Cancer dual-targeting of an infectivity-enhance CRAd

增强感染性的 CRAd 的癌症双重靶向

• 批准号: 7537705
• 负责人: J. Michael Mathis
• 金额: $ 41.25万
• 依托单位: VECTORLOGICS, INC.
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7537705
• 关键词: 5' Untranslated Regions; A549; Adenovirus Vector; Adenoviruses; Advanced Malignant Neoplasm; Affinity; Animal Model; Biodistribution; Biological; Biological Models; Biology; Breast; CAR receptor; CXCR4 gene; Cancer Control; Cell Line; Cells; Class; Clinical; Clinical Trials; Condition; Cyclic GMP; Cytolysis; Development; Disease; Elements; Fiber; Fibroblast Growth Factor 2; Figs - dietary; Gene Expression; Genes; Genetic; Genetic Transcription; Genetic Translation; Glioma; Goals; Head and Neck Squamous Cell Carcinoma; Hereditary Disease; Human; Immunologics; In Vitro; Indium; Infection; Intervention; Knowledge; Lead; Lesion; Liver; Malignant Neoplasms; Mammary Gland Parenchyma; Marketing; Mediating; Messenger RNA; Methods; Modeling; Modification; Molecular; Mus; Neoplastic Cell Transformation; Normal Cell; Normal tissue morphology; Numbers; ONYX-015; Oncolytic; Operative Surgical Procedures; Organ; Ovarian; Patients; Phase; Phase I Clinical Trials; Public Health; RGD (sequence); Radiation; Refractory; Regulation; Relative (related person); Resistance; Series; Serotyping; Slice; Solid Neoplasm; Specificity; Standards of Weights and Measures; System; Technology; Testing; Therapeutic; Therapeutic Clinical Trial; Therapeutic Index; Tissues; Toxic effect; Toxicology; Transcriptional Regulation; Transduction Gene; Translation Initiation; Translational Regulation; Treatment Protocols; Tumor Tissue; United States Food and Drug Administration; Untranslated Regions; Viral; Viral Genome; Virus; base; cancer cell; cancer therapy; cell killing; cell type; cellular transduction; chemotherapy; conditionally replicative adenovirus; design; gene therapy; improved; in vivo; killings; malignant breast neoplasm; neoplastic; neoplastic cell; novel; oncolysis; pre-clinical; promoter; research and development; research study; three dimensional structure; transduction efficiency; tumor; vector

DESCRIPTION (provided by applicant): Studies of the molecular mechanisms underlying neoplastic transformation and progression have resulted in the understanding that cancer is a genetic disease, deriving from the accumulation of a series of acquired genetic lesions. Despite advances in chemotherapy, radiation delivery, and surgical treatment regimens, survival from many advanced cancers remains poor, and it is apparent that alternative treatment approaches are necessary. Gene therapy/virotherapy is a promising strategy for the treatment of cancer. Although attempted in the past and abandoned because of toxicity and inefficacy, the virotherapy approach has reemerged with great promise, in large part due to better understanding of virus biology and the ability to genetically modify viruses. With this knowledge, we can now design viruses to better replicate in and specifically kill tumor cells. Using conditionally replicative adenoviruses (CRAds) represent a method to achieve efficient tumor cell oncolysis and mitigate tumor cell infection limitations. Ideally, cancer-specific replication of CRAds would result in viral-mediated oncolysis of infected tumor tissues and release of the virus progeny, capable of further propagating in surrounding tumor cells but not in those of normal tissues, which would be refractory to CRAd replication. In our Phase I study, we exploited a novel cancer-specific control of mRNA translation initiation in order to achieve enhanced replicative specificity of a CRAd virotherapy agent. In contrast, control of mRNA translation has not been exploited for the design of tumor specific replicating viruses to date. The technical and scientific merit and feasibility of this approach that combines both transcriptional and translational regulation strategies for the key goal of CRAd replicative specificity has now been established. Our Phase I in vitro and in vivo studies demonstrated strong proof-of-principle that this CRAd agent, utilizing a heterologous mRNA translational control element, retains anti-tumor potency. The objective of this Phase II application is to continue the R&D efforts initiated in Phase I by optimizing the CRAd virotherapy agent with enhanced tumor infectivity. Relative resistance of tumor tissues to adenovirus serotype 5 (Ad5) infections has been noted in a number of in vivo gene therapy trials. Deficiency of the primary Ad receptor CAR, is understood to be the biologic basis of this phenomenon. The inclusion of a high affinity Arg-Gly-Asp (RGD) motif into the HI loop of the Ad5 fiber knob has been shown to overcome low CAR expression on tumor cells, thereby enhancing transduction. In Specific Aim 1, cancer cell transduction of the CRAd virotherapy agent will be enhanced by inserting an RGD motif. In Specific Aim 2, in vivo experiments will be conducted to evaluate the biological efficacy and establish specific treatment protocols in animal models of loco-regional and disseminated disease. Finally, in Specific Aim 3, biodistribution and toxicology studies required for IND submission to the FDA will be performed. Successful completion of this Phase II application will lead directly to clinical investigation of the modified CRAd agent (CXCR4-5'-UTR-RGD CRAd) in patients with disseminated disease. PUBLIC HEALTH RELEVANCE: Despite many advances in standard treatment regimens, survival from many advanced cancers remains poor, and it is apparent that new alternative treatment approaches are necessary. Using viruses designed to divide in and specifically kill tumor cells has become a promising approach to better understanding of virus biology and the ability to genetically modify viruses. The objective of this application is to further develop a conditionally replicative adenovirus (CRAd) that has been designed to infect, divide and lyse efficiently in tumor cells but not in normal cells; successful completion.

描述（由申请人提供）：对肿瘤转化和进展的分子机制的研究使人们认识到癌症是一种遗传性疾病，源自一系列获得性遗传病变的积累。尽管化疗、放射治疗和手术治疗方案取得了进步，但许多晚期癌症的生存率仍然很低，显然需要替代治疗方法。基因疗法/病毒疗法是治疗癌症的一种有前途的策略。尽管过去曾尝试过，但因毒性和无效而被放弃，但病毒疗法已经重新出现，前景广阔，这在很大程度上是由于对病毒生物学的更好理解和对病毒进行基因改造的能力。有了这些知识，我们现在可以设计病毒来更好地在肿瘤细胞中复制并特异性杀死肿瘤细胞。使用条件复制腺病毒（CRAd）代表了一种实现有效肿瘤细胞溶瘤并减轻肿瘤细胞感染限制的方法。理想情况下，CRAd 的癌症特异性复制将导致病毒介导的受感染肿瘤组织的溶瘤作用，并释放病毒子代，这些子代病毒能够在周围的肿瘤细胞中进一步传播，但不能在正常组织中传播，因为正常组织对 CRAd 复制是难以抵抗的。在我们的 I 期研究中，我们利用了一种新型的癌症特异性 mRNA 翻译起始控制，以增强 CRAd 病毒治疗剂的复制特异性。相比之下，迄今为止，mRNA 翻译的控制尚未被用于设计肿瘤特异性复制病毒。这种结合转录和翻译调控策略以实现 CRAd 复制特异性关键目标的方法的技术和科学优点和可行性现已确立。我们的 I 期体外和体内研究证明，这种 CRAd 药物利用异源 mRNA 翻译控制元件，保留了抗肿瘤效力。该二期申请的目的是通过优化具有增强肿瘤感染性的 CRAd 病毒治疗剂来继续一期启动的研发工作。许多体内基因治疗试验已注意到肿瘤组织对腺病毒血清型 5 (Ad5) 感染的相对抵抗力。主要 Ad 受体 CAR 的缺陷被认为是这种现象的生物学基础。 Ad5 纤维旋钮的 HI 环中包含高亲和力的 Arg-Gly-Asp (RGD) 基序已被证明可以克服肿瘤细胞上的低 CAR 表达，从而增强转导。在具体目标 1 中，CRAd 病毒治疗剂的癌细胞转导将通过插入 RGD 基序得到增强。在具体目标2中，将进行体内实验以评估生物学功效并在局部和播散性疾病的动物模型中建立具体的治疗方案。最后，在具体目标 3 中，将进行向 FDA 提交 IND 所需的生物分布和毒理学研究。该II期申请的成功完成将直接导致改良CRAd药物（CXCR4-5'-UTR-RGD CRAd）在播散性疾病患者中的临床研究。公共卫生相关性：尽管标准治疗方案取得了许多进展，但许多晚期癌症的生存率仍然很低，显然需要新的替代治疗方法。使用旨在分裂并特异性杀死肿瘤细胞的病毒已成为更好地了解病毒生物学和基因改造病毒能力的一种有前途的方法。本申请的目的是进一步开发一种条件复制腺病毒（CRAd），该病毒旨在在肿瘤细胞中有效感染、分裂和裂解，但在正常细胞中则不然；成功完成。