Neural Progenitor Cells as Cancer Therapy Vectors

描述(申请人提供)：几乎无一例外，局部肿瘤患者的预后好于转移性疾病患者。我们研究的长期目标是开发安全、有效、系统的转移性实体肿瘤治疗方法。本申请中所描述的方法的基础是使用神经前体细胞(NPC)选择性地将编码治疗性转基因的cDNA递送到转移的肿瘤部位。我们建议确定是否可以利用静脉注射的鼻咽癌细胞的亲肿瘤特性来选择性地将编码CPT-11激活酶的cDNA运送到转移的肿瘤部位。我们将评估随后给予转移性神经母细胞瘤(NB)小鼠的CPT-11是否会根除微转移疾病。初步和已发表的数据表明，在小鼠模型中，尾静脉注射给药的神经前体细胞迁移到肿瘤部位，而与肿瘤的解剖位置无关。初步数据还显示，转导复制缺陷型腺病毒编码CPT-11激活酶兔羧酸酯酶(RCE)的NC表达的CE活性水平比人类正常细胞或肿瘤细胞高1000倍。这些数据支持这样的假设，即静脉注射编码RCE和CPT-11的鼻咽癌细胞可能在肿瘤部位产生足以根除残留疾病的SN-38水平，但将毒性降至最低。疗效和毒性研究将用酯酶缺陷的Es1e/SCID小鼠进行，这些小鼠携带播散性NB。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。这项研究的目的是提供关于鼻咽癌导向的酶前药疗法(NDEPT)与RCE和CPT-11联合治疗NB的疗效的原则证据。然而，临床前数据表明，鼻咽癌细胞也迁移到几种类型的实体肿瘤，如胶质母细胞瘤和乳腺癌。因此，所产生的数据也可能为更普遍的假设提供原则性证据，即鼻咽癌细胞可以用作治疗性DNA的有效的肿瘤特异性递送载体。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肿瘤的治疗。

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.