Park Jee Soo, Lee Myung Eun, Kim Jongchan, Oh Keunhee, Lee Namhee, Jung Minsun, Jang Won Sik, Ham Won Sik
Department of Urology and Urological Science Institute, Yonsei University College of Medicine, Seoul, Republic of Korea.
Department of Urology, Yongin Severance Hospital, Yonsei University Health System, Yongin, Republic of Korea.
Cancer Cell Int. 2024 Jan 30;24(1):50. doi: 10.1186/s12935-024-03238-z.
Although a combination of immune checkpoint inhibitors (ICIs) is recommended as the first line treatment option for metastatic renal cell carcinoma (mRCC), several immune-related adverse events (irAEs) occur, especially hepatitis. We explored the therapeutic benefits and safety profile of combining oncolytic vaccinia virus, JX-594, with a programmed cell death protein-1 (PD-1) inhibitor.
We used early-stage and advanced-stage orthotopic murine mRCC models developed by our group. PD-1 inhibitor monotherapy or a PD-1 inhibitor combined with either JX-594 or a cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitor were systemically injected through the peritoneum. An immunofluorescence analysis was performed to analyze the tumor immune microenvironment (TIME). irAEs were assessed in terms of hepatitis.
In the early-stage mRCC model mice, the combination of JX-594 and a PD-1 inhibitor significantly decreased the primary tumor size and number of lung nodules, compared with the ICI combination, but the JX-594 and PD-1 inhibitor combination and ICI combination did not differ significantly in the advanced-stage mRCC model mice. The JX-594 and PD-1 inhibitor combination induced tumor-suppressing TIME changes in both the early- and advanced-stage mRCC models. Furthermore, mice treated with the ICI combination had significantly greater hepatic injuries than those treated with the JX-594 and PD-1 inhibitor combination which was evaluated in early-stage mRCC model.
The JX-594 and PD-1 inhibitor combination effectively reduced primary tumors and the metastatic burden, similar to ICI combination therapy, through dynamic remodeling of the TIME. Furthermore, hepatitis was significantly decreased in the JX-594 and PD-1 inhibitor combination group, suggesting the potential benefit of that combination for reducing ICI-induced toxicity.
尽管免疫检查点抑制剂（ICI）联合疗法被推荐为转移性肾细胞癌（mRCC）的一线治疗方案，但会出现几种免疫相关不良事件（irAE），尤其是肝炎。我们探讨了溶瘤痘苗病毒JX - 594与程序性细胞死亡蛋白1（PD - 1）抑制剂联合使用的治疗益处和安全性。
我们使用了本研究团队构建的早期和晚期原位小鼠mRCC模型。通过腹腔系统性注射PD - 1抑制剂单药疗法，或PD - 1抑制剂与JX - 594或细胞毒性T淋巴细胞相关抗原4（CTLA - 4）抑制剂的联合疗法。进行免疫荧光分析以分析肿瘤免疫微环境（TIME）。从肝炎方面评估irAE。
在早期mRCC模型小鼠中，与ICI联合疗法相比，JX - 594与PD - 1抑制剂联合使用显著减小了原发肿瘤大小和肺结节数量，但在晚期mRCC模型小鼠中，JX - 594与PD - 1抑制剂联合疗法和ICI联合疗法之间无显著差异。JX - 594与PD - 1抑制剂联合疗法在早期和晚期mRCC模型中均诱导了肿瘤抑制性的TIME变化。此外，在早期mRCC模型中评估发现，接受ICI联合疗法治疗的小鼠肝损伤明显大于接受JX - 594与PD - 1抑制剂联合疗法治疗的小鼠。
JX - 594与PD - 1抑制剂联合疗法通过动态重塑TIME，与ICI联合疗法类似，有效减少了原发肿瘤和转移负担。此外，JX - 594与PD - 1抑制剂联合治疗组的肝炎明显减轻，表明该联合疗法在降低ICI诱导毒性方面具有潜在益处。
