Immunization using autologous dendritic cells pulsed with the melanoma-associated antigen gp100-derived G280-9V peptide elicits CD8+ immunity
Immunization using autologous dendritic cells pulsed with the melanoma-associated antigen gp100-derived G280-9V peptide elicits CD8+ immunity
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DOI：
10.1158/1078-0432.ccr-05-1198
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发表时间：
2005-11-01
影响因子：
11.5
通讯作者：
Haluska, FG
中科院分区：
文献类型：
--
作者：
Linette, GP;Zhang, DS;Haluska, FG
目的：确定用黑色素瘤相关抗原 gp100 衍生的 G280-9V 肽脉冲的自体树突状细胞的毒性、最大耐受剂量以及临床和免疫反应。患者和方法：12 名患有晚期黑色素瘤的 HLA-A*0201(+) 患者接受用 G280-9V 脉冲的树突状细胞给药 肽。三名患者的队列分别静脉注射 5 x 10(6)、15 x 10(6) 和 50 x 10(6) 个细胞。根据剂量递增方案，每 3 周注射六剂。另外三名患者接受了最高剂量的治疗。没有同时施用额外的细胞因子或疗法。通过 IFN-gamma ELISPOT 测定、四聚体测定和 Cr-51 释放测定来测量 G280-9V 脉冲树突状细胞的免疫原性，并比较疫苗接种前和疫苗后的血液样本。通过实体瘤反应评估标准评估治疗反应。结果：通过 ELISPOT 测量，在 8 名 (67%) 患者中观察到对天然 G280 的 CD8(+) 免疫力，通过四聚体测定测量，在 12 名 (100%) 患者中观察到 CD8(+) 免疫力。在接受测试的 9 名患者中，9 名 (100%) 具有可测量的高亲和力 CTL 活性（通过同种异体黑色素瘤系的裂解来定义），这些黑色素瘤系共表达 HLA-A*0201 和 gp100。整个队列的中位随访时间为 43.8 个月。观察到 2 名 (17%) 患者部分缓解，3 名 (25%) 患者病情稳定。接受治疗的人群的中位生存期为 37.6 个月。此时，三名患者还活着，其中一名患者无需额外治疗即可继续做出反应。结论：通过三项独立测定测量的高免疫率和临床回归的发生支持继续研究 G280-9V 肽作为黑色素瘤疫苗制剂中的候选表位。
Purpose: To determine the toxicity, maximal tolerated dose, and clinical and immunologic response to autologous dendritic cells pulsed with melanoma-associated antigen gp100-derived G280-9V peptide.Patients and Methods: Twelve HLA-A*0201(+) patients with advanced melanoma were administered dendritic cells pulsed with G280-9V peptide. Cohorts of three patients were administered 5 x 10(6), 15 x 10(6), and 50 x 10(6) cells i.v. every 3 weeks for six doses according to a dose escalation scheme. Three additional patients were treated at the highest dose. No additional cytokines or therapies were coadministered. The immunogenicity of G280-9V-pulsed dendritic cells was measured by IFN-gamma ELISPOT assay, tetramer assay, and Cr-51 release assay comparing prevaccination to postvaccination blood samples. Response to treatment was assessed by Response Evaluation Criteria in Solid Tumors.Results: CD8(+) immunity to the native G280 was observed in 8 (67%) patients as measured by ELISPOT and in 12 (100%) patients as measured by tetramer assay. Of the 9 patients tested, 9 (100%) had measurable high-avidity CTL activity as defined by lysis of allogeneic melanoma lines, which coexpress HLA-A*0201 and gp100. The median follow-up of the entire cohort is 43.8 months. Two (17%) partial responses were observed and 3 (25%) patients had stable disease. The median survival of the treated population was 37.6 months. At this time, three patients are alive, including one patient who continues to respond without additional treatment.Conclusion: The high rate of immunization as measured by three independent assays and the occurrence of clinical regression support continued investigation of G280-9V peptide as a candidate epitope in melanoma vaccine formulations.