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Induction of cytotoxicity of human tumor-infiltrating lymphocytes against autologous tumor cells and its application for cancer therapy

人肿瘤浸润淋巴细胞对自体肿瘤细胞的细胞毒性诱导及其在癌症治疗中的应用

基本信息

批准号：
63570599
负责人：
HIZUTA Akio
金额：
$ 0.19万
依托单位：
Okayama University
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1988
资助国家：
日本
起止时间：
1988 至 1989
项目状态：
已结题

项目摘要

1) Cancer patients were treated with the adoptive immunotherapy with lymphokine-activated killer (LAK) cells which were induced by culture of autologous peripheral blood lymphocytes (PBL) with interleukin-2(IL-2). Local administration by intraarterial or intracavital infusions of LAK cells produced a superior therapeutic efficacy to systemic administration by intravenous infusions.2)A half of tumor-infiltrating cells into human solid cancers consisted of T lymphocytes and the proportion of CD8^+T lymphocytes were greater than that of PBL.Tumor-infiltrating lymphocytes (TIL) contained gammadelta T cells and the majority of those cells in colorectal cancers were CD8^+ gammadelta T cells whose lineage was different from that of PBL.Hepatocellular carcinoma contained a greater number of gammadelta TIL than other human solid cancers.3)Culture of TIL with IL-2 alone was inadequate for their in vitro expansion, and we found that TIL effectively expanded in culture by addition of 20% conditioned medium derived from LAK cell induction.4)Cytotoxicity against tumor cells was notdetected in freshly isolated TIL.Cytotoxicity of TIL gradually increased in culture, reached its maximum at 2 to 3 weeks, and disappeared at 4 to 7 weeks. Phytohemagglutinin (PHA) was found to be capable of partial restoration of the diminished cytotoxicity of cultured TIL.5) TIL of advanced gastric cancer were activated in vivo by preoperative intratumoral injection with a biological response modifier, OK-432, and survival of patients after curative sugery was compared with control patients. Although there was no difference in survival of patients with scanty TIL,the activation of TIL improved 3-year survival in patients with TIL of a medium or over degree.

1)用白细胞介素2(IL-2)诱导的自体外周血淋巴细胞(PBL)诱导LAK细胞过继免疫治疗癌症患者。LAK细胞动脉或腔内局部输注的治疗效果优于静脉输注。2)人实体瘤的肿瘤浸润性细胞中有一半由T淋巴细胞组成，CD8~+T细胞的比例高于PBL。肿瘤浸润性淋巴细胞(TIL)中含有Gammadelta T细胞，其中大部分是CD8~+Gammadelta T细胞，其谱系与PBL不同。肝细胞癌中含有较多的Gammadelta T细胞。3)单独使用TIL和IL-2联合培养不足以进行体外扩增，4)新鲜分离的TIL对肿瘤细胞无杀伤作用，在培养过程中TIL的杀伤作用逐渐增强，2~3周达到最大，4~7周消失。发现植物血凝素(PHA)能部分恢复培养的TIL的细胞毒作用。在进展期胃癌术前瘤内注射生物反应调节剂OK-432激活TIL，并比较根治术后患者与对照组的存活率。尽管缺乏TIL的患者的存活率没有差异，但TIL的激活提高了中等或以上TIL患者的3年存活率。