bonini, Chiara;Bordignon, Claudio
异基因造血干细胞移植(allo-HSCT)后输注的供者淋巴细胞抗肿瘤作用的广泛开发受到移植物抗宿主病(GvHD)风险的限制。为了克服这一局限，我们研究了用单纯疱疹病毒(TK)自杀基因胸苷激酶(TK)工程的供者淋巴细胞在23例异基因造血干细胞移植(allo-HSCT)后复发的恶性血液病患者中的治疗潜力。输注患者的长期随访包括分析基因工程淋巴细胞的植入，体内抗肿瘤效果的评估，以及更昔洛韦对GvHD的控制。所有17名可评估植入和移植物抗白血病(GVL)的患者都有循环中的TK+细胞可检测到，中位时间为18天。11名患者(65%)经历了实质性的临床益处，导致6名(35%)完全缓解和5名(29%)部分缓解。其抗肿瘤作用与体内应用更昔洛韦后TK+细胞被清除，GvHD得到有效的选择性治疗密切相关。有7名患者观察到了针对HSV-TK的免疫，但不排除有效的GVL。这些数据验证了TK+细胞在同种异体移植中的可行性、安全性和有效性，并为这项技术的更广泛应用奠定了基础。
The extensive exploitation of the antitumor effect of donor lymphocytes infused after allogeneic hematopoietic stem-cell transplantation (allo-HSCT) is limited by the risk of graft-versus-host disease (GvHD). To overcome this limitation, we investigated the therapeutic potential of donor lymphocytes engineered with the suicide gene thymidine kinase of herpes simplex virus (TK) in 23 patients experiencing recurrence of hematologic malignancies after allo-HSCT. Long-term follow-up of infused patients included analysis of engraftment of genetically engineered lymphocytes, in vivo assessment of antitumor effect, and control of GvHD by ganciclovir. All 17 patients evaluable for engraftment and graft-versus-leukemia (GvL) had circulating TK+ cells detectable beginning at a median time of 18 days. Eleven patients (65%) experienced a substantial clinical benefit resulting in 6 (35%) complete remissions and 5 (29%) partial responses. The antitumor effect tightly correlated with the in vivo received ganciclovir, resulting in elimination of TK+ cells and effective and selective treatment of GvHD. Immunization against HSV-TK was observed in 7 patients but did not preclude an effective GvL. These data validate the feasibility, safety, and efficacy of TK+ cells in the context of allografting and represent the basis for a broader application of this technology.