ADENOVIRUS REPLICATION COMPETENT ANTICANCER VECTOR

我们构建了两种新的人类腺病毒复制能力载体，分别命名为KD1和KD3，用于治疗不同的人类癌症。这些载体杀死癌细胞，在细胞间迅速传播，对非癌细胞的影响最小。与大多数表达外源基因且不能复制的腺病毒载体不同，KD1和KD3有三个治疗原则。首先，它们表达一种蛋白质，这种蛋白质可以介导有效的细胞裂解和病毒在细胞间的传播。其次，它们含有一种突变，可以减少非分裂细胞的复制。因此，它们只能在癌细胞中很好地复制。第三，KD1和KD3应刺激炎症细胞和免疫细胞向肿瘤浸润，从而破坏局部肿瘤和已经转移的肿瘤。在Specific Aim 1中，我们提出注射KD1和KD3，并全身控制病毒，确定KD1和KD3是否引起肿瘤消退。在Aim 2中，我们将检测KD1和KD3在裸鼠体内生长的人类肿瘤中补充腺病毒复制缺陷载体传播的能力。在目标3中，我们将在KD1和KD3背景下制备组织特异性腺病毒复制能力抗癌载体，然后检测它们破坏裸鼠中生长的组织特异性肿瘤的能力。

We have constructed two novel human adenovirus replication competent vectors, named KD1 and KD3, for use in treating different human cancers. These vectors kill cancer cells, spread rapidly from cell-to-cell, and have minimal effect on non-cancerous cells, Unlike most adenovirus vectors which express a foreign gene and cannot replicate, KD1 and KD3 have three therapeutic principles. First, they express a protein that mediates efficient cell lysis and virus spread from cell-to-cell. Second, they contain a mutation that reduces replication in non-dividing cells. As a result, they only replicate well in cancer cells. Third, KD1 and KD3 should stimulate the infiltration of inflammatory and immune cells into the tumor, which would destroy the local tumor as well as tumors that have metastasized. In Specific Aim 1, we propose to inject KD1 and KD3, and also control viruses, systemically, and determine whether KD1 and KD3 cause regression of tumors. In Aim 2, we will examine KD1 and KD3 for their ability to complement the spread of adenovirus replication- defective vectors in human tumors growing in nude mice. In Aim 3, we will prepare tissue-specific adenovirus replication-competent anti-cancer vectors in a KD1 and KD3 background, then examine their ability to destroy tissue-specific tumors growing in nude mice.