Vaxiion Therapeutics, San Diego, California.
San Diego State University, San Diego, California.
Cancer Immunol Res. 2022 Aug 3;10(8):978-995. doi: 10.1158/2326-6066.CIR-21-0879.
Emerging clinical evidence indicates that the combination of local administration of immunotherapy with systemic immune-checkpoint blockade targeting the PD-1/PD-L1 pathway improves response rates in select solid tumor indications; however, limited clinical experience with this approach exists in advanced bladder cancer patients. VAX014 is a novel bacterial minicell-based, integrin-targeted oncolytic agent undergoing clinical investigation for intravesical (IVE) treatment of nonmuscle-invasive bladder cancer. Here, we demonstrated that the antitumor activity of VAX014 following IVE administration was dependent upon CD4+ and CD8+ T cells in two syngeneic orthotopic bladder tumor models (MB49 and MBT-2). PD-L1 upregulation was found to be an acquired immune-resistance mechanism in the MB49 model, and the combination of VAX014 with systemic PD-L1 blockade resulted in a significant improvement in bladder tumor clearance rates and development of protective antitumor immunologic memory. Combination treatment also led to enhanced systemic antitumor immune responses capable of clearing distal intradermal tumors and controlling pulmonary metastasis. Distal tumors actively responding to combination therapy demonstrated a phenotypic shift from regulatory T cell to Th1 in intratumoral CD4+ T cells, which was accompanied by a higher percentage of activated CD8+ T cells and higher IFNγ. Finally, VAX014's target integrins α3β1 and α5β1 were overexpressed in tumor biopsies from advanced-stage bladder cancer patients, as well as in both the MB49 and MBT-2 orthotopic mouse models of bladder cancer. These collective findings provide a rationale for the clinical investigation of VAX014 and systemic PD-1/PD-L1 blockade in advanced-stage bladder cancer.
新兴的临床证据表明，将免疫疗法与针对 PD-1/PD-L1 通路的全身免疫检查点阻断联合应用于局部治疗，可提高某些实体瘤适应证的反应率；然而，晚期膀胱癌患者对此方法的临床经验有限。VAX014 是一种新型的基于细菌微细胞的、整合素靶向的溶瘤药物，正在进行临床试验，用于治疗非肌肉浸润性膀胱癌的膀胱内（IVE）治疗。在这里，我们证明了 VAX014 在IVE 给药后的抗肿瘤活性依赖于两种同源原位膀胱癌模型（MB49 和 MBT-2）中的 CD4+和 CD8+T 细胞。发现 PD-L1 的上调是 MB49 模型中获得性免疫抵抗的机制，VAX014 与全身 PD-L1 阻断联合使用可显著提高膀胱癌清除率并产生保护性抗肿瘤免疫记忆。联合治疗还导致增强的全身抗肿瘤免疫反应，能够清除远处皮肤内肿瘤并控制肺转移。对联合治疗有积极反应的远端肿瘤在肿瘤内 CD4+T 细胞中从调节性 T 细胞向 Th1 的表型转变，同时伴随着激活的 CD8+T 细胞比例增加和 IFNγ水平升高。最后，VAX014 的靶整合素 α3β1 和 α5β1 在晚期膀胱癌患者的肿瘤活检中以及 MB49 和 MBT-2 原位膀胱癌小鼠模型中过度表达。这些综合发现为 VAX014 和全身 PD-1/PD-L1 阻断联合治疗晚期膀胱癌的临床研究提供了依据。
