Neural Progenitor Cells as Cancer Therapy Vectors

描述（申请人提供）：几乎无一例外地，局部肿瘤患者的预后比转移性疾病患者更好。我们研究的长期目标是为转移性实体瘤开发安全，有效，系统的治疗方法。本申请中描述的方法的基础是使用神经祖细胞（NPC）将编码治疗性转基因的cDNA选择性地递送至转移性肿瘤位点。我们建议，以确定是否可以利用静脉注射的NPC的肿瘤嗜性提供编码CPT-11激活酶的cDNA选择性转移肿瘤部位。我们将评估CPT-11对转移性神经母细胞瘤（NB）小鼠的后续给药是否会根除微转移性疾病。初步和公开的数据显示，通过尾静脉注射给予的NPC迁移到肿瘤位点，而不管小鼠模型中肿瘤的解剖位置如何。初步数据还显示，用编码CPT-11激活酶兔羧酸酯酶（rCE）的复制缺陷型腺病毒转导的NPC表达的CE活性水平比人正常细胞或肿瘤细胞高1000倍。这些数据支持以下假设：静脉内给予编码rCE和CPT-11的NPC可能在肿瘤位点产生足以根除残留疾病的SN-38水平，但使毒性最小化。将使用携带播散性NB的酯酶缺陷型Es 1 e/SCID小鼠进行疗效和毒性研究。初步数据显示NPC迁移到转移性NB肿瘤，临床试验表明CPT-11具有治疗NB的潜力。本研究旨在证明与rCE和CPT-11联合使用NPC导向酶前体药物治疗（NDEPT）治疗NB的疗效相关的原则证据。然而，临床前数据证明，NPC也迁移到几种类型的实体瘤，如胶质母细胞瘤和乳腺癌的位点。因此，所产生的数据也可以为NPC可以用作治疗性cDNA的有效肿瘤特异性递送载体的更一般的假设提供原理证明。然后，通过仔细选择适当的治疗性转基因，所描述的方法可能适用于其他实体瘤的治疗。

DESCRIPTION (provided by applicant): Almost without exception, patients with localized tumors have better prognoses than patients with metastatic disease. The long-range goal of our studies is to develop safe, effective, systemic treatments for metastatic solid tumors. The basis of the approach described in this application is the use of neural progenitor cells (NPCs) to deliver cDNAs encoding therapeutic transgenes selectively to metastatic tumor loci. We propose to determine whether the tumor-tropic property of intravenously injected NPCs can be exploited to deliver the cDNA encoding a CPT-11-activating enzyme selectively to metastatic tumor sites. We will evaluate whether subsequent administration of CPT-11 to mice with metastatic neuroblastoma (NB) will eradicate micrometastatic disease. Preliminary and published data show that NPCs given by tail vein injection migrate to tumor loci regardless of the anatomic location of the tumors in mouse models. Preliminary data also show that NPCs transduced with replication-defective adenovirus encoding the CPT-11-activating enzyme rabbit carboxylesterase (rCE) express up to 1000-fold higher levels of CE activity than do human normal or tumor cells. The data support the hypothesis that intravenous administration of NPCs encoding rCE and CPT-11 may produce levels of SN-38 at tumor loci sufficient to eradicate residual disease, but minimize toxicity. Efficacy and toxicity studies will be done using esterase-deficient Es1e/SCID mice bearing disseminated NB. Preliminary Data show that NPCs migrate to metastatic NB tumors, and clinical trials indicate that CPT-11 has potential for the treatment of NB. This study is intended to show proof of principle specifically regarding the efficacy of NPC-directed enzyme prodrug therapy (NDEPT) with rCE and CPT-11 for NB. However, preclinical data document that NPCs also migrate to loci of several types of solid tumors such as glioblastoma and breast cancer. Therefore, the data generated may also provide proof of principle for the more general hypothesis that NPCs can be used as effective tumor-specific delivery vectors for therapeutic cDNAs. The described approach might then be adapted to the treatment of other solid tumors by careful choice of appropriate therapeutic transgenes.