Background:Bladder cancer is the ninth most prevalent cancer globally. Most cases are urothelial carcinoma, classified as non-muscle invasive bladder cancer (NMIBC) or muscle invasive bladder cancer (MIBC); approximately 70% are diagnosed as NMIBC. Current standard of care for high-risk NMIBC includes transurethral tumour resection, followed by intravesical therapy withBacillus Calmette-Guérin(BCG). However, significant unmet needs persist due to disease recurrence, BCG unresponsiveness, or progression to MIBC. Radical cystectomy is recommended after BCG unresponsiveness but may not be viable due to its invasiveness and morbidity. The paucity of treatment options for BCG-unresponsive NMIBC has driven research into alternatives such as gene therapy. The bladder’s anatomy allows direct vector–tumour contact, while urine and tissue samples allow for easy monitoring of therapeutic effects.Methods:This narrative review integrates findings from recent clinical and preclinical studies identified through comprehensive searches of peer-reviewed literature to provide an overview of the current landscape of gene therapy for BCG-unresponsive NMIBC.Results:Nadofaragene firadenovec, a recombinant adenovirus delivering interferon alpha-2b (IFNα2b), is the first FDA-approved gene therapy for BCG-unresponsive NMIBC with carcinoma in situ (CIS). A phase III nadofaragene firadenovec study (NCT02773849) demonstrated a 53% complete response (CR) rate at 3 months; and 43% of patients with CIS had bladder preservation at 60 months. Cretostimogene grenadenorepvec (CG0070), an oncolytic vector, demonstrated a 47% 6-month CR rate in a phase II study (NCT02365818). Detalimogene voraplasmid (EG-70), a nonviral gene therapy, demonstrated a 47% 6-month CR in a phase I/II study (NCT04752722). Future advances are likely to focus on patient selection, novel vectors, and combination strategies to improve treatment outcomes.Conclusions:Gene therapy represents a significant addition to the bladder cancer treatment landscape by offering bladder-sparing alternatives where conventional therapies are limited.
背景：膀胱癌是全球第九大常见癌症。大多数病例为尿路上皮癌，可分为非肌层浸润性膀胱癌（NMIBC）或肌层浸润性膀胱癌（MIBC）；约70%的患者确诊时为NMIBC。目前高危NMIBC的标准治疗方案包括经尿道肿瘤切除术，随后进行卡介苗（BCG）膀胱灌注治疗。然而，由于疾病复发、BCG治疗无效或进展为MIBC，仍存在显著的未满足临床需求。BCG治疗无效后建议进行根治性膀胱切除术，但因其创伤性和高并发症发生率可能无法实施。针对BCG无效型NMIBC的治疗选择匮乏，推动了基因治疗等替代方案的研究。膀胱的解剖结构允许载体与肿瘤直接接触，而尿液和组织样本便于监测治疗效果。 方法：本叙述性综述整合了通过同行评审文献全面检索获得的最新临床和临床前研究结果，旨在概述BCG无效型NMIBC基因治疗的现状。 结果：Nadofaragene firadenovec是一种递送干扰素α-2b（IFNα2b）的重组腺病毒载体，是首个获美国FDA批准用于治疗BCG无效型原位癌（CIS）NMIBC的基因疗法。一项III期nadofaragene firadenovec研究（NCT02773849）显示3个月时完全缓解（CR）率达53%；60个月时43%的CIS患者实现膀胱保留。溶瘤病毒载体Cretostimogene grenadenorepvec（CG0070）在II期研究（NCT02365818）中显示6个月CR率为47%。非病毒基因疗法Detalimogene voraplasmid（EG-70）在I/II期研究（NCT04752722）中显示6个月CR率达47%。未来进展可能聚焦于患者筛选、新型载体及联合策略以改善治疗效果。 结论：在传统疗法受限的情况下，基因治疗为膀胱癌治疗领域提供了重要的保膀胱替代方案。
肿瘤(癌症)患者之家