Immunophysiological Mechanisms in the Biological Therapy of Cancer
癌症生物治疗中的免疫生理学机制
基本信息
- 批准号:8157221
- 负责人:
- 金额:$ 44.44万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:
- 资助国家:美国
- 起止时间:至
- 项目状态:未结题
- 来源:
- 关键词:
项目摘要
Successful development of new approaches for the immunotherapy of cancer requires an understanding of complex, interdependent activities of early innate response elements with subsequent powerful adaptive immune responses. We are taking several novel approaches to maximize the host's ability to mount an effective antitumor response. These approaches include optimizing antigen presenting capability through the use of CD40, a TNF superfamily receptor that serves as a potent trigger for dendritic cells which provide a key interface between innate and adaptive responses. The potency of dendritic cell stimulation by agonist CD40 antibodies is enhanced when used in conjunction with IL-2 and the combination of agonist anti-CD40 plus IL-2 shows enhanced antitumor activity against metastatic kidney cancer in mice. Because CD40 is present on various hematopoietic-derived cells, endothelial cells, and some tumors themselves, we have also performed studies to definitively determine if the antitumor effects of CD40 stimulation and IL-2 were primarily mediated by CD40+ hematopoietic-derived cells. We have developed an approach where only tumor cells express functional CD40; specifically we have used models where CD40+ human tumors that respond only to anti-human CD40 were implanted in SCID mice that express only mouse CD40 and do not respond to the administration of the anti-human CD40. These two models have allowed us to show that tumor cells do respond to ligation with agonist CD40 and this response does contribute to limiting tumor growth. Another approach we have taken focuses on the fact that many successful cytokine-based therapies are totally dependent on the ability of the host to produce IFN-gamma, yet the administration of pure IFN-gamma protein has virtually no antitumor benefit in both mouse tumor models or human cancer patients. We have now developed mice lacking a functional IFN-gamma receptor (IFN-gammaR) that have allowed us to show that exposure of tumor growth and increase metastasis. Present studies are focused on how to preferentially stimulate IFN-gamma host responses while minimizing the ability of IFN-gamma to trigger immune-evading activities by the tumor itself. In addition, targeted disruption of other events in the tumor microenvironment may ultimately reveal new approaches for combining immunotherapy with other molecularly targeted strategies. In this regard, we have made expression vectors encoding the soluble forms of the VEGF receptors (VEGFRs), Flk-1 and Flt-1, linked to the constant region of human IgG1, and delivered these plasmids to Balb/c mice by highly efficient hydrodynamic injection, this strategy resulted in up to 0.1mg/ml of the appropriate gene products in mouse serum and successfully inhibited angiogenesis in VEGF-containing matrigel. Growth in vivo of a Balb/c mouse renal cancer was also blocked by the same treatment, particularly with soluble Flt-1. Overall, these types of complementary approaches seek to trigger several pathways through which the host can recognize or impair tumor growth, while also targeting the ability of tumor cells to enhance their own survival or inhibit antitumor host responses.
成功开发了用于癌症免疫疗法的新方法需要了解早期先天反应元素的复杂,相互依存的活动,并随后具有强大的适应性免疫反应。我们正在采用几种新颖的方法来最大程度地提高宿主安装有效抗肿瘤反应的能力。这些方法包括通过使用CD40来优化抗原表现能力,CD40是一种TNF超家族受体,可作为树突状细胞的有效触发,该树突细胞提供了先天和适应性反应之间的关键接口。当与IL-2结合使用时,激动剂CD40抗体刺激树突状细胞刺激的效力会增强,而激动剂抗CD40和IL-2的组合显示出针对小鼠转移性肾癌的抗肿瘤活性增强。由于CD40存在于各种造血细胞,内皮细胞和某些肿瘤本身上,因此我们还进行了研究,以确定确定CD40刺激和IL-2的抗肿瘤作用是否主要由CD40+造血细胞介导。我们已经开发了一种方法,只有肿瘤细胞表达功能性CD40。具体而言,我们使用的模型仅将仅对抗人CD40反应的CD40+人类肿瘤植入仅表达小鼠CD40并且不响应抗人类CD40的SCID小鼠。这两个模型使我们能够证明肿瘤细胞确实对激动剂CD40的连接响应,这种反应确实有助于限制肿瘤生长。我们采用的另一种方法集中在这样一个事实上,许多成功的基于细胞因子的疗法完全取决于宿主产生IFN-gamma的能力,但是在小鼠肿瘤模型或人类癌症患者中,纯净IFN-GAMMA蛋白的给药实际上没有抗肿瘤益处。现在,我们已经开发出缺乏功能性IFN-gamma受体(IFN-gammar)的小鼠,这些小鼠使我们能够显示出肿瘤生长的暴露并增加转移。目前的研究集中在如何优先刺激IFN-GAMMA宿主反应上,同时最大程度地降低IFN-GAMMA触发肿瘤本身触发免疫蒸发活性的能力。此外,肿瘤微环境中其他事件的有针对性破坏最终可能会揭示将免疫疗法与其他分子靶向策略相结合的新方法。 In this regard, we have made expression vectors encoding the soluble forms of the VEGF receptors (VEGFRs), Flk-1 and Flt-1, linked to the constant region of human IgG1, and delivered these plasmids to Balb/c mice by highly efficient hydrodynamic injection, this strategy resulted in up to 0.1mg/ml of the appropriate gene products in mouse serum and successfully inhibited angiogenesis in含VEGF的母质。 BALB/C小鼠肾癌的体内生长也被相同的治疗所阻断,尤其是在可溶性FLT-1的情况下。总体而言,这些类型的互补方法试图触发几种途径,宿主可以识别或损害肿瘤的生长,同时还针对肿瘤细胞增强自己的生存或抑制抗肿瘤宿主反应的能力。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Robert Wiltrout其他文献
Robert Wiltrout的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Robert Wiltrout', 18)}}的其他基金
Mechanisms of Leukocyte Migration Following Cytokine Administration to Mice
小鼠细胞因子给药后白细胞迁移的机制
- 批准号:
7965165 - 财政年份:
- 资助金额:
$ 44.44万 - 项目类别:
Immunophysiological Mechanisms in the Biological Therapy of Cancer
癌症生物治疗中的免疫生理学机制
- 批准号:
8937669 - 财政年份:
- 资助金额:
$ 44.44万 - 项目类别:
Characterization of the interaction between inflammation and cancer progression
炎症与癌症进展之间相互作用的表征
- 批准号:
8763266 - 财政年份:
- 资助金额:
$ 44.44万 - 项目类别:
Tumor models for the study of inflammation and oncogenesis
用于研究炎症和肿瘤发生的肿瘤模型
- 批准号:
8937889 - 财政年份:
- 资助金额:
$ 44.44万 - 项目类别:
Characterization of the interaction between inflammation and cancer progression
炎症与癌症进展之间相互作用的表征
- 批准号:
8349226 - 财政年份:
- 资助金额:
$ 44.44万 - 项目类别:
Tumor models for the study of inflammation and oncogenesis
用于研究炎症和肿瘤发生的肿瘤模型
- 批准号:
8349227 - 财政年份:
- 资助金额:
$ 44.44万 - 项目类别:
Immunophysiological Mechanisms in the Biological Therapy of Cancer
癌症生物治疗中的免疫生理学机制
- 批准号:
8348921 - 财政年份:
- 资助金额:
$ 44.44万 - 项目类别:
相似国自然基金
麻醉涂层伪装胶原酶细菌治疗恶性肿瘤及抑制转移的研究
- 批准号:82302377
- 批准年份:2023
- 资助金额:20 万元
- 项目类别:青年科学基金项目
武装化溶瘤病毒M1重编程IL18配体-受体相互作用实现对恶性肿瘤持久完全缓解的机制研究
- 批准号:82373285
- 批准年份:2023
- 资助金额:48 万元
- 项目类别:面上项目
截断型ASXL1蛋白相分离调控髓系恶性肿瘤发生发展的机制研究
- 批准号:82370150
- 批准年份:2023
- 资助金额:49 万元
- 项目类别:面上项目
基于神经-免疫-肿瘤类器官互作芯片的恶性肿瘤调控机制和治疗研究
- 批准号:
- 批准年份:2023
- 资助金额:130 万元
- 项目类别:
基于功能化微针-微电极的犬尿氨酸分析系统在恶性肿瘤进展、治疗监测和预后的应用研究
- 批准号:82302585
- 批准年份:2023
- 资助金额:30 万元
- 项目类别:青年科学基金项目
相似海外基金
Targeting the CCR6-CCL20 pathway for treatment of psoriatic joint and entheseal inflammation
靶向 CCR6-CCL20 通路治疗银屑病关节和附着点炎症
- 批准号:
10699251 - 财政年份:2023
- 资助金额:
$ 44.44万 - 项目类别:
A Novel Immunological-Directed Biotherapy for Treating Rheumatoid Arthritis
治疗类风湿关节炎的新型免疫导向生物疗法
- 批准号:
10760183 - 财政年份:2023
- 资助金额:
$ 44.44万 - 项目类别:
Exploiting translation elongation for improved biologics manufacturing
利用平移伸长来改进生物制品的制造
- 批准号:
10760927 - 财政年份:2023
- 资助金额:
$ 44.44万 - 项目类别:
Selective Activators of Nrf2 for Neurodegenerative Disease
Nrf2 选择性激活剂治疗神经退行性疾病
- 批准号:
10758091 - 财政年份:2023
- 资助金额:
$ 44.44万 - 项目类别:
Probing in situ higher order structures of monoclonal antibodies at water-air and water-oil interfaces via high-field nuclear magnetic resonance spectroscopy for viral infections
通过高场核磁共振波谱技术在水-空气和水-油界面原位探测单克隆抗体的高阶结构以检测病毒感染
- 批准号:
10593377 - 财政年份:2023
- 资助金额:
$ 44.44万 - 项目类别: