Vaccination of melanoma patients with peptide- or tumor lysate-pulsed dendritic cells
Vaccination of melanoma patients with peptide- or tumor lysate-pulsed dendritic cells
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DOI：
10.1038/nm0398-328
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发表时间：
1998-03-01
期刊：
影响因子：
82.9
通讯作者：
Schadendorf, D
中科院分区：
文献类型：
--
作者：
Nestle, FO;Alijagic, S;Schadendorf, D
黑色素瘤是皮肤癌患者死亡的主要原因(1)。细胞毒性T淋巴细胞（ctl）以hla限制性和肿瘤抗原特异性的方式攻击黑色素瘤细胞。已经发现了几种与黑色素瘤相关的肿瘤抗原(2)。这些抗原是黑色素瘤疫苗治疗的合适候选抗原。树突状细胞（dc）是抗原呈递细胞（APCs），专门用于诱导原代t细胞反应(3)。小鼠研究已经证明dc具有诱导抗肿瘤免疫的强大能力（4-11）。在目前的临床试点研究中，DCs是在粒细胞/巨噬细胞集落刺激因子（CM-CSF）和白细胞介素4 （IL-4）存在的情况下产生的，并根据患者的HLA单倍型，用肿瘤裂解液或已知可被ctl识别的肽混合物进行脉冲。添加Keyhole帽贝血青素（KLH）作为CD4辅助抗原和免疫示踪分子。16名晚期黑色素瘤患者在门诊进行了免疫接种。疫苗接种耐受良好。所有患者均未发现自身免疫的体征。DC疫苗接种诱导所有患者对KLH的延迟型超敏反应（DTH），以及11例患者对肽脉冲DC的DTH阳性反应。还证实了肽特异性ctl在DTH攻击部位的招募。因此，在DC疫苗接种过程中可诱导抗原特异性免疫。16例评估患者中有5例（2例完全缓解，3例部分缓解）有明显的客观缓解，各器官（皮肤、软组织、肺、胰腺）转移灶消退，另有1例轻微缓解。这些数据表明，接种来自外周血的自体dc是治疗转移性黑色素瘤的一种安全且有前景的方法。需要进一步的研究来证明临床有效性和对黑色素瘤患者生存的影响。
Melanoma is the main cause of death in patients with skin cancer(1). Cytotoxic T lymphocytes (CTLs) attack melanoma cells in an HLA-restricted and tumor antigen-specific manner. Several melanoma-associated tumor antigens have been identified(2). These antigens are suitable candidates for a vaccination therapy of melanoma. Dendritic cells (DCs) are antigen-presenting cells (APCs) specialized for the induction of a primary T-cell response(3). Mouse studies have demonstrated the potent capacity of DCs to induce antitumor immunity(4-11). In the present clinical pilot study, DCs were generated in the presence of granulocyte/macrophage-colony stimulating factor (CM-CSF) and interleukin 4 (IL-4) and were pulsed with tumor lysate or a cocktail of peptides known to be recognized by CTLs, depending on the patient's HLA haplotype. Keyhole limpet hemocyanin (KLH) was added as a CD4 helper antigen and immunological tracer molecule. Sixteen patients with advanced melanoma were immunized on an outpatient basis. Vaccination was well tolerated. No physical sign bf autoimmunity was detected in any of the patients. DC vaccination induced delayed-type hypersensitivity (DTH) reactivity toward KLH in all patients, as well as a positive DTH reaction to peptide-pulsed DCs in 11 patients. Recruitment of peptide-specific CTLs to the DTH challenge site was also demonstrated. Therefore, antigen-specific immunity was induced during DC vaccination. Objective responses were evident in 5 out of 16 evaluated patients (two complete responses, three partial responses) with regression of metastases in various organs (skin, soft tissue, lung, pancreas) and one additional minor response. These data indicate that vaccination with autologous DCs generated from peripheral blood is a safe and promising approach in the treatment of metastatic melanoma. Further studies are necessary to demonstrate clinical effectiveness and impact on the survival of melanoma patients.