Steinmetz Alexis R, Mokkapati Sharada, McConkey David, Dinney Colin P
Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Johns Hopkins Greenberg Bladder Cancer Institute, Brady Urological Institute, Johns Hopkins University, Baltimore, MD, USA.
Bladder Cancer. 2024 Jun 18;10(2):105-112. doi: 10.3233/BLC-230083. eCollection 2024.
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.
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.
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.
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.
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.
膀胱内基因疗法纳多法基因菲拉地诺韦（rAd-IFNα/Syn3）于2022年获美国食品药品监督管理局（FDA）批准，用于治疗对卡介苗（BCG）一线治疗无反应的非肌肉浸润性膀胱癌（NMIBC），是首个针对膀胱癌开发的基因疗法。这种非复制型重组腺病毒载体将人干扰素α-2b基因的一个副本递送至尿路上皮细胞和肿瘤细胞，使其表达这种具有多种抗肿瘤作用的多效性细胞因子。
提供一份历史概述，描述几十年来关于干扰素在膀胱癌治疗中作用的临床前和临床研究如何最终促成了用于NMIBC的纳多法基因基因疗法的开发。
我们使用PubMed、谷歌学术和ClinicalTrials.gov对文献进行了综述，以总结我们对NMIBC中基于干扰素的治疗方法演变的认识。
该疗法获得FDA批准是泌尿肿瘤学的一个重要里程碑，也是几十年来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成果。从1期、2期和3期临床试验收集的数据继续为纳多法基因的疗效和耐药性背后的确切机制提供更多见解。
纳多法基因利用干扰素的细胞毒性、抗血管生成和免疫调节作用，有效治疗对BCG耐药的NMIBC。对耐药机制和预后生物标志物的正在进行的研究很有前景；这些研究最终将改善患者选择，并能够调节肿瘤或免疫微环境中的因素，以进一步提高治疗反应。
