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

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

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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妇女死亡的主要原因，总体5年生存率<50％。复发通常是区域性的，涉及腹膜和腹部器官，尤其是抗铂疾病的器官，该疾病显示对化学疗法的反应率降低，需要改进的治疗方法。我们使用逆转录病毒复制向量（RRV）制定了一种新颖的策略前药激活剂（自杀'）基因（例如胞嘧啶脱氨酶）的高效和肿瘤选择性递送（CD），并基于我们的临床前发现，RRV-CD自杀基因的首次人类多中心临床试验在美国各地启动了当地肿瘤部位注射的治疗并显示出高度有希望的临床益处，放射学反应和增加生存的迹象，并且 IIB/III期注册试验现在正在进行中。此外，根据我们最近显示的临床前数据即使是全身静脉输送，RRV也高度限于主动分裂肿瘤细胞，而无需传播到免疫能力宿主中的正常组织，并在前药时长期生存 FDA没有系统性副作用，最近批准了一项静脉输送的新临床试验 RRV。现在已经有临床先例了，及时考虑在系统上或局部使用也为卵巢癌等系统性恶性肿瘤提供了RRV。因此，在这里我们提出了首先评估RRV介导的自杀基因治疗的可行性，安全性和功效的首次临床前研究治疗难治性复发性卵巢癌。在细胞水平，我们将执行基因表达分析评估原发性患者衍生的卵巢癌细胞是否表达候选抗病毒限制因素这可能会影响此策略的未来临床应用，并经验测试RRV复制和是否是否使用RRV 用不同的信封进行假型，以启用共同感染（AIM 1）。转移性卵巢癌将需要通过静脉内或腹膜内给药的广泛矢量输送，将评估这两种途径用于卵巢癌腹膜癌模型的转导效率和生物分布/安全性，使用免疫能力小鼠中免疫缺陷小鼠和同性模型中的人异种移植物（AIM 2）。下一个，我们将使用临床RRV-CD（TOCA 511）和新开发的自杀基因治疗评估自杀基因治疗编码细菌硝酸还原酶（NTR）的RRV，该硝酸还原酶（NTR）在内部产生促烷基化剂单独和组合感染的癌细胞（AIM 3）。作为RRV的肿瘤 - 定位前药转换破坏免疫抑制性肿瘤基质，同时产生最小的全身性骨髓毒性并保持完整的免疫系统，我们还将测试促进免疫原性自杀基因疗法的疗效具有遗传免疫检查点抑制。如果当前提出的临床前研究证明了成功，则可以将方法迅速转化为诊所，以治疗难治性晚期卵巢癌。