There is a critical unmet need for safe and efficacious neoadjuvant treatment for cisplatin-ineligible patients with muscle-invasive bladder cancer. Here we launched a phase 1b study using the combination of intravesical cretostimogene grenadenorepvec (oncolytic serotype 5 adenovirus encoding granulocyte–macrophage colony-stimulating factor) with systemic nivolumab in cisplatin-ineligible patients with cT2-4aN0-1M0 muscle-invasive bladder cancer. The primary objective was to measure safety, and the secondary objective was to assess the anti-tumor efficacy as measured by pathologic complete response along with 1-year recurrence-free survival. No dose-limiting toxicity was encountered in 21 patients enrolled and treated. Combination treatment achieved a pathologic complete response rate of 42.1% and a 1-year recurrence-free survival rate of 70.4%. Pathologic response was associated with baseline free E2F activity and tumor mutational burden but not PD-L1 status. Although T cell infiltration was broadly induced after intravesical oncolytic immunotherapy, the formation, enlargement and maturation of tertiary lymphoid structures was specifically associated with complete response, supporting the importance of coordinated humoral and cellular immune responses. Together, these results highlight the potential of this combination regimen to enhance therapeutic efficacy in cisplatin-ineligible patients with muscle-invasive bladder cancer, warranting additional study as a neoadjuvant therapeutic option. ClinicalTrials.gov identifier: NCT04610671.

对于不适合顺铂的肌层浸润性膀胱癌患者，对安全有效的新辅助治疗存在关键的未满足需求。在这里，我们启动了一项 1b 期研究，使用膀胱内新色蛋白刺激基因 grenadenorepvec（溶瘤血清型 5 腺病毒编码粒细胞-巨噬细胞集落刺激因子）与全身性纳武利尤单抗联合治疗 cT2-4aN0-1M0 肌层浸润性膀胱癌患者。主要目标是测量安全性，次要目标是评估通过病理完全缓解和 1 年无复发生存期来衡量的抗肿瘤疗效。在入组和治疗的 21 例患者中未遇到剂量限制性毒性。联合治疗病理完全缓解率为 42.1%，1 年无复发生存率为 70.4%。病理反应与基线游离 E2F 活性和肿瘤突变负荷相关，但与 PD-L1 状态无关。尽管膀胱内溶瘤免疫治疗后广泛诱导 T 细胞浸润，但三级淋巴结构的形成、扩大和成熟与完全反应特别相关，支持协调体液和细胞免疫反应的重要性。总之，这些结果强调了这种联合方案在增强顺铂不合格肌层浸润性膀胱癌患者的治疗效果方面的潜力，值得作为新辅助治疗选择进行额外研究。ClinicalTrials.gov 标识符：NCT04610671。