Neural Progenitor Cells as Cancer Therapy Vectors

描述（由申请人提供）：几乎无一例外，局部肿瘤患者的预后优于转移性肿瘤患者。我们研究的长期目标是为转移性实体瘤开发安全、有效、全身的治疗方法。本应用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选择性地传递到转移性肿瘤位点。我们打算确定静脉注射NPCs的致瘤性是否可以被利用来选择性地将编码cpt -11激活酶的cDNA传递到转移性肿瘤部位。我们将评估转移性神经母细胞瘤（NB）小鼠随后给予CPT-11是否会根除微转移性疾病。初步和已发表的数据表明，在小鼠模型中，无论肿瘤的解剖位置如何，尾静脉注射给予的npc都可以迁移到肿瘤位点。初步数据还显示，用复制缺陷腺病毒编码cpt -11激活酶兔羧酸酯酶（rCE）转导的npc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npc可能在肿瘤位点产生足以根除残留疾病的SN-38水平，但将毒性降到最低。药效和毒性研究将在酯酶缺乏的Es1e/SCID小鼠中进行，小鼠携带弥散性NB。初步数据显示NPCs会向转移性NB肿瘤转移，临床试验表明CPT-11具有治疗NB的潜力。本研究旨在证明npc定向酶前药物治疗（NDEPT）与rCE和CPT-11治疗NB的疗效。然而，临床前数据表明，npc也会迁移到几种实体肿瘤的基因座，如胶质母细胞瘤和乳腺癌。因此，生成的数据也可以为更一般的假设提供原理证明，即npc可以用作治疗性cdna的有效肿瘤特异性传递载体。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.