Intravesical VAX014 Synergizes with PD-L1 Blockade to Enhance Local and Systemic Control of Bladder Cancer.
Intravesical VAX014 Synergizes with PD-L1 Blockade to Enhance Local and Systemic Control of Bladder Cancer.
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VAX014膀胱内注射与PD-L1阻滞剂协同作用，加强对膀胱癌的局部和系统控制。
DOI：
10.1158/2326-6066.cir-21-0879
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发表时间：
2022-08-03
影响因子：
10.1
通讯作者：
中科院分区：
文献类型：
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VAX 014是一种正在进行膀胱癌临床试验的早期溶瘤剂。与抗PD-L1的组合导致增强的抗肿瘤应答、免疫记忆的产生和远位效应，表明该组合用于晚期膀胱癌的临床效用。新出现的临床证据表明，局部给予免疫治疗与靶向PD-1/PD-L1通路的全身免疫检查点阻断相结合，可改善选定实体瘤适应症的缓解率;然而，在晚期膀胱癌患者中使用该方法的临床经验有限。VAX 014是一种新型的基于细菌小细胞的整合素靶向溶瘤剂，正在进行膀胱内（IVE）治疗非肌层浸润性膀胱癌的临床研究。在此，我们证明了在两种同基因原位膀胱肿瘤模型（MB 49和MBT-2）中，IVE施用后VAX 014的抗肿瘤活性依赖于CD 4+和CD 8 + T细胞。在MB 49模型中发现PD-L1上调是一种获得性免疫耐药机制，VAX 014与全身性PD-L1阻断剂的组合导致膀胱肿瘤清除率的显著改善和保护性抗肿瘤免疫记忆的发展。联合治疗还导致能够清除远端皮内肿瘤和控制肺转移的增强的全身抗肿瘤免疫应答。对联合治疗有积极反应的远端肿瘤表现出肿瘤内CD 4 + T细胞从调节性T细胞向Th 1的表型转变，伴随着较高百分比的活化CD 8 + T细胞和较高的IFNγ。最后，VAX 014的靶整联蛋白α3β1和α5β1在来自晚期膀胱癌患者的肿瘤活检组织中以及在膀胱癌的MB 49和MBT-2原位小鼠模型中过表达。这些共同的发现为VAX 014和全身PD-1/PD-L1阻断在晚期膀胱癌中的临床研究提供了理论基础。
VAX014 is an early-stage oncolytic agent undergoing clinical testing for bladder cancer. Combinationwith anti–PD-L1 leads to enhanced antitumor responses, generation of immunologic memory, and abscopal effects, suggesting clinical utility of this combination for advanced bladder cancer. 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.