Angiogenesis antagonist plus CD40-TLR agonist adjuvant combination vaccine

描述（由申请人提供）：白细胞早期浸润肿瘤微环境导致新生血管形成，增强肿瘤生长、转移和宿主的致死率。值得注意的是，白细胞促进肿瘤的形成，正如Virchow在1826年早期提出的，最近被其他人证实的那样（例如Manning等人，2007年clinclinca Res 13:3951； review Wasiuk/Noelle等人，2009年clineximmunol 155:140）。我们自己的初步数据（Noelle等）表明，如果干扰抑制性白细胞的早期浸润，可以大大增强宿主保护性肿瘤免疫的发展和存活。此外，根除肥大细胞可使小鼠的免疫原性肿瘤存活率从5%提高到80%以上。我们的研究评估了阻断血管生成是否可以增强抗肿瘤免疫，而不是根除肥大细胞。初步数据显示，使用功能等同于根除肥大细胞的anti-VEGFR2 Ab，同样可以提高宿主对免疫原性肿瘤的存活率。该建议的前提是，诱导对B16黑色素瘤等非免疫原性肿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免疫（CMI），以及细胞减少/化疗药物，为有效的CMI的发展提供免疫空间。

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.