PDF(Pubmed)
Abstract：
BACKGROUND: The intravesical gene therapy nadofaragene firadenovec (rAd-IFNα/Syn3) was FDA approved in 2022 for non-muscle invasive bladder cancer (NMIBC) unresponsive to frontline treatment with BCG, and the first gene therapy developed for bladder cancer. This non-replicating recombinant adenovirus vector delivers a copy of the human interferon alpha-2b gene into urothelial and tumor cells, causing them to express this pleotropic cytokine with potent antitumor effects.
OBJECTIVE: To provide a historical overview describing how several decades of preclinical and clinical studies investigating the role of interferon in the treatment of bladder cancer ultimately led to the development of gene therapy with nadofaragene for NMIBC.
METHODS: We conducted a review of the literature using PubMed, Google Scholar, and ClinicalTrials.gov to summarize our knowledge of the evolution of interferon-based therapy in NMIBC.
RESULTS: The FDA approval of this therapy represents an important landmark in urologic oncology and several decades of research dedicated to the study of interferon\'s direct and indirect antitumor properties in NMIBC. The data gathered from the phase 1, 2, and 3 clinical trials continue to provide additional insights into the precise mechanisms underlying both the efficacy of and resistance to nadofaragene.
CONCLUSIONS: Nadofaragene leverages the cytotoxic, anti-angiogenic, and immune-modulatory roles of interferon to effectively treat NMIBC that is resistant to BCG. Ongoing studies of resistance mechanisms and prognostic biomarkers have been promising; these will ultimately improve patient selection and allow for the modulation of factors in the tumor or immune microenvironment to further increase therapeutic response.
OBJECTIVE: To provide a historical overview describing how several decades of preclinical and clinical studies investigating the role of interferon in the treatment of bladder cancer ultimately led to the development of gene therapy with nadofaragene for NMIBC.
METHODS: We conducted a review of the literature using PubMed, Google Scholar, and ClinicalTrials.gov to summarize our knowledge of the evolution of interferon-based therapy in NMIBC.
RESULTS: The FDA approval of this therapy represents an important landmark in urologic oncology and several decades of research dedicated to the study of interferon\'s direct and indirect antitumor properties in NMIBC. The data gathered from the phase 1, 2, and 3 clinical trials continue to provide additional insights into the precise mechanisms underlying both the efficacy of and resistance to nadofaragene.
CONCLUSIONS: Nadofaragene leverages the cytotoxic, anti-angiogenic, and immune-modulatory roles of interferon to effectively treat NMIBC that is resistant to BCG. Ongoing studies of resistance mechanisms and prognostic biomarkers have been promising; these will ultimately improve patient selection and allow for the modulation of factors in the tumor or immune microenvironment to further increase therapeutic response.
摘要：
背景：FDA于2022年批准了膀胱内基因治疗nadofaragenefiradenovec（rAd-IFNα/Syn3），用于对BCG一线治疗无反应的非肌肉浸润性膀胱癌（NMIBC），和第一个基因疗法开发的膀胱癌。这种非复制型重组腺病毒载体将人干扰素α-2b基因的拷贝传递到尿路上皮和肿瘤细胞中，使它们表达这种具有强效抗肿瘤作用的多功能细胞因子。
目的：提供一个历史概述，描述几十年来研究干扰素在膀胱癌治疗中的作用的临床前和临床研究如何最终导致纳多芬拉因基因治疗NMIBC的发展。
方法：我们使用PubMed对文献进行了综述，谷歌学者，和ClinicalTrials.gov总结了我们对NMIBC中基于干扰素的治疗发展的认识。
结果：FDA对该疗法的批准代表了泌尿外科肿瘤学的重要里程碑，也是数十年致力于研究干扰素在NMIBC中的直接和间接抗肿瘤特性的研究。从1、2和3期临床试验中收集的数据继续为纳多芬的疗效和耐药性的确切机制提供了更多的见解。
结论：Nadofaragene利用细胞毒性，抗血管生成，和干扰素的免疫调节作用，以有效治疗对卡介苗耐药的NMIBC。抗性机制和预后生物标志物的持续研究是有希望的;这些将最终改善患者选择并允许调节肿瘤或免疫微环境中的因子以进一步增加治疗反应。
目的：提供一个历史概述，描述几十年来研究干扰素在膀胱癌治疗中的作用的临床前和临床研究如何最终导致纳多芬拉因基因治疗NMIBC的发展。
方法：我们使用PubMed对文献进行了综述，谷歌学者，和ClinicalTrials.gov总结了我们对NMIBC中基于干扰素的治疗发展的认识。
结果：FDA对该疗法的批准代表了泌尿外科肿瘤学的重要里程碑，也是数十年致力于研究干扰素在NMIBC中的直接和间接抗肿瘤特性的研究。从1、2和3期临床试验中收集的数据继续为纳多芬的疗效和耐药性的确切机制提供了更多的见解。
结论：Nadofaragene利用细胞毒性，抗血管生成，和干扰素的免疫调节作用，以有效治疗对卡介苗耐药的NMIBC。抗性机制和预后生物标志物的持续研究是有希望的;这些将最终改善患者选择并允许调节肿瘤或免疫微环境中的因子以进一步增加治疗反应。
