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细胞与几乎每种检查的每种肿瘤类型的预后都改善有关。实际上，在慢性炎症反应的发展过程中，他们的招募可能会被修改。癌症是在慢性炎症的情况下引起的 - 引起对能够介导持续和更有效抗肿瘤活性的新的T细胞的急性炎症反应是该提议的主要前提。将NK和DC整合到癌症治疗中，直接注射到肿瘤中，或与作为免疫原施用的肿瘤或肿瘤抗原共同孵育，将导致肿瘤破坏并产生有效的适应性免疫反应。使用现代蛋白质组学，基因组和大细胞策略来鉴定关键的生物标志物和替代物，将纳入所有项目中，以便在早期疾病中更容易测试这些策略。我们假设通过将NK和DC引导到原位谣言地点，我们可以增强既定局部疾病的回归，从而促进对肿瘤的系统性免疫。 NK和DC之间必须进行坐标信号传导，以启动最佳的Th1极化，然后驱动对癌症的有效自适应T细胞反应。的确，经过二十年的NK/ANK/LAK收养转移和接受DC的1000多名患者的经验，很明显，NK和DC之间的合作相互作用是为了改变对癌症的既定免疫反应。我们将在四个项目中进行调查：I. Project I.发起对癌症的适应性免疫反应；项目II。 NK细胞诱导DC1介导的抗肿瘤免疫和III。 IL-1同源物促进了对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）行政，生物信息学和生物统计学核心以及b）成像核心。项目我将在黑色素瘤和结直肠癌患者中进一步开发提出的临床试验，这些试验将在项目II和III项目中进行评估和治疗。 NK成熟DC 1的直接淋巴内注射评估肿瘤抗原或裂解物将与使用NK和DC的肿瘤内注射直接注射的策略对比。

项目成果

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.

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

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

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

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