Vaccination with irradiated autologous tumor cells engineered to secrete granulocyte-macrophage colony-stimulating factor augments antitumor immunity in some patients with metastatic non-small-cell lung carcinoma
Vaccination with irradiated autologous tumor cells engineered to secrete granulocyte-macrophage colony-stimulating factor augments antitumor immunity in some patients with metastatic non-small-cell lung carcinoma
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DOI：
10.1200/jco.2003.03.091
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发表时间：
2003-02-15
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：
Salgia, R;Lynch, T;Dranoff, G
问题：我们证明，用经辐照的肿瘤细胞（经工程改造以分泌粒细胞-巨噬细胞集落刺激因子（GM-CSF））接种疫苗可在多种小鼠模型和转移性黑色素瘤患者中刺激强效、特异性和持久的抗肿瘤免疫力。为了测试这种疫苗接种策略是否能增强转移性非小细胞肺癌（NSCLC）患者的抗肿瘤免疫力，我们进行了I期临床试验。Patients and Methods：切除的转移瘤被处理成单细胞悬液，用编码GM-CSF的复制缺陷型腺病毒载体感染，照射，冷冻保存。单个疫苗由1 × 10（6），4 × 10（6），或1 × 10（7）个细胞，这取决于总产量，并在每周和每两周的间隔皮内和皮下给药。平均GM-CSF分泌量为513 ng/ 10（6）个细胞/24 h。毒性仅限于1 - 2级局部皮肤反应。9名患者因疾病进展迅速而提前退出。在25例可评估的患者中，18例接种疫苗引起树突状细胞、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的辐射，解离，自体，非转染的肿瘤细胞在22例患者中的18。接种疫苗后切除的转移灶显示T淋巴细胞和浆细胞浸润，其中3例肿瘤坏死。两名患者在入组时手术表现为无疾病证据，在43个月和42个月时仍无疾病。5例患者显示稳定的疾病持续时间为33、19、12、10和3个月。结论：经放射治疗的分泌GM-CSF的自体非小细胞肺癌细胞接种可增强部分转移性非小细胞肺癌患者的抗肿瘤免疫力。
Puspose : We demonstrated that vaccination with irradiated tumor cells engineered to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulates potent, specific, and long-lasting antitumor immunity in multiple murine models and patients with metastatic melanoma. To test whether this vaccination strategy enhances antitumor immunity in patients with metastatic non-small-cell lung cancer (NSCLC), we conducted a phase I clinical trial.Patients and Methods: Resected metastases were processed to single-cell suspension, infected with a replication-defective adenoviral vector encoding GM-CSF, irradiated, and cryopreserved. Individual vaccines consisted of 1 x 10(6), 4 x 10(6), or 1 x 10(7) cells, depending on overall yield, and were administered 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 513 ng/ 10(6) cells/24 h. Toxicities were restricted to grade 1 to 2 local skin reactions. Nine patients were withdrawn early because of rapid disease progression. Vaccination elicited dendritic cell, macrophage, granulocyte, and lymphocyte infiltrates in 18 of 25 assessable patients. Immunization stimulated the development of delayed-type hypersensitivity reactions to irradiated, dissociated, autologous, nontransfected tumor cells in 18 of 22 patients. Metastatic lesions resected after vaccination showed T lymphocyte and plasma cell infiltrates with tumor necrosis in three of six patients. Two patients surgically rendered as having no evidence of disease at enrollment remain free of disease at 43 and 42 months. Five patients showed stable disease durations of 33, 19, 12, 10, and 3 months. One mixed response was observed.Conclusion: Vaccination with irradiated autologous NSCLC cells engineered to secrete GM-CSF enhances antitumor immunity in some patients with metastatic NSCLC.