Platinum Opinion

Adjuvant Immune Checkpoint Inhibition in Muscle-invasive Bladder Cancer: Is It Ready for Prime Time?

Several recent phase 2 and 3 trials have evaluated the efficacy and toxicity of checkpoint inhibitor (CPI) therapy for urothelial carcinoma (UC) in the metastatic, localized muscle-invasive UC (MIUC), upper tract UC, and non–muscle-invasive bladder cancer (NMIBC) disease state.

To assess the outcomes and toxicity of CPIs across the treatment landscape of UC and contextualize their application to current real-world treatment.

We queried PubMed, Web of Science, and EMBASE databases and conference abstracts to identify prospective trials examining CPIs in UC. The primary endpoints included overall survival, recurrence-free survival, and toxicity (when available). A secondary analysis included biomarker evaluation of response.

We identified 21 trials, 12 phase 2 and nine phase 3 trials, in which a CPI was used for metastatic UC (seven), MIUC (nine), and NMIBC (five). For first-line (1L) metastatic UC, concurrent chemotherapy with CPIs failed to show superiority. Improved overall and progression-free survival for switch maintenance avelumab (after achieving stable disease or response with induction systemic chemotherapy) has established the current standard of care for 1L metastatic UC. A single-agent CPI is a consideration for patients unable to tolerate chemotherapy. CPIs in the perioperative setting are limited to only the adjuvant treatment with nivolumab after radical surgery for MIUC in patients at a higher risk of recurrence based on pathologic stage. Only pembrolizumab is approved by the Food and Drug Administration for carcinoma in situ unresponsive to bacillus Calmette-Guérin (BCG) in patients who are not fit for or who refuse radical cystectomy. Trials investigating CPIs in combination with multiple immune regulators, antibody drug conjugates, targeted therapies, antiangiogenic agents, chemotherapy, and radiotherapy are enrolling patients and may shape the future treatment of patients with UC.

CPIs have an established role across multiple states of UC, with broadened applications likely to occur in the future. Several combinations are being evaluated, while the development of predictive biomarkers and their validation may help identify patients who are most likely to respond.

Our findings highlight the broad activity of checkpoint inhibitors in urothelial carcinoma, noting the need for further investigation for the best application of combinations and patient selection to patient care.

To explore mechanisms of response to combined PD-1/CTLA-4 immune checkpoint blockade (ICB) treatment in individual cell types, we generated scRNA-seq using a mouse model of invasive urothelial carcinoma with three conditions: untreated tumor, treated tumor, and tumor treated after CD4⁺ T cell depletion. After classifying tumor cells based on detection of somatic variants and assigning non-tumor cell types using SingleR, we performed differential expression analysis, overrepresentation analysis, and gene set enrichment analysis (GSEA) within each cell type. GSEA revealed that endothelial cells were enriched for upregulated IFN-g response genes when comparing treated cells to both untreated cells and cells treated after CD4⁺ T cell depletion. Functional analysis showed that knocking out IFNgR1 in endothelial cells inhibited treatment response. Together, these results indicated that IFN-g signaling in endothelial cells is a key mediator of ICB induced anti-tumor activity.

SLC17A9 is a vesicular ATP transport protein that plays an important role in determining cell functions and the onset and progression of different diseases. In this study, SLC17A9 was initially identified as a potential diagnostic and prognostic risk biomarker for clear cell renal cell carcinoma (ccRCC). Then, the aberrant expression levels of SLC17A9 were confirmed in both the cell lines and clinical tissues. Mechanistically, SLC17A9 could upregulate the expression of PTHLH, thus promoting epithelial-mesenchymal transition (EMT) in ccRCC. Functionally, SLC17A9 knockdown inhibited the proliferation, migration, and invasion activity of renal cancer cells, whereas its overexpression led to stronger cell viability and more malignant phenotype in vitro. The overexpression of SLC17A9 in vivo could significantly contribute to the growth of tumors. Finally, we found that SLC17A9 might be related to the drug resistance of vorinostat. Cumulatively, this study demonstrated that the SLC17A9-PTHLH-EMT axis could promote the progression of ccRCC.