Integrating NK and DC into Cancer Therapy

将 NK 和 DC 整合到癌症治疗中

• 批准号: 7938140
• 负责人: MICHAEL T LOTZE
• 金额: $ 13.73万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2010-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7938140
• 关键词: Integrating; NK; DC; into; Cancer

DESCRIPTION (provided by applicant): DCs, NK and T-cells found within human tumors have been associated with an improved prognosis in almost every tumor type examined. Indeed their recruitment may be modified during development of the chronic inflammatory response. Cancer arises in the setting of chronic inflammation - inducing an acute inflammatory response to elicit new T-cells capable of mediating sustained and more effective antitumor activity is the central premise of this proposal. Integrating NK and DC into Cancer Therapy with direct injection into tumor or coincubated ex vivo with tumor or tumor antigens administered as an immunogen, will result in tumor destruction and elicit an effective adaptive immune response. The identification of critical biomarkers and surrogates using modern proteomic, genomic, and cellomic strategies will be integrated into all projects as a means to test these strategies more readily in early disease. We hypothesize that by directing NK and DC to rumor sites in situ, that we can enhance regression of established local disease, promoting a more effective systemic immunity to tumor. Coordinate signaling is necessary between NK and DCs to initiate optimal TH1 polarization, subsequently driving an effective adaptive T-cell response to cancer. Indeed, after two decades of NK/ANK/LAK adoptive transfer and several years of experience with over 1000 patients receiving DCs, it is becoming apparent that cooperative interactions between NK and DC will be necessary to modify the established immune response to cancer. We will investigate this in four projects: Project I. Initiating the Adaptive Immune Response to Cancer; Project II. NK cells induce DC1-mediated anti-tumor immunity, and Project III. IL-1 Homologues Promote the Acute Inflammatory Response to Melanoma. Development of these three projects will be supported by two cores: A) Administrative, Bioinformatics and Biostatistics Core, and B) Imaging Core. Project I will enable further development of the clinical trials proposed in patients with melanoma and colorectal cancer who will be evaluated and treated in Projects II and III. Evaluation of direct intralymphatic injection of NK matured DC 1 fed tumor antigen or lysates will be contrasted with strategies using direct intratumoral injection of NK and DC.

描述（由申请人提供）：在人类肿瘤中发现的 DC、NK 和 T 细胞几乎与所检查的每种肿瘤类型的预后改善相关。事实上，它们的募集可能在慢性炎症反应的发展过程中发生改变。癌症产生于慢性炎症——诱导急性炎症反应以引发能够介导持续且更有效的抗肿瘤活性的新T细胞是该提议的核心前提。将 NK 和 DC 整合到癌症治疗中，直接注射到肿瘤中或与肿瘤或作为免疫原施用的肿瘤抗原离体共孵育，将导致肿瘤破坏并引发有效的适应性免疫反应。使用现代蛋白质组学、基因组学和细胞组学策略鉴定关键生物标志物和替代物将被整合到所有项目中，作为在早期疾病中更容易测试这些策略的手段。我们假设，通过将 NK 和 DC 引导至原位肿瘤位点，我们可以增强已确定的局部疾病的消退，从而促进更有效的针对肿瘤的全身免疫。 NK 和 DC 之间需要协调信号传导以启动最佳 TH1 极化，从而驱动有效的适应性 T 细胞对癌症的反应。事实上，经过二十年的 NK/ANK/LAK 过继转移以及数年超过 1000 名接受 DC 的患者的经验，很明显，NK 和 DC 之间的合作相互作用对于改变已建立的癌症免疫反应是必要的。我们将在四个项目中对此进行研究： 项目 I. 启动对癌症的适应性免疫反应；项目二。 NK 细胞诱导 DC1 介导的抗肿瘤免疫，以及项目 III。 IL-1 同系物促进黑色素瘤的急性炎症反应。这三个项目的开发将得到两个核心的支持：A) 管理、生物信息学和生物统计核心，以及 B) 成像核心。项目一将进一步开展针对黑色素瘤和结直肠癌患者的临床试验，这些患者将在项目二和项目三中接受评估和治疗。将直接淋巴内注射NK成熟的DC 1饲喂肿瘤抗原或裂解物的评估与使用直接肿瘤内注射NK和DC的策略进行对比。

项目成果

Type-1 polarized dendritic cells primed for high IL-12 production show enhanced activity as cancer vaccines.

• DOI: 10.1007/s00262-008-0648-5
• 发表时间: 2009-08
• 期刊: CANCER IMMUNOLOGY IMMUNOTHERAPY
• 影响因子: 5.8
• 作者: Giermasz, Adam S.;Urban, Julie A.;Nakamura, Yutaro;Watchmaker, Payal;Cumberland, Rachel L.;Gooding, William;Kalinski, Pawel
• 通讯作者: Kalinski, Pawel

High-mobility group box 1 and cancer.

• DOI: 10.1016/j.bbagrm.2009.11.014
• 发表时间: 2010-01
• 期刊: BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS
• 影响因子: 4.7
• 作者: Tang, Daolin;Kang, Rui;Zeh, Herbert J., III;Lotze, Michael T.
• 通讯作者: Lotze, Michael T.

Damage associated molecular pattern molecule-induced microRNAs (DAMPmiRs) in human peripheral blood mononuclear cells.

• DOI: 10.1371/journal.pone.0038899
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Unlu S;Tang S;Wang E;Martinez I;Tang D;Bianchi ME;Zeh HJ 3rd;Lotze MT
• 通讯作者: Lotze MT

The receptor for advanced glycation end products (RAGE) sustains autophagy and limits apoptosis, promoting pancreatic tumor cell survival.

• DOI: 10.1038/cdd.2009.149
• 发表时间: 2010-04
• 期刊: Cell death and differentiation
• 影响因子: 12.4
• 作者: Kang R;Tang D;Schapiro NE;Livesey KM;Farkas A;Loughran P;Bierhaus A;Lotze MT;Zeh HJ
• 通讯作者: Zeh HJ

Independent regulation of chemokine responsiveness and cytolytic function versus CD8+ T cell expansion by dendritic cells.

趋化因子反应性和细胞溶解功能与树突状细胞的 CD8 T 细胞扩增的独立调节。

• DOI: 10.4049/jimmunol.0902062
• 发表时间: 2010
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Watchmaker,PayalB;Berk,Erik;Muthuswamy,Ravikumar;Mailliard,RobbieB;Urban,JulieA;Kirkwood,JohnM;Kalinski,Pawel
• 通讯作者: Kalinski,Pawel