DENDRITIC CELL IMMUNOTHERAPY FOR LUNG AND COLON CANCER

肺癌和结肠癌的树突状细胞免疫疗法

• 批准号: 2892590
• 负责人: Lawrence Fong
• 金额: $ 12.48万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-06 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2892590
• 关键词: antigen antibody reaction; carcinoembryonal antigen; cellular immunity; chimeric proteins; clinical research; colon neoplasms; dendritic cells; human subject; immune tolerance /unresponsiveness; immunogenetics; lung neoplasms; neoplasm /cancer immunotherapy; neoplasm /cancer vaccine; peptide analog; protein structure function; recombinant proteins; tumor antigens; urinalysis; vaccine development

Despite the identification of tumor-associated antigens in various malignancies, the vast majority of the antigens are at best weakly immunogenic. Explanations for this include preexisting tolerance to self-antigens, poor antigen presentation by tumor cells, and immune inhibition by mediators secreted by tumors (e.g. vascular endothelial growth factor and IL-10). Dendritic cells (DC), which are extremely efficient antigen presenting cells (APC) uniquely capable of sensitizing nave T cells to antigen, have been used to reverse this immunologic unresponsiveness. Armed with tumor associated antigens, DC are capable of priming tumor specific immune responses in vitro and in vivo, often leading to tumor protection in various animal model systems. Recent clinical trials using DC have demonstrated that they can induce T cell and B cell immune responses against tumor associated antigens. Moreover, clinical responses have been observed in some patients. Representing less than 1 percent of circulating white blood cells, modest numbers of DC can be obtained from human peripheral blood by several techniques including density centrifugation and in vitro culture with exogenous cytokines. Advances making DC-based vaccination more potent and less complex will be required if this immunotherapeutic approach is to succeed clinically. The current proposal seeks to address several fundamental issues in DC immunotherapy in patients with lung and colorectal tumors with a peptide derived from carcinoembryonic antigen (CEA) as the immunologic target. We will explore the ability of a novel modified CEA peptide, with an amino acid substitution making it more immunogenic, to help break tolerance to this self-antigen. We will also examine approaches to increase tumor antigen delivery into DC via a targeting peptide. We will develop in vitro assays to evaluate the immunologic efficacy of these vaccine strategies. Finally, we will investigate the ability of a novel cytokine Flt3L to expand DC in vivo for DC harvesting in a clinical trial. The proposed studies will provide the foundation for simplified yet more potent DC targeted cancer immunotherapy for the future.

尽管在各种恶性肿瘤中发现了与肿瘤相关的抗原，但绝大多数抗原充其量只能是弱免疫原性。对此的解释包括先前存在的对自身抗原的耐受性，肿瘤细胞的抗原提呈不良，以及肿瘤分泌的介质(如血管内皮生长因子和IL-10)的免疫抑制。树突状细胞(DC)是一种非常有效的抗原提呈细胞(APC)，能够使原始T细胞对抗原敏感，已被用来逆转这种免疫无应答。树突状细胞携带肿瘤相关抗原，能够在体外和体内启动肿瘤特异性免疫反应，在各种动物模型系统中往往起到肿瘤保护作用。最近的临床试验表明，DC可以诱导T细胞和B细胞对肿瘤相关抗原的免疫反应。此外，在一些患者中观察到了临床反应。人外周血中DC的数量不到循环白细胞的1%，可以通过密度离心法和外源性细胞因子体外培养等多种技术获得DC。如果这种免疫治疗方法要在临床上取得成功，就需要取得进展，使基于DC的疫苗更有效、更简单。目前的提案旨在解决肺癌和结直肠肿瘤患者DC免疫治疗中的几个基本问题，以癌胚抗原(CEA)衍生的多肽为免疫靶点。我们将探索一种新的修饰CEA肽的能力，通过氨基酸取代使其更具免疫原性，以帮助打破对这种自身抗原的耐受性。我们还将研究通过靶向多肽增加肿瘤抗原进入DC的方法。我们将开发体外试验来评估这些疫苗策略的免疫效果。最后，我们将研究一种新的细胞因子Flt3L在体内扩增DC的能力，以便在临床试验中获取DC。拟议的研究将为未来简化但更有效的DC靶向癌症免疫治疗提供基础。