Retroviral Replicating Vector-mediated Gene Therapy for Ovarian Cancer

逆转录病毒复制载体介导的卵巢癌基因治疗

基本信息

批准号：
9754592
负责人：
NORIYUKI KASAHARA
金额：
$ 51.15万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9754592
关键词：
Abdomen Address Adverse effects Alkylating Agents Antifungal Agents Antimetabolites Antineoplastic Agents Antiviral Agents Benchmarking Biodistribution Breast Canada Cancer Model Carcinomatosis Cause of Death Cells Clinic Clinical Clinical Trials Colorectal Combination Drug Therapy Cytosine deaminase DNA DNA Damage Data Development Diagnostic radiologic examination Disease Disease Resistance Down-Regulation Engineering Enzymes Escherichia coli Expression Profiling Flucytosine Fluorouracil Future Gene Expression Profiling Gene Transfer Genes Genetic Glioma Human Immune system Immunocompetent Immunodeficient Mouse Immunosuppressive Agents In Situ In Vitro Individual Injections Intravenous Intravenous infusion procedures Kidney Kinetics Lung Malignant Female Reproductive System Neoplasm Malignant Neoplasms Malignant neoplasm of ovary Measures Mediating Medical Methods Modeling Multi-Institutional Clinical Trial Mus Neoplasm Metastasis Nitroreductases Normal tissue morphology Organ PDCD1LG1 gene Pancreas Patients Peritoneal Peritoneum Phase Phase I Clinical Trials Platinum Prodrugs Recurrence Refractory Reporter Genes Resistance Route Safety Site Suicide Gene Therapy Surgically-Created Resection Cavity Testing Time Translating Treatment Efficacy Tumor Immunity Universities Virus Virus Replication Woman Xenograft Model Xenograft procedure Yeasts anti-tumor immune response base cancer cell cancer type cell killing checkpoint inhibition chemotherapy clinical application co-infection cytotoxic design effective therapy efficacy testing first-in-human fluoropyrimidine gene therapy genotoxicity human model immunogenic improved in vivo Model intraperitoneal knock-down melanoma neoantigens neoplastic cell novel novel strategies peritoneal cancer permissiveness pre-clinical preclinical study response side effect small hairpin RNA suicide gene suicide vector systemic autoimmunity systemic toxicity therapeutic gene transcriptome transduction efficiency tumor tumor DNA vector

项目摘要

Ovarian cancer is the leading cause of death in women with gynecological malignancies in the U.S., with an overall 5-year survival of <50%. Recurrences are often locoregional, involving peritoneum and abdominal organs, and especially for platinum-resistant disease which shows reduced response rates to chemotherapy, improved treatments are needed. We developed a novel strategy using retroviral replicating vectors (RRV) for highly efficient and tumor-selective delivery of prodrug activator (`suicide') genes such as cytosine deaminase (CD), and based on our preclinical findings, first-in-human multi-center clinical trials of RRV-CD suicide gene therapy delivered by local tumor site injection were initiated throughout the U.S. for recurrent high-grade glioma, and have shown highly promising signs of clinical benefit, radiographic responses, and increased survival, and a Phase IIB/III registrational trial is now on-going. Furthermore, based on our recent preclinical data showing that, even with systemic intravenous delivery, RRV is highly restricted to actively dividing tumor cells, without spread to normal tissues in immunocompetent hosts, and results in prolonged survival upon prodrug administration without systemic side effects, FDA recently approved a new clinical trial for intravenous delivery of RRV. Now that there is clinical precedent, it is timely to consider applying systemically or locoregionally administered RRV also to systemic malignancies such as ovarian cancer. Accordingly, here we propose the first preclinical studies to evaluate the feasibility, safety, and efficacy of RRV-mediated suicide gene therapy for treatment-refractory recurrent ovarian cancer. At the cellular level, we will perform gene expression profiling to evaluate whether primary patient-derived ovarian cancer cells express candidate anti-viral restriction factors that might impact future clinical application of this strategy, and empirically test whether RRV replication and suicide gene activity in ovarian cancer cells correlates with gene expression profiling results, using RRV pseudotyped with different envelopes to enable co-infection (Aim 1). Metastatic ovarian cancer will necessitate widespread vector delivery via intravenous or intraperitoneal administration, and both routes will be evaluated for transduction efficiency and biodistribution/safety in ovarian cancer peritoneal carcinomatosis models, using human xenografts in immunodeficient mice and syngeneic models in immunocompetent mice (Aim 2). Next, we will evaluate suicide gene therapy with both the clinical RRV-CD (Toca 511) vector and a newly developed RRV encoding bacterial nitroreductase (NTR), which generates a pro-immunogenic alkylating agent within infected cancer cells, individually and in combination (Aim 3). As tumor-localized prodrug conversion by RRV destroys immunosuppressive tumor stroma, while incurring minimal systemic myelotoxicity and maintaining an intact immune system, we will also test the efficacy of pro-immunogenic RRV suicide gene therapy combined with genetic immune checkpoint inhibition. If the currently proposed preclinical studies prove successful, these approaches could be rapidly translated to the clinic for treatment-refractory advanced ovarian cancer.

卵巢癌是美国妇科恶性肿瘤女性死亡的主要原因，总体 5 年生存率 <50%。复发通常是局部区域的，涉及腹膜和腹部器官，特别是对铂类耐药的疾病，其对化疗的反应率降低，需要改进的治疗方法。我们开发了一种使用逆转录病毒复制载体（RRV）的新策略高效且肿瘤选择性地递送前药激活剂（“自杀”）基因，例如胞嘧啶脱氨酶 (CD)，并基于我们的临床前发现，RRV-CD自杀基因的首次人体多中心临床试验美国各地开始采用局部肿瘤部位注射治疗复发性高级别神经胶质瘤，并显示出非常有希望的临床效益、放射学反应和增加生存率的迹象，并且 IIB/III 期注册试验正在进行中。此外，根据我们最近的临床前数据显示即使采用全身静脉注射，RRV 也高度限制于活跃分裂的肿瘤细胞，而无需扩散到免疫功能正常宿主的正常组织，并导致前药存活时间延长给药无全身副作用，FDA最近批准了一项新的静脉给药临床试验的RRV。既然已有临床先例，是时候考虑全身或局部应用了 RRV 也可用于治疗卵巢癌等全身恶性肿瘤。据此，我们在此提出首次临床前研究评估 RRV 介导的自杀基因治疗的可行性、安全性和有效性治疗难治性复发性卵巢癌。在细胞水平上，我们将进行基因表达谱分析评估原发性患者来源的卵巢癌细胞是否表达候选抗病毒限制因子这可能会影响该策略未来的临床应用，并实证检验 RRV 复制和使用 RRV 将卵巢癌细胞中的自杀基因活性与基因表达谱结果相关联使用不同的包膜进行假型化以实现共同感染（目标 1）。转移性卵巢癌需要通过静脉内或腹膜内给药进行广泛的载体递送，两种途径都将进行评估对于卵巢癌腹膜癌病模型中的转导效率和生物分布/安全性，使用免疫缺陷小鼠中的人类异种移植物和免疫功能正常小鼠中的同基因模型（目标 2）。下一个，我们将使用临床 RRV-CD (Toca 511) 载体和新开发的自杀基因疗法来评估自杀基因疗法 RRV 编码细菌硝基还原酶 (NTR)，可在内部产生促免疫原性烷化剂单独或联合感染癌细胞（目标 3）。作为 RRV 的肿瘤局部前药转化破坏免疫抑制性肿瘤基质，同时引起最小的全身性骨髓毒性并维持完整的免疫系统，我们还将测试促免疫原性 RRV 自杀基因疗法联合治疗的疗效具有遗传免疫检查点抑制作用。如果目前提出的临床前研究证明是成功的，这些这些方法可以迅速转化为临床治疗难治性晚期卵巢癌。