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

使用成熟树突状细胞针对包括肺癌在内的晚期实体癌患者进行特异性免疫治疗的临床试验

基本信息

批准号：
15590812
负责人：
NISHIOKA Yasuhiko
金额：
$ 2.18万
依托单位：
The University of Tokushima
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15590812/
关键词：
lung cancer specific immunotherapy mature dendritic cells MAGE-3 cancer vaccine OK-432

项目摘要

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

树突状细胞（Dendritic cells，DC）是目前发现的最有效的抗原提呈细胞。用肿瘤相关抗原（TAA）的肽脉冲的DC已用于癌症免疫治疗。早期的临床研究证明了这些试验的安全性，但临床效果并不充分。大多数研究使用由外周血单核细胞与粒细胞-巨噬细胞集落刺激因子（GM-CSF）和白细胞介素-4（IL-4）产生的未成熟DC。在这里，我们进行了主动免疫治疗的I期临床试验，使用由链球菌衍生物OK-432诱导的成熟DC。通过用GM-CSF和IL-4培养6天，然后用GM-CSF、IL-4和OK-432培养2天，从血液单核细胞产生DC。在注射前，用HLA-A^*2402限制性的法师-3肽（IMPKAGLLI）和作为对照抗原的钥孔血蓝蛋白（KLH）脉冲DC。我们选择了HLA-A^*2402阳性的晚期实体瘤患者，这些患者表达法师-3 mRNA。皮下注射DC疫苗 ...更多信息每2周皮下注射一次，共接种4次，剂量递增设计，每个队列的剂量水平为0.1（第1组）、0.3（第2组）和1（第3组）× 10^8个DC/注射。每组入组3例患者。采用迟发型超敏反应（DTH）和MHC四聚体进行免疫学监测。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）。当给予高剂量的DC时，法师-3肽的DTH在早期变为阳性。1 x 10^8 DC/注射对诱导阳性DTH反应最有效。肿瘤标志物（CEA）下降1例。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，成熟DC疫苗是安全可行的，但要获得客观的临床应答还需要进一步的研究，寻找能更有效地诱导肿瘤特异性免疫的肺癌新抗原是提高DC疫苗临床效果的途径之一。我们发现了这些肿瘤抗原的候选者，HM 1.24抗原。此外，我们还鉴定了HM1.24抗原的肿瘤肽，该肿瘤肽仅限于HLA-A24，并且可以诱导细胞毒性T淋巴细胞。使用HM 1.24肽的临床试验是预期的。少