Angiogenesis antagonist plus CD40-TLR agonist adjuvant combination vaccine

描述（由申请方提供）：白细胞早期浸润到肿瘤微环境中导致新生血管形成、增强的肿瘤生长、转移和宿主致死。值得注意的是，白细胞使肿瘤能够建立，如Virchow在1826年早期提出的和最近由其他人证明的（例如Manning等，2007 Clin Ca Res 13：3951;综述Wasiuk/Noelle等，2009 Clin Exp Immunol 155：140）。我们自己的初步数据（Noelle等人）显示如果干扰抑制性白细胞的早期浸润，则可以大大增强保护性肿瘤免疫的发展和宿主的存活。此外，根除肥大细胞使免疫原性肿瘤小鼠的存活率从5%增加到80%以上。代替根除肥大细胞，我们的研究评估了是否可以通过阻断血管生成来增强抗肿瘤免疫。初步数据显示，使用抗VEGFR 2 Ab（其在功能上等同于根除肥大细胞）可类似地增加宿主对免疫原性肿瘤的存活。该提议的前提是，诱导对非免疫原性肿瘤如B16黑色素瘤的免疫的肿瘤疫苗需要抗血管生成/肥大细胞方法以确保肿瘤部位抑制性白细胞不会抑制原本高效的肿瘤特异性细胞介导的免疫（CMI），以及细胞减少/化疗剂以提供有效CMI发展的免疫学空间。 虽然大多数抗血管生成的研究直接集中在肿瘤部位的血管，研究人员已经开始评估阻断血管生成对宿主对肿瘤的反应的影响。基于我们的研究和已发表的研究，我们假设抗血管生成因子将极大地增强我们的肿瘤疫苗的功效，以引发上级保护性的、获得性的、肿瘤特异性细胞介导的免疫。在目标1中，我们建议使用我们在开发黑色素瘤疫苗方面的经验，为联合疫苗提供概念验证，该联合疫苗1）使用我们专有的CD 40/TLR激动剂佐剂疫苗，相对于其他人目前使用的疫苗技术，诱导针对肿瘤的上级CMI，2）在几种其他肿瘤模型中广泛消除血管生成/肥大细胞诱导的CMI抑制。此外，在目标2中，细胞减灭/化疗方法在临床上显示出一定的有效性，将与该方法重叠，以测试额外的疗效。 公共卫生相关性：该提议的前提是，诱导对免疫原性差或非免疫原性肿瘤（如B16黑色素瘤）的免疫的肿瘤疫苗需要抗血管生成/肥大细胞方法加上细胞减少性化疗，以确保肿瘤部位不会抑制原本高效的抗肿瘤白细胞。根据我们的初步结果，这里的方法是开发一种联合治疗，使用我们专有的抗CD 40/TLR佐剂疫苗与血管生成因子VEGFR 2的阻断性抗体以及细胞减少性化疗药物环磷酰胺。我们预测，我们可以提高对一系列难以治疗的肿瘤状态的抗肿瘤免疫力。

DESCRIPTION (provided by applicant): The early infiltration by leukocytes into the tumor microenvironment leads to neovascularization, enhanced tumor growth, metastasis and lethality of the host. Notably, leukocytes enable tumor establishment, as suggested early on by Virchow in 1826 and proven more recently by others (e.g. Manning et al, 2007 Clin Ca Res 13:3951; review Wasiuk/Noelle et al. 2009 Clin Exp Immunol 155:140). Our own preliminary data (Noelle et al.) show that if one interferes with the early infiltration of inhibitory leukocytes, one can greatly enhance the development of protective tumor immunity and survival of the host. Further, eradicating mast cells increases survival from 5% to over 80% of mice to immunogenic tumors. In lieu of eradicating mast cells, our studies have evaluated if anti-tumor immunity can be enhanced by blocking angiogenesis. The preliminary data show that the use of anti-VEGFR2 Ab, which is functionally equivalent to the eradication of mast cells, can similarly increase survival of the host to immunogenic tumors. The premise of this proposal is that tumor vaccines that induce immunity to a non-immunogenic tumor like B16 melanoma, require an anti-angiogenic/mast cell approach to ensure that tumor site inhibitory leukocytes do not inhibit otherwise highly effective tumor-specific cell mediated immunity (CMI), as well as a cytoreduction/chemotherapeutic agent to provide immunologic space for effective CMI to develop. While most anti-angiogenesis studies focus directly on tumor site vasculature, investigators have begun to evaluate the impact of blocking angiogenesis on host responses to tumors. Based on our studies and those published, we hypothesize that anti-angiogenic factors will greatly enhance the efficacy of our tumor vaccine to elicit superior protective, acquired, tumor-specific cell-mediated immunity. In Aim 1 we propose to use our experience in developing melanoma vaccines to provide proof-of-concept for a combination vaccine that 1) uses our proprietary CD40/TLR agonist adjuvant vaccine to induce superior CMI against tumors relative to vaccine technologies currently used by others, and 2) broadly abrogates angiogenesis/mast cell-induced inhibition of CMI across several additional tumor models. Furthermore, in Aim 2, cytoreductive/chemotherapy methods, shown to be somewhat effective in the clinic, will be overlaid on this approach to test for additional efficacy. PUBLIC HEALTH RELEVANCE: The premise of this proposal is that tumor vaccines that induce immunity to poorly or non-immunogenic tumors like B16 melanoma, require an anti-angiogenic/mast cell approach plus cytoreductive chemotherapy to ensure that the tumor site does not inhibit otherwise highly effective anti-tumor leukocytes. The approach here, based on our preliminary results, is to develop a combination therapy using our proprietary anti-CD40/TLR adjuvant vaccine combined with blocking Ab to the angiogenesis factor VEGFR2 as well as the cytoreductive chemotherapeutic Cytoxan. We predict that we can improve anti-tumor immunity against a range of otherwise hard-to-treat tumor states.