Survivin-DNA vaccine for active anti-tumor immunotherapy

总体目标是建立一种新的范式，即针对凋亡抑制蛋白Survivin的新型口服DNA疫苗足够强大，以促进肿瘤细胞凋亡和肿瘤相关血管生成的崩溃，从而根除肿瘤转移。我们将在神经母细胞瘤的同基因模型中建立概念证明，神经母细胞瘤是一种具有治疗挑战性的儿科肿瘤。具体目的是：第一，构建编码Survivin H-2Kk和H-2DD预测表位的新型口服DNA疫苗，并鉴定其生物学功能；第二，在同基因神经母细胞瘤小鼠模型中评价其在预防和治疗环境下防止肿瘤转移的有效性；第三，探讨基于Survivin DNA疫苗诱导的CTL应答触发抑制血管生成和诱导肿瘤细胞凋亡的免疫学机制。

The overall objective is to establish the new paradigm that novel, oral DNA vaccines against the inhibitor of apoptosis protein, survivin, are sufficiently robust to promote both tumor cell apoptosis and collapse of tumor-associated angiogenesis leading to eradication of tumor metastases. We will establish proof of concept in a syngeneic model of neuroblastoma, a therapeutically challenging pediatric tumor. The specific aims are: first, to construct a newly designed oral DNA vaccine encoding H-2Kk and H-2Dd predicted epitopes of survivin and to characterize its biological functions; second, to evaluate efficacy in a syngenic neuroblastoma mouse model to prevent dissemination of tumor metastases in a prophylactic setting and therapeutic setting; third, to investigate immunological mechanisms involved in survivin-based DNA vaccine-induced CTL responses triggering suppression of angiogenesis and induction of tumor cell apoptosis.