Recent developments in perioperative combination therapy in muscle-invasive bladder cancer.

PURPOSE OF REVIEW: A summary of recent literature to provide a comprehensive overview of the current state of systemic perioperative treatment combinations for muscle-invasive bladder cancer (MIBC). RECENT FINDINGS: We discuss recent developments in standard and experimental treatment modalities. The VESPER trial has shown that six cycles of neoadjuvant dose-dense MVAC are superior to four cycles of gemcitabine/cisplatin (GC), though it is unclear whether the superiority is derived from the specific regimen or number of cycles. Adjuvant cisplatin-based chemotherapy, a subject of longstanding debate, was shown to have comparable overall survival-benefit to neoadjuvant chemotherapy in an updated meta-analysis. Neoadjuvant chemotherapy and anti-PD-(L)1 show encouraging results, but with no comparative studies to standard care, context is lacking. Immunotherapeutic neoadjuvant anti-CTLA-4/PD-(L)1 combinations or combinations of checkpoint inhibitors with antibody-drug-conjugates are in early stages of development and show promising preliminary results. SUMMARY: Six cycles of neoadjuvant dose-dense MVAC are superior to four cycles of gemcitabine/cisplatin. Adjuvant cisplatin-based chemotherapy is a viable option for patients with high-risk tumours who did not receive prior neoadjuvant treatment. The added value of anti-PD-(L)1 to chemotherapy still needs to be established. Novel developments in immunotherapy combinations, while promising, are still in an early stage and randomized studies are ongoing.

Platinum-based chemotherapy induces opposing effects on immunotherapy response-related spatial and stromal biomarkers in the bladder cancer microenvironment.

PURPOSE: Platinum-based chemotherapy and immune checkpoint inhibitors are key components of systemic treatment for muscle-invasive and advanced urothelial cancer. The ideal integration of these two treatment modalities remains unclear as clinical trials have led to inconsistent results. Modulation of the tumor-immune microenvironment by chemotherapy is poorly characterized. We aimed to investigate this modulation, focusing on potential clinical implications for immune checkpoint inhibitor response. EXPERIMENTAL DESIGN: We assessed immune cell densities, spatial relations, and tumor/stromal components from 116 urothelial bladder cancer patients (paired data for 95 patients), before and after platinum-based chemotherapy. RESULTS: Several published biomarkers for immunotherapy response changed upon chemotherapy-treatment. The intratumoral CD8+ T cell percentage increased after treatment and was associated with increased TNFα-via-NFκB signaling. The percentage of PD-L1+ immune cells was higher after chemotherapy. An increase in chemo-induced changes that potentially inhibit an anti-tumor immune response was also observed, including increased fibroblast-based TGF-ß signaling and distances from immune cells to the nearest cancer cell. The latter two parameters correlated significantly in post-treatment samples, suggesting that TGF-ß signaling in fibroblasts may play a role in spatially separating immune cells from cancer cells. We examined specific chemotherapy regimens and found that MVAC was associated with an increase in the macrophage cell percentage. Gemcitabine-containing chemotherapy was associated with upregulation of fibroblast TGF-ß signaling. CONCLUSIONS: The opposing effects of platinum-based chemotherapy on the immune cell composition and stromal context of the tumor-immune microenvironment may explain the inconsistent results of clinical trials investigating chemotherapy and immune checkpoint inhibitor combinations in bladder cancer.