Allogeneic hematopoietic cell transplantation for metastatic renal cell carcinoma after nonmyeloablative conditioning: Toxicity, clinical response, and immunological response to minor histocompatibility antigens
Allogeneic hematopoietic cell transplantation for metastatic renal cell carcinoma after nonmyeloablative conditioning: Toxicity, clinical response, and immunological response to minor histocompatibility antigens
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DOI：
10.1158/1078-0432.ccr-04-0072
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发表时间：
2004-12-01
影响因子：
11.5
通讯作者：
Sandmaier, BM
中科院分区：
文献类型：
--
作者：
Tykodi, SS;Warren, EH;Sandmaier, BM
目的：这个I期试验评估的安全性，疗效和免疫反应，以次要的组织相容性抗原后nonmyeloablastic异基因造血细胞移植作为治疗转移性renal cell carcinoma.Experimental Design：8例患者接受了调节与氟达拉滨和低剂量全身照射，然后从HLA匹配的同胞供体造血细胞移植。给予环孢素和霉酚酸酯作为移植后免疫抑制剂。监测患者的骨髓和淋巴样细胞的供体植入，通过系列成像的临床反应，并通过体外分离供体来源的CD 8（+）CTL识别受体的次要组织相容性（H）antigens.Results的免疫反应：所有患者实现了最初的混合造血嵌合体与两名患者排斥他们的移植物和恢复宿主造血。4例患者发生2 - 3级急性移植物抗宿主病，4例患者发生广泛的慢性移植物抗宿主病。5例患者病情进展，2例患者病情稳定，1例患者在接受供体淋巴细胞输注和IFN-α后出现部分应答。识别次要H抗原的CD 8（+）CTL克隆分离自所研究的5名患者。克隆从三个患者的部分反应或稳定的疾病识别抗原表达的肾细胞癌tumor cells.Conclusions：治疗转移性肾细胞癌与异基因造血细胞移植后nonmyeloablative空调氟达拉滨/全身照射是可行的，并可能导致肿瘤消退或稳定在一些患者。肿瘤细胞上的CD 8（+）CTL识别次要H抗原可在移植后分离，并可能有助于移植物抗肿瘤效应。这些抗原可能代表移植后疫苗接种或过继性T细胞治疗的治疗靶点，以增强同种异体造血细胞移植的抗肿瘤作用。
Purpose: This phase I trial assessed the safety, efficacy, and immunologic responses to minor histocompatibility antigens following nonmyeloablative allogeneic hematopoietic cell transplantation as treatment for metastatic renal cell carcinoma.Experimental Design: Eight patients received conditioning with fludarabine and low-dose total body irradiation followed by hematopoietic cell transplantation from an HLA-matched sibling donor. Cyclosporine and mycophenolate mofetil were administered as posttransplant immunosuppression. Patients were monitored for donor engraftment of myeloid and lymphoid cells, for clinical response by serial imaging, and for immunologic response by in vitro isolation of donor-derived CD8(+) CTLs recognizing recipient minor histocompatibility (H) antigens.Results: All patients achieved initial mixed hematopoietic chimerism with two patients rejecting their graft and recovering host hematopoiesis. Four patients developed acute, grade 2 to 3, graft-versus-host disease and four patients developed extensive chronic graft-versus-host disease. Five patients had progressive disease, two patients had stable disease, and one patient experienced a partial response after receiving donor lymphocyte infusions and IFN-alpha. CD8(+) CTL clones recognizing minor H antigens were isolated from five patients studied. Clones from three patients with a partial response or stable disease recognized antigens expressed on renal cell carcinoma tumor cells.Conclusions: Treatment of metastatic renal cell carcinoma with allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning with fludarabine/total body irradiation is feasible and may induce tumor regression or stabilization in some patients. CD8(+) CTL-recognizing minor H antigens on tumor cells can be isolated posttransplant and could contribute to the graft-versus-tumor effect. Such antigens may represent therapeutic targets for posttransplant vaccination or adoptive T-cell therapy to augment the antitumor effects of allogeneic hematopoietic cell transplantation.