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
• 负责人: Robert Wiltrout
• 金额: $ 50.31万
• 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/8348921
• 关键词: Agonist; Angiogenesis Inhibitors; Antibodies; Antigens; Antitumor Response; Biological Response Modifier Therapy; Bypass; CD8B1 gene; Cell Death; Cells; Complex; Dendritic Cells; Development; Endothelial Cells; Event; FDA approved; Goals; Growth; Hematopoietic; Human; IgG1; Immune response; Immunity; Immunoglobulin Constant Region; Immunologic Receptors; Immunotherapy; Implant; Injection of therapeutic agent; Interferon Type II; Interferons; Interleukin-12; Interleukin-15; Interleukin-18; Interleukin-2; Ligation; Link; Maintenance; Malignant Neoplasms; Mediating; Memory; Modeling; Mus; Pathway interactions; Phase I Clinical Trials; Plasmids; Pre-Clinical Model; Proteins; Regulatory T-Lymphocyte; Renal carcinoma; Response Elements; SCID Mice; Serum; T cell response; T memory cell; T-Lymphocyte; TNF gene; TNFRSF5 gene; Therapeutic; Translating; Tumor Necrosis Factor Receptor; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factors; angiogenesis; antiangiogenesis therapy; cancer immunotherapy; design; expression vector; in vivo; matrigel; melanoma; member; neoplastic cell; novel strategies; response; tumor; tumor growth

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. 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.

成功开发癌症免疫治疗的新方法需要了解复杂的、相互依赖的早期先天反应元件的活动，以及随后强大的适应性免疫反应。我们正在采取几种新的方法来最大限度地提高宿主的能力，以实现有效的抗肿瘤反应。这些方法包括通过使用CD40来优化抗原提呈能力，CD40是一种肿瘤坏死因子超家族受体，可有效触发树突状细胞，在先天反应和适应性反应之间提供关键接口。当激动剂CD40抗体与IL-2联合使用时，激动剂CD40抗体刺激树突状细胞的效力增强，并且激动剂抗CD40+IL-2的组合显示出对小鼠转移性肾癌的增强的抗肿瘤活性。由于CD40存在于各种造血细胞、内皮细胞和一些肿瘤本身，我们也进行了研究，以明确CD40刺激和IL-2的抗肿瘤作用是否主要由CD40+造血细胞介导。我们已经开发出一种只有肿瘤细胞表达功能性CD40的方法；具体地说，我们使用了一些模型，其中只对抗人CD40有反应的CD40+人类肿瘤被植入只表达小鼠CD40而对给予抗人CD40没有反应的SCID小鼠。这两个模型使我们能够证明，肿瘤细胞对激动剂CD40的连接确实有反应，这种反应确实有助于限制肿瘤的生长。此外，靶向干扰肿瘤微环境中的其他事件可能最终揭示将免疫治疗与其他分子靶向策略相结合的新方法。在这方面，我们构建了编码血管内皮生长因子受体(VEGFRs)的可溶性形式Flk-1和Flt-1的表达载体，并将其连接到人IgG1的恒定区，并通过高效的流体动力注射将这些表达载体输送到Balb/c小鼠，该策略导致了小鼠血清中高达0.1 mg/ml的适当基因产物，并成功地抑制了含有VEGF的基质细胞的血管生成。Balb/c小鼠肾癌的体内生长也被同样的治疗方法阻止，特别是可溶性Flt-1。总体而言，这些类型的互补方法寻求触发几种途径，通过这些途径，宿主可以识别或损害肿瘤生长，同时也针对肿瘤细胞提高自身生存或抑制抗肿瘤宿主反应的能力。