Abstract 34P
Background
The role of cytoreductive nephrectomy (CN) remains controversial in the era of advancement of new immunotherapeutic and targeted agents. We compared the therapeutic potential of JX-594 in combination with ipilimumab and nivolumab (ipi/nivo) which is the conventional first-line treatment settings of metastatic renal cell carcinoma (mRCC), with CN in two preclinical murine mRCC models.
Methods
Early-stage and advanced-stage highly pulmonary metastatic orthotopic Renca, a murine renal adenocarcinoma cell line models have been developed. JX-594 and anti-PD-1 and/or anti-CTLA-4 antibodies were systemically injected through the peritoneum. Renca implanted kidney was removed in CN group. The remodeling of the tumor immune microenvironment (TIME) was determined using immunofluorescence analysis.
Results
Systemic injection of JX-594 significantly reduced the primary tumor burden and the number of metastatic lung nodules compared to control (p<0.01) and addition of anti-PD-1 demonstrated significantly stronger therapeutic effects compared to JX-594 monotherapy (p<0.01) both in early- and advanced-stage models. JX-594 plus anti-PD-1 therapy induced changes in TIME of lung metastatic sites, where tumor-infiltrating CD8+ T cells and tumor-suppressing M1 tumor-associated macrophages were increased while tumor-promoting myeloid-derived suppressor cells and regulatory T cells were decreased. Furthermore, addition of JX-594 to combination of anti-PD-1/anti-CTLA-4 antibodies demonstrated no peritoneal tumor and similar lung metastatic burden compared to addition of CN to combination of anti-PD-1/anti-CTLA-4 antibodies.
Conclusions
JX-594 effectively induced regression of primary tumors and metastatic burdens. Increased expression of PD-L1 by JX-594 supported the rationale for combining with ipi/nivo, and anti-PD-1 modulated the TIME to tumor-suppressing environment which complemented the therapeutic effects of JX-594. Furthermore, JX-594 has successfully demonstrated it as the promising alternative therapy option to CN, without concern for surgical morbidity by the CN.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute funded by the Ministry of Health & Welfare, Republic of Korea [grant number: HI17C1095], and the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) [grant number: 2019R1A2C1002863 and 2022R1A2C2003831].
Disclosure
All authors have declared no conflicts of interest.