Clinical trial of specific immuno-therapy against patients with advanced solid cancer including lung cancer using mature dendritic cells

树突状细胞（dc）是最有效的抗原呈递细胞。以肿瘤相关抗原（TAA）肽为脉冲的树突状细胞已被用于肿瘤免疫治疗。早期的临床研究证明了这些试验的安全性，但临床效果还不够。大多数研究使用的是由外周血单核细胞产生的未成熟dc，其中含有粒细胞-巨噬细胞集落刺激因子（GM-CSF）和白细胞介素-4 （IL-4）。在这里，我们进行了一项I期临床试验，利用链球菌衍生物OK-432诱导的成熟树突状细胞进行主动免疫治疗。用GM-CSF、IL-4培养6 d， GM-CSF、IL-4、OK-432培养2 d，生成dc。注射前，用限定于HLA-A^*2402的MAGE-3肽（IMPKAGLLI）和锁孔帽贝血青素（KLH）作为对照抗原脉冲dc。我们选择HLA-A^*2402阳性的晚期实体肿瘤患者表达MAGE-3 mRNA。采用剂量递增设计，每组接种剂量水平为0.1（第1组）、0.3（第2组）和1（第3组）× 10^8 DC /次注射。每组入组3名患者。用延迟型超敏反应（DTH）和MHC四聚体进行免疫监测。该方案耐受性良好。所有患者均出现轻度发热（1 ~ 2级）和注射部位局部反应（红斑和硬结：1级）。大剂量DCs给药早期，MAGE-3肽DTH呈阳性。1 × 10^8 dc /次注射诱导DTH阳性反应最有效。1例患者肿瘤标志物（CEA）下降。1例患者病情稳定（SD） 4个月，但其他患者病情进展。这些结果表明，接种成熟dc是安全可行的，但需要进一步的研究来获得客观的临床反应。为了提高DC疫苗的临床效果，寻找在肺癌中表达的新的肿瘤抗原，从而更有效地诱导肿瘤特异性免疫是途径之一。我们找到了这些肿瘤抗原的候选物HM1.24抗原。此外，我们还鉴定了HM1.24抗原的肿瘤肽，该肽限制于HLA-A24，并能诱导细胞毒性T淋巴细胞。使用HM 1.24肽的临床试验是预期的。少

Dendritic cells (DCs) are the most potent antigen-presenting cells. DCs pulsed with peptides of tumor-associated antigens (TAA) have been used in cancer immunotherapy. An early clinical study demonstrated the safety of these trials, but the clinical effect was not sufficient. Most studies have used immature DCs generated from peripheral blood monocytes with granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4). Here, we conducted phase I clinical trial of active immunotherapy using mature DCs induced by a streptococcus derivatives OK-432. DCs were generated from blood monocytes by culturing with GM-CSF and IL-4 for 6 days and then GM-CSF,IL-4 and OK-432 for 2 days. Before injection, DCs were pulsed with MAGE-3 peptide (IMPKAGLLI), which is restricted for HLA-A^*2402, and keyhole limpet hemocyanin (KLH) as a control antigen. We selected HLA-A^*2402-positive patients who had advanced solid tumors expressing MAGE-3 mRNA. DC vaccine was administered subcutaneou … More sly every 2 weeks for a total of four vaccinations in a dose-escalation design at the dose level per cohort of 0.1 (Group 1),0.3 (Group 2) and 1 (Group 3) x 10^8 DCs/injection. Three patients were enrolled in each group. Immunological monitoring with delayed type hypersensitivity (DTH) reaction and MHC tetramer was performed. This protocol was well tolerated. A mild fever (Grade 1 to 2) and local reaction of injection site (erythema and induration : Grade 1) were found in all patients. DTH for MAGE-3 peptide became to be positive in the earlier period when a high dose of DCs was administered. 1 x 10^8 DCs/injection was most effective to induce a positive DTH reaction. The decrease of tumor marker (CEA) was found in one patient. One patient showed the stable disease (SD) for four months, but others were progressive. These results indicated that vaccination with mature DCs was safe and feasible, but further studies were required to obtain the objective clinical responses.To enhance the clinical effects of DC vaccine, one of the approaches was to find the novel tumor antigen expressing in lung cancer which more effectively induce tumor specific immunity. We found the candidate for these tumor antigens, HM1.24 antigen. Furthermore, we identified the tumor peptide of HM1.24 antigen which are restricted to HLA-A24 and can induce cytotoxic T lymphocytes. The clinical trial using HM 1.24 peptide was expected. Less