Myeloid-derived suppressor cells (MDSCs) are one of the key players that contribute to immune evasion. The purpose of the present study was to investigate whether MDSCs could be a novel target for the treatment of cisplatin-resistant bladder cancer. We established cisplatin-resistant bladder cancer cell lines (MB49R, MBT-2R, and T24R) and evaluated chemokine expression and MDSC expansion. We also assessed the antitumor effect by depleting MDSCs with or without a α-PD-L1 antibody using MB49R xenograft models. The chemokine expression of CXCL1, CXCL2, and CCL2 increased in cisplatin-resistant cells compared to those in their parent strains. Monocytic MDSCs (Mo-MDSCs) were observed more frequently compared to polymorphonuclear MDSCs (PMN-MDSCs) in MB49R tumors. The immunosuppressive genes arginase 1 and iNOS were comparably expressed in each MDSC subtype. In vivo, combination therapy targeting both PMN- and Mo-MDSCs using α-Gr1 and α-Ly6C antibodies significantly reduced tumor volume with increased infiltration of CD8 T cells in the tumor. Finally, co-targeting pan-MDSCs and PD-L1 remarkably reduced the tumor growth. These findings suggest that targeting MDSCs might enhance the therapeutic effect of immune checkpoint inhibitors in cisplatin-resistant bladder cancers.

Time to progression to castration-resistant prostate cancer after commencing combined androgen blockade for advanced hormone-sensitive prostate cancer Time to progression to castration-resistant prostate cancer after commencing combined androgen blockade for advanced hormone-sensitive prostate cancer

Background: In the phase III open-label KEYNOTE-426 (NCT02853331) study, first-line pembrolizumab and axitinib improved overall survival (OS) and progression-free survival (PFS) versus sunitinib for metastatic renal cell carcinoma (mRCC). KEYNOTE-426 evaluated patients enrolled from 25 sites in Japan.Methods: Patients enrolled in Japan were included in this post hoc subgroup analysis. Adults with clear cell mRCC were randomly assigned 1:1 to receive intravenous pembrolizumab 200 mg every 3 weeks plus oral axitinib 5 mg twice daily or oral sunitinib 50 mg once daily (4 weeks on/2 weeks off). Dual primary endpoints were OS and PFS as assessed by blinded independent central review. Objective response rate (ORR) and safety were secondary endpoints.Results: The Japanese subgroup comprised 94 patients (pembrolizumab–axitinib,n = 44; sunitinib,n = 50; 11% of the intent-to-treat population). Median time from randomization to data cutoff (January 6, 2020) was 29.5 months (range 24.6–37.3). Consistent with the intent-to-treat population, the OS, PFS, and ORR suggested improvement with pembrolizumab–axitinib versus sunitinib in the Japanese subgroup. Grade ≥ 3 treatment-related adverse events (TRAEs) occurred in 70% of patients receiving pembrolizumab–axitinib versus 78% receiving sunitinib; 11 (25%) patients receiving pembrolizumab–axitinib and 13 (27%) patients receiving sunitinib discontinued the study medication due to AEs. TRAEs led to the discontinuation of pembrolizumab, axitinib, pembrolizumab–axitinib, or sunitinib in 32%, 34%, 14%, and 20%, respectively. No deaths from TRAEs occurred.Conclusions: Efficacy outcomes for the Japanese subgroup were consistent with those of the global population. Safety in Japanese patients was consistent with the results from the global population.

Purpose: To compare treatment outcomes, more specifically patency rate, of polymeric and metallic stents for malignant ureteral obstruction. Patients and methods: Between August 2007 and September 2017, we retrospectively analyzed the data of 92 patients (126 ureters) having a diagnosis of malignant extrinsic ureteral obstruction treated with indwelling ureteral stents (polymeric and full-length metallic stents). Of these patients, 35 (54 ureters) were treated with polymeric stents and 57 (72 ureters) with a Resonance® metallic stent. The observation period was censored to 1 year. Survival rate in cases of malignant ureteral obstruction was calculated, and the relationship between the causes of ureteral obstruction, the stent type, and the patency rate was evaluated. Results: The median observation period was 145 days, with a median survival time of 258 days. The stent patency rate was 70.9% at 1 year, regardless of stent type. Stent occlusion was observed in 20 patients (33 ureters). According to stent type, occlusion of the polymeric and metallic stents was identified in 12 (22%) and 8 (11%) cases, respectively. The clinical features associated with stent failure were assessed. In univariate analysis, the patency rate was significantly better for the metallic stent than for the polymeric stent (1-year patency rate; 78.4%, 61.1%, respectively, HR, 2.15; 95% CI, 1.07–4.33; p=0.031). However, the patency rate among patients with abdominal dissemination, lymph node metastasis, and direct compression by tumor was not significantly different. Conclusion: Indwelling ureteral stents, particularly metallic stents, are effective for the treatment of malignant ureteral obstruction.

Expression of androgen receptor (AR) splice variant 7 (AR-V7) has been identified as the mechanism associated with the development of castration-resistant prostate cancer (CRPC). However, a potential link between AR-V7 expression and resistance to taxanes, such as docetaxel or cabazitaxel, has not been unequivocally demonstrated. To address this, we used LNCaP95-DR cells, which express AR-V7 and exhibit resistance to enzalutamide and docetaxel. Interestingly, LNCaP95-DR cells showed cross-resistance to cabazitaxel. Furthermore, these cells had increased levels of P-glycoprotein (P-gp) and their sensitivity to both docetaxel and cabazitaxel was restored through treatment with tariquidar, a P-gp antagonist. Results generated demonstrated that P-gp mediated cross-resistance between docetaxel and cabazitaxel. Although the LNCaP95-DR cells had increased expression of AR-V7 and its target genes (UBE2C, CDC20), the knockdown of AR-V7 did not restore sensitivity to docetaxel or cabazitaxel. However, despite resistance to docetaxel and carbazitaxel, EPI-002, an antagonist of the AR amino-terminal domain (NTD), had an inhibitory effect on the proliferation of LNCaP95-DR cells, which was similar to that achieved with the parental LNCaP95 cells. On the other hand, enzalutamide had no effect on the proliferation of either cell line. In conclusion, our results suggested that EPI-002 may be an option for the treatment of AR-V7-driven CRPC, which is resistant to taxanes.