Development of new diagnostic and immunotherapeutic methods for patients with cancer

为癌症患者开发新的诊断和免疫治疗方法

• 批准号: 14104013
• 负责人: KAWAKAMI Yutaka
• 金额: $ 70.14万
• 依托单位: KEIO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (S)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-14104013/
• 关键词: Tumor antigens; Immunotherapy; Colon cancer; Pancreas cancer; DNA chip; Tumor markers; Immune escape; Microsatellite instability; 膵癌; 癌幹細胞; 樹状細胞; SEREX; 免疫不全マウス; p53; 潰瘍性大腸炎; 癌精巣抗原; MSI; SCID; K-ras; RDA

We have established basics for development of new diagnostic and therapeutic methods for various cancers of digestive organs. 1) Identification of human tumor antigens and individualized immunotherapy : Various tumor antigens and T cell epitopes were identified by using systematic gene analysis and cDNA cloning using human IgG from immunodeficient mice implanted with human cancer tissues. The analysis of the immune responses revealed importance of individualized immunotherapy. Intratumoral administration of peptide pulsed dendritic cells was developed, and it resulted in induction of strong immune responses and anti-tumor effects through antigen spreading. 2) Immune responses to MSI^+ cancers : The immune response to tumor specific frameshift peptides was found to explain good prognosis of patients with MSI^+ cancers, indicating possible immunotherapy to MSI^+ cancers. The immune response to a cancer-testis antigen CAGE was frequently detected in the patients with MSI^+ cancers, sugges … More ting its use in the immunotherapy. 3) Mechanisms for immune escape of cancer cells : Using newly developed mutation specific viral shRNAs, enhanced MAPK signaling through the BRAF or RAS mutation was found to cause production of multiple immunosuppressive factors, indicating immunotherapy in combination with signal inhibitors. 4) Immunological implications of cancer stem cells and epithelial mescenchymal transition (EMT) : Differential expression of tumor antigens in the established stem like pancreatic cancer SP cells and EMT cells was found. EMT was found to enhance tumor metastasis through immunosuppression. 5) Clinical applications of the identified tumor antigens : IgG Abs for tumor antigens were found to be useful for prognostic diagnosis. Anti-p53 Ab was found to be useful for early diagnosis of colon cancer in the patients with ulcerative colitis. Tumor markers useful for diagnosis of high metastatic ability were identified. The identified tumor antigens and immune-interventions are expected to be evaluated in the future clinical trials. KU-CR4 is a potential target for antibody therapy. Less

我们已经为各种消化器官癌症的新诊断和治疗方法的发展奠定了基础。1)人肿瘤抗原鉴定及个体化免疫治疗：利用植入人癌组织的免疫缺陷小鼠的人IgG进行系统基因分析和cDNA克隆，鉴定多种肿瘤抗原和T细胞表位。免疫反应的分析揭示了个体化免疫治疗的重要性。肿瘤内注射肽脉冲树突状细胞，通过抗原扩散诱导强烈的免疫反应和抗肿瘤作用。2)对MSI^+癌症的免疫应答：发现对肿瘤特异性移码肽的免疫应答可以解释MSI^+癌症患者预后良好，提示可能对MSI^+癌症进行免疫治疗。在MSI +癌患者中经常检测到对癌睾丸抗原CAGE的免疫应答，提示其在免疫治疗中的应用。3)癌细胞免疫逃逸的机制：利用新发现的突变特异性病毒shrna，通过BRAF或RAS突变增强MAPK信号，可引起多种免疫抑制因子的产生，提示联合信号抑制剂进行免疫治疗。4)肿瘤干细胞和上皮间充质转化（epithelial mesenchymal transition， EMT）的免疫学意义：在已建立的干细胞如胰腺癌SP细胞和EMT细胞中发现肿瘤抗原的差异表达。发现EMT通过免疫抑制促进肿瘤转移。5)肿瘤抗原鉴定的临床应用：肿瘤抗原IgG抗体可用于预后诊断。发现抗p53抗体可用于溃疡性结肠炎患者结肠癌的早期诊断。确定了用于诊断高转移能力的肿瘤标志物。确定的肿瘤抗原和免疫干预措施有望在未来的临床试验中进行评估。KU-CR4是抗体治疗的潜在靶点。少

项目成果

Endo T., Kawakami Y., et al.: "In Situ Cancer Vaccination with a Replication-Conditional HSV for the Treatment of Liver Metastasis of Colon Cancer"Cancer Gene Ther.. 9. 142-148 (2002)

Endo T.、Kawakami Y.等人：“用复制条件 HSV 进行原位癌症疫苗接种治疗结肠癌肝转移”Cancer Gene Ther.. 9. 142-148 (2002)

A new melanoma antigen FABP7 involved in proliferation and invasion is a potential target for immunotherapy and molecular target therapy

一种参与增殖和侵袭的新黑色素瘤抗原FABP7是免疫治疗和分子靶向治疗的潜在靶点

• 期刊: Cancer Res in press
• 作者: Goto Y;Kawakami Y;et al.
• 通讯作者: et al.

Human melanoma antigens recognized by CD8+ T cells, in "Tumor Antigens Recognized by T cells and Antibodies"Tumor Immunology Series volume III ( eds, Stauss H, Kawakami Y, and Parmiani G)

CD8 T 细胞识别的人类黑色素瘤抗原，见“T 细胞和抗体识别的肿瘤抗原”肿瘤免疫学系列第三卷（编辑，Stauss H、Kawakami Y 和 Parmiani G）

• 发表时间: 2003
• 作者: T.Shimizu;S.Arai;H.Imai;T.Oishi;M.Hirama;A.Koito;Y.Kida;K.Kuwano;Kawakami Y.
• 通讯作者: Kawakami Y.

Iizuka Y., Kawakami Y., et al.: "Augmentation of Antitumor Immune Responses by Multiple Intratumoral Inoculations of Replication-Conditional HSV and Interleukin-12."J.Immunother.. 27. 92-98 (2004)

Iizuka Y.、Kawakami Y. 等人：“通过复制条件性 HSV 和 Interleukin-12 的多次肿瘤内接种来增强抗肿瘤免疫反应。”J.Immunother.. 27. 92-98 (2004)

Ueda R., Kawakami Y., et al.: "Identification of a human glioma antigen, SOX6, recognized by patients' sera."Oncogene.. 22. 8823-8834 (2004)

Ueda R.、Kawakami Y. 等人：“患者血清识别的人类神经胶质瘤抗原 SOX6 的鉴定。”Oncogene.. 22. 8823-8834 (2004)