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: 8157221
• 负责人: Robert Wiltrout
• 金额: $ 44.44万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8157221
• 关键词: Biological Response Modifier Therapy; Malignant Neoplasms; Biological Response Modifier Therapy; Malignant Neoplasms

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。