靶向FGFR1增强型体内DC疫苗抗肿瘤血管生成研究

Recent studies have found that immunotherapy with programmed cell death protein 1(PD1) could rescue exhausted T lymphocyte and enhances anti-cancer immunity, and induce very durable immunity responses. MIP3α, the most important specific chemokine, can effectively improve the antigens presenting ability of dendritic cells (DC). We have previously proved that immunotherapy targeting FGFR1-mediated angiogenesis has obvious anti-tumor effect, and found that the oncolytic virus recombinant herpes simplex virus type 1 (HSV1)-MIP3α not only retains the oncolytic properties of HSV1, but also carries the information of MIP3α. On the basis of previous work, We propose here to use the virus recombinant transfected with MIP3α/PD1 antibody, along with FGFR1 aptamer (aFR1) encapsulated by nanoliposome and produce a final complex product “aFR1/HSV1-MIP3α-PD1” bioreactor. This bioreactor will generate high concentrated MIP3α combined with PD1 at the targeted tumor tissue and possess muti-functions inducing tumor-cell lysis (HSV1),enhanced the immune effect (MIP3) and eliminated the immunosuppressive effect of T lymphocyte (PD1 antibody),and the aFR1 can also inhibit angiogenesis targeting FGFR1 in tumor, which will greatly enhance specifically targeted killing effect on tumor cells and/or tumor angiogenesis. Accordingly, the "aFR1/HSV1-MIP3α-PD1"bioreacctor is very likely a promising vaccine with in vivo DC characteristics, and we will investigate the mechanism by in vivo and in vitro approach to explore a new strategy of tumor biotherapy.

现已证实针对程序性细胞死亡蛋白1（PD1）的免疫治疗能有效清除免疫抑制、诱发持久性免疫应答。MIP3α是树突状细胞（DC）特异性趋化因子，能有效提高DC递呈抗原能力。前期我们证实靶向FGFR1免疫治疗具有显著抗肿瘤效果（Eur J Cancer，封面文章），还发现重组溶瘤病毒（HSV1-MIP3α）既保留了HSV1溶瘤特性，还携带有MIP3α信息。在此基础上，拟将FGFR1适配体(aFR1)与共表达MIP3α/PD1抗体的病毒重组子用纳米脂质体包裹偶联成“aFR1/HSV1-MIP3α-PD1”生物反应器进行体内外试验，该反应器兼具靶向和抗肿瘤血管生成双功能（aFR1）、溶瘤（HSV1）、促免疫效应（MIP3α）、消除免疫抑制作用（PD1抗体）等多重功效，将大大增强它们对肿瘤细胞和/或肿瘤新生血管特异性靶向杀伤作用，极有可能是一种简单而有效的体内DC疫苗模式，将为肿瘤生物治疗提供新思路。

本研究成功制备了一种复方生物反应器aFR1/HSV1-MIP3α-PD1（简称aFHMPD1）并在体内外进行抗肿瘤作用观察。研究发现，aFHMPD1复方生物反应器能够明显抑制肿瘤生长，提高抗肿瘤免疫效应。该生物反应器不仅具有良好的肿瘤组织特异性和血管靶向性，能够靶向抑制肿瘤血管生成作用；还具有较好体内DC趋化募集、一定程度的免疫抑制消除和溶瘤作用。此外，增加了Fc融合蛋白FGFR1-PD1、FGFR1-MIP3α和FGFR1-MIP3α-PD1抗肿瘤作用系列研究，发现其不仅具有良好肿瘤组织特异性和血管靶向性，而且可以抑制肿瘤血管生成、消除免疫抑制，并趋化募集DC到达肿瘤部位进而发挥多重抗肿瘤功效，上述成果将为靶向FGFR1肿瘤生物治疗提供新的策略。