Integrating NK and DC into Cancer Therapy

描述(申请人提供)：在人类肿瘤中发现的DC、NK和T细胞与几乎所有被检查的肿瘤类型的预后改善有关。事实上，在慢性炎症反应的发展过程中，它们的招募可能会发生变化。癌症是在慢性炎症的背景下产生的--诱导急性炎症反应，激发新的T细胞，能够介导持续和更有效的抗肿瘤活性，是这一提议的中心前提。将NK和DC整合到肿瘤治疗中，直接注射到肿瘤内，或与肿瘤或肿瘤抗原共孵育，作为免疫原，将导致肿瘤的破坏，并引发有效的适应性免疫反应。使用现代蛋白质组、基因组和细胞组学策略识别关键生物标记物和替代物将被整合到所有项目中，作为一种手段更容易在早期疾病中测试这些策略。我们推测，通过将NK和DC引导到原位肿瘤部位，我们可以促进已建立的局部疾病的消退，促进对肿瘤的更有效的系统免疫。NK和DC之间的协调信号是必要的，以启动最佳的TH1极化，随后驱动有效的适应性T细胞对癌症的反应。事实上，经过20年的NK/ANK/LAK过继转移和几年接受DC治疗的1000多名患者的经验，很明显，NK和DC之间的合作相互作用将是改变对癌症的既定免疫反应所必需的。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II.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核心，以及B)成像核心。项目I将推动在黑色素瘤和结直肠癌患者中拟议的临床试验的进一步发展，这些患者将在项目II和项目III中接受评估和治疗。对直接淋巴内注射NK成熟的DC 1肿瘤抗原或裂解物的评估将与直接肿瘤内注射NK和DC的策略进行对比。

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.