Nestle F O, Alijagic S, Gilliet M, Sun Y, Grabbe S, Dummer R, Burg G, Schadendorf D
Department of Dermatology, University of Zurich Medical School, Switzerland.
Nat Med. 1998 Mar;4(3):328-32. doi: 10.1038/nm0398-328.
Melanoma is the main cause of death in patients with skin cancer. Cytotoxic T lymphocytes (CTLs) attack melanoma cells in an HLA-restricted and tumor antigen-specific manner. Several melanoma-associated tumor antigens have been identified. 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. Mouse studies have demonstrated the potent capacity of DCs to induce antitumor immunity. In the present clinical pilot study, DCs were generated in the presence of granulocyte/macrophage-colony stimulating factor (GM-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 of 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.
黑色素瘤是皮肤癌患者死亡的主要原因。细胞毒性T淋巴细胞（CTL）以HLA限制和肿瘤抗原特异性的方式攻击黑色素瘤细胞。已鉴定出几种与黑色素瘤相关的肿瘤抗原。这些抗原是黑色素瘤疫苗治疗的合适候选物。树突状细胞（DC）是专门用于诱导原发性T细胞反应的抗原呈递细胞（APC）。小鼠研究已证明DC具有强大的诱导抗肿瘤免疫的能力。在本临床前期研究中，在粒细胞/巨噬细胞集落刺激因子（GM-CSF）和白细胞介素4（IL-4）存在的情况下生成DC，并根据患者的HLA单倍型用肿瘤裂解物或已知可被CTL识别的肽混合物进行脉冲处理。添加匙孔血蓝蛋白（KLH）作为CD4辅助抗原和免疫示踪分子。16例晚期黑色素瘤患者在门诊接受免疫接种。疫苗接种耐受性良好。所有患者均未检测到自身免疫的体征。DC疫苗接种在所有患者中均诱导了对KLH的迟发型超敏反应（DTH）反应性，11例患者对肽脉冲DC产生了阳性DTH反应。还证明了肽特异性CTL募集到DTH激发部位。因此，在DC疫苗接种期间诱导了抗原特异性免疫。16例评估患者中有5例出现客观反应（2例完全缓解，3例部分缓解），各器官（皮肤、软组织、肺、胰腺）的转移灶消退，另有1例轻微反应。这些数据表明，用外周血生成的自体DC进行疫苗接种是治疗转移性黑色素瘤的一种安全且有前景的方法。需要进一步研究以证明其临床有效性以及对黑色素瘤患者生存的影响。
