Vaccination with irradiated, autologous melanoma cells engineered to secrete granulocyte-macrophage colony-stimulating factor by adenoviral-mediated gene transfer augments antitumor immunity in patients with metastatic melanoma
Vaccination with irradiated, autologous melanoma cells engineered to secrete granulocyte-macrophage colony-stimulating factor by adenoviral-mediated gene transfer augments antitumor immunity in patients with metastatic melanoma
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DOI：
10.1200/jco.2003.07.005
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发表时间：
2003-09-01
影响因子：
45.3
通讯作者：
Dranoff, G
中科院分区：
文献类型：
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作者：
Soiffer, R;Hodi, FS;Dranoff, G
目的：用经辐照的自体黑色素瘤细胞接种疫苗，通过逆转录病毒介导的基因转移分泌粒细胞-巨噬细胞集落刺激因子（GM-CSF），可在转移性黑色素瘤患者中产生有效的抗肿瘤免疫力。这种免疫方案的进一步临床开发需要简化疫苗生产。我们进行了一项I期临床试验，测试用经辐照的自体黑色素瘤细胞接种疫苗的生物活性，所述细胞通过腺病毒介导的基因转移而被工程化以分泌GM-CSF。患者和方法：将切除的转移瘤处理成单细胞，用编码GM-CSF的复制缺陷型腺病毒载体转导，照射并冷冻保存。单个疫苗由1 × 10（6）、4 × 10（6）或1 × 10（7）个肿瘤细胞组成，这取决于总产量，并以每周和每两周的间隔皮内和皮下注射。平均GM-CSF分泌为745 ng/10（6）个细胞/24小时。毒性仅限于1 - 2级局部皮肤反应。8例患者因疾病进展迅速而提前退出研究。在26例可评估患者中，19例在注射部位接种疫苗引起密集的树突状细胞、巨噬细胞、粒细胞和淋巴细胞浸润。免疫刺激的发展迟发型超敏反应，辐射，解离，自体，非转导的肿瘤细胞在25例患者中的17。疫苗接种后切除的转移性病变显示，16名患者中有10名出现活跃或局灶性T淋巴细胞和浆细胞浸润，伴肿瘤坏死。观察到1例完全缓解、1例部分缓解和1例混合缓解。十名患者（29%）是活着的，最低随访36个月，这些患者中有四个没有证据的diseases.Conclusion：疫苗接种与辐射，自体黑色素瘤细胞工程分泌GM-CSF腺病毒介导的基因转移增强抗肿瘤免疫转移性黑色素瘤患者。(C)2003年，美国临床肿瘤学会。
Purpose : Vaccination with irradiated, autologous melanoma cells engineered to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF) by retroviral-mediated gene transfer generates potent antitumor immunity in patients with metastatic melanoma. Further clinical development of this immunization scheme requires simplification of vaccine manufacture. We conducted a phase I clinical trial testing the biologic activity of vaccination with irradiated, autologous melanoma cells engineered to secrete GM-CSF by adenoviral-mediated gene transfer. Patients and Methods: Excised metastases were processed to single cells, transduced with a replication-defective adenoviral vector encoding GM-CSF, irradiated, and cryopreserved. Individual vaccines were composed of I x 10(6), 4 x 10(6), or 1 x 10(7) tumor cells, depending on overall yield, and were injected intradermally and subcutaneously at weekly and biweekly intervals.Results: Vaccines were successfully manufactured for 34 (97%) of 35 patients. The average GM-CSF secretion was 745 ng/10(6) cells/24 hours. Toxicities were restricted to grade 1 to 2 local skin reactions. Eight patients were withdrawn early because of rapid disease progression. Vaccination elicited dense dendritic cell, macrophage, granulocyte, and lymphocyte infiltrates at injection sites in 19 of 26 assessable patients. Immunization stimulated the development of delayed-type hypersensitivity reactions to irradiated, dissociated, autologous, nontransduced tumor cells in 17 of 25 patients. Metastatic lesions that were resected after vaccination showed brisk or focal T-lymphocyte and plasma cell infiltrates with tumor necrosis in 10 of 16 patients. One complete, one partial, and one mixed response were noted. Ten patients (29%) are alive, with a minimum follow-up of 36 months; four of these patients have no evidence of disease.Conclusion: Vaccination with irradiated, autologous melanoma cells engineered to secrete GM-CSF by adenoviral-mediated gene transfer augments antitumor immunity in patients with metastatic melanoma. (C) 2003 by American Society of Clinical Oncology.