Chandrasekaran Devikha, Nakamoto Betty, Watts Korashon L, Kiem Hans-Peter, Papayannopoulou Thalia
1 Clinical Research Division, Fred Hutchinson Cancer Research Center , Seattle, WA 98109.
Hum Gene Ther. 2014 Dec;25(12):1013-22. doi: 10.1089/hum.2014.031.
Minimal conditioning or even no conditioning would be the preferred preparation for most gene therapy applications for nonmalignant diseases. However, reduced intensity conditioning (RIC) regimens in patients with nonhematologic malignancies have not led to long-term engraftment unless a selective advantage was present for the transplanted donor cells. Similar findings have also been observed in a number of large animal studies. Inadequate myelosuppression levels were thought to be responsible for the outcomes. To address this issue several innovative protocols in small animals have been presented with selective hematopoietic myelosuppression and less systemic toxicity. Such protocols promised to curb the transplant-related morbidity and mortality in myeloablative conditioning and provide effective long-term engraftment, especially in patients with gene-corrected autografts. In the present study we have tested some of these promising RIC regimens in nonhuman primates, a clinically relevant large animal model. Our data suggest that transient myelosuppression induced by anti-c-Kit antibody in conjunction with low-dose irradiation may lead to long-term engraftment, albeit at low levels. The animals with busulfan conditioning with or without anti-c-Kit that received gene-modified autologous transplants with green fluorescent protein expression had similar myelosuppression, but failed long-term engraftment and despite immunosuppressive treatment had all the hallmarks seen previously in similar models without immunosuppression. Our preliminary data expand current knowledge of RIC and emphasize the need to explore whether specific and directed myelosuppression alone is adequate in the absence of microenvironmental modulation, or whether innovative combinations are necessary for safe and effective engraftment.
对于大多数非恶性疾病的基因治疗应用而言，最小预处理甚至无预处理将是首选方案。然而，对于非血液系统恶性肿瘤患者，降低强度预处理（RIC）方案并未导致长期植入，除非移植的供体细胞具有选择性优势。在一些大型动物研究中也观察到了类似的结果。骨髓抑制水平不足被认为是导致这些结果的原因。为了解决这个问题，在小动物中提出了几种创新方案，具有选择性造血骨髓抑制和较低的全身毒性。这些方案有望控制清髓性预处理中与移植相关的发病率和死亡率，并提供有效的长期植入，特别是在基因校正自体移植的患者中。在本研究中，我们在非人类灵长类动物（一种临床相关的大型动物模型）中测试了一些这些有前景的RIC方案。我们的数据表明，抗c-Kit抗体联合低剂量照射诱导的短暂骨髓抑制可能导致长期植入，尽管植入水平较低。接受绿色荧光蛋白表达的基因修饰自体移植的接受白消安预处理（无论有无抗c-Kit）的动物具有相似的骨髓抑制，但未能实现长期植入，并且尽管进行了免疫抑制治疗，但仍具有先前在无免疫抑制的类似模型中所见的所有特征。我们的初步数据扩展了当前对RIC方案的认识，并强调需要探索在没有微环境调节的情况下，单独的特异性和定向骨髓抑制是否足够，或者是否需要创新组合来实现安全有效的植入。
