Combining allogeneic immunotherapy with an mTOR inhibitor for advanced renal cell carcinoma.
Combining allogeneic immunotherapy with an mTOR inhibitor for advanced renal cell carcinoma.
复制标题
将同种异体免疫疗法与 mTOR 抑制剂相结合治疗晚期肾细胞癌。
DOI：
10.1038/bmt.2009.338
复制
发表时间：
2010
影响因子：
4.8
通讯作者：
Warren,EH
中科院分区：
文献类型：
--
作者：
Tykodi,SS;Voong,LN;Warren,EH
晚期肾细胞癌（RCC）对低强度预处理（RIC）和异基因造血干细胞移植（HCT）后的移植物抗肿瘤（GVT）效应有反应。1，2然而，由于完全缓解率低以及与治疗相关的毒性（包括移植物抗宿主病和感染性并发症），对该方法的热情受到了抑制。在他们最近的报告中，Bregni及其同事观察到25例转移性RCC患者接受RIC和来自HLA相容的同胞供体的同种异体HCT治疗的5年生存率为20%。值得注意的是，3名长期存活者有稳定的转移性疾病，并接受了移植后血管内皮生长因子（VEGF）受体靶向酪氨酸激酶抑制剂，包括舒尼替尼或索拉非尼。3作者进一步推测，通过将同种异体HCT与新型靶向治疗相结合治疗转移性RCC，可能会带来临床益处。对接受RIC和同种异体HCT治疗的RCC患者的回顾性分析表明，来自纪念斯隆-凯特琳癌症中心预后标准定义的有利或中等风险组的RCC患者和透明细胞肿瘤患者取得了更好的结局。2，3然而，根据III期临床研究的结果，具有这些临床特征的RCC患者最有可能接受VEGF靶向治疗的初始治疗，包括舒尼替尼或贝伐单抗加IFN-α。4，5 VEGF导向治疗失败患者的最佳挽救策略仍不清楚。哺乳动物雷帕霉素激酶靶点的抑制剂（mTOR抑制剂）包括替西罗莫司、依维莫司和雷帕霉素作为单一疗法具有针对RCC的临床活性。透明细胞肾细胞癌患者在VEGF导向治疗失败后接受二线依维莫司治疗，其临床获益程度适中，客观缓解率仅为1%，中位PFS为4.0个月。6因此，mTOR抑制剂与其他疗法相结合的可能性具有重大意义。最近有报道称，接受RIC和同种异体HCT治疗的淋巴瘤患者在移植后也接受了雷帕霉素治疗，其生存率有所提高。7接受雷帕霉素治疗的患者队列的OS益处是由于移植后复发或进展的显著减少（风险比为0.5）。作者推测，雷帕霉素联合RIC同种异体HCT治疗淋巴瘤的获益与mTOR抑制剂的直接抗肿瘤作用有关。这些观察结果可能与通过同种异体HCT治疗RCC的努力具有重要的相关性。
Advanced renal cell carcinoma (RCC) is responsive to a graft-vs-tumor (GVT) effect following reduced-intensity conditioning (RIC) and allogeneic hematopoietic stem cell transplantation (HCT). 1, 2 However, enthusiasm for the approach has been tempered by the low rate of complete responders and treatment-related toxicities that include graft-vs-host disease and infectious complications. In their recent report, Bregni and co-workers observed a 5-year survival rate of 20% for 25 patients with metastatic RCC treated by RIC and allogeneic HCT from HLA-compatible sibling donors. Of interest, three long-term survivors had stable metastatic disease and had received post transplant vascular endothelial growth factor (VEGF) receptortargeted tyrosine kinase inhibitors including sunitinib or sorafenib. 3 The authors further speculate on the potential for clinical benefit by combining allogeneic HCT with novel targeted therapies for metastatic RCC. Retrospective analyses of RCC patients treated by RIC and allogeneic HCT have suggested that RCC patients from favorable or intermediate risk groups defined by the Memorial Sloan-Kettering Cancer Center prognostic criteria and with clear-cell tumors have achieved better outcomes. 2, 3 However, RCC patients with these clinical features are most likely to receive initial treatment with VEGF-targeted therapies including sunitinib or bevacizumab plus IFN-α based on the results of phase III clinical studies. 4, 5 The optimal salvage strategy for patients failing VEGF-directed therapies remains unclear. Inhibitors of the mammalian target of rapamycin kinase (mTOR inhibitors) including temsirolimus, everolimus and rapamycin have clinical activity against RCC as monotherapy. For patients with clear-cell RCC receiving second-line everolimus after failing a VEGF-directed therapy, the magnitude of clinical benefit was modest, with an objective response rate of only 1% and a median PFS of 4.0 months. 6 Thus, the potential for combining mTOR inhibitors with other therapies is of significant interest.Improved survival for lymphoma patients treated by RIC and allogeneic HCT who also received post transplant rapamycin has recently been reported. 7 The OS benefit for the patient cohort treated with rapamycin was due to a significant decrease in post transplant relapse or progression (hazard ratio of 0.5). The authors speculated that the benefit of rapamycin in combination with RIC allogeneic HCT for lymphoma was related to a direct antitumor effect of the mTOR inhibitor. These observations may have important relevance to efforts to treat RCC by allogeneic HCT.