Safety outcomes and immunological correlates in a prospective clinical trial of immune checkpoint therapy plus debulking surgery for patients with metastatic renal cell carcinoma.

Surgical removal of primary tumors was shown to reverse tumor-mediated immune suppression in pre-clinical models with metastatic disease. However, how cytoreductive surgery in the metastatic setting modulates the immune responses in patients, especially in the context of immune checkpoint therapy (ICT)-containing treatments is not understood. Here, we report the first prospective, non-comparative clinical trial to evaluate the feasibility, clinical benefits, and immunologic changes of combining three different ICT-containing strategies with cytoreductive surgery or biopsy for patients with metastatic clear cell renal cell carcinoma (mccRCC). Based upon baseline evaluation and surgical eligibility after 6 weeks of ICT treatment, 43 patients on this trial proceeded with cytoreductive surgery, while 36 patients who had medical comorbidities preventing surgery or did not have a lesion amenable for surgical resection underwent post-ICT biopsy as specified in the clinical trial protocol, and 25 patients who discontinued study participation due to progressive disease or toxicities or withdrawal of consent did not receive either procedure (total N=104). Our data demonstrated that, in the subgroup of patients receiving the combination of ICT with cytoreductive surgery or biopsy, no additional ICT- or procedure-related toxicities were observed as compared to historical data. The median OS (overall survival) was 54.7 months for patients who received ICT-containing regimens plus cytoreductive surgery (n=43). Immune-monitoring studies with co-detection by indexing (CODEX) identified distinct tumor spatial conformation of cellular subsets as a novel and improved predictor of response to ICT. Importantly, single-cell RNA-sequencing (sc-RNA-seq) data demonstrated that surgical removal of the tumor increased antigen-presenting dendritic cell population with a concurrent reduction in KDM6B-expressing immune-suppressive myeloid cells in the peripheral blood. Together, this study highlighted the feasibility of combining ICT with cytoreductive surgery in a metastatic setting and demonstrated the potential enhancement of immune responses following ICT plus cytoreductive surgery in patients with metastatic disease.