Role of immunotherapy in bladder cancer.

The role of immunotherapy in bladder urothelial cancers is rapidly expanding. Since the initial second-line therapy approval for patients who fail prior platinum-based chemotherapy, the use of immunotherapy with checkpoint inhibitors has been rapidly evolving. There are approved indications for first-line metastatic disease in the platinum-ineligible patients or the cisplatin-ineligible PD-L1 positive patients, and there is a label for high-risk non-muscle-invasive bladder cancer who are BCG-refractory. In addition, a trial on maintenance immunotherapy with avelumab showed positive findings with improvement in overall survival that has also changed standard of care for these patients. There are ongoing clinical trials evaluating its use in the neoadjuvant and adjuvant perioperative muscle-invasive bladder cancer setting. The pivotal trials that led to these FDA approvals and promising and ongoing trials are discussed herein.

Rhea LP ，Mendez-Marti S ，Kim D ，Aragon-Ching JB ... -  《-》

Rationale and Outcomes for Neoadjuvant Immunotherapy in Urothelial Carcinoma of the Bladder.

Immune therapy has emerged as a powerful treatment of metastatic urothelial carcinoma. Over 20 ongoing studies are exploring this strategy in the neoadjuvant setting in patients with localized muscle-invasive bladder cancer. To summarize the rationale and the clinical outcomes regarding the use of immune checkpoint blockade in the neoadjuvant setting before radical cystectomy. A systematic review of the literature in the MEDLINE database was performed. The central search strategy used the terms bladder cancer, urothelial carcinoma, mice, human, immunotherapy, neoadjuvant therapy, atezolizumab, pembrolizumab, durvalumab, nivolumab, avelumab, ipilimumab, and tremelimumab. The search was limited to publications between January 2008 and February 2020. Publicly available relevant abstracts from recent meetings were also included. Phase II trials investigating neoadjuvant immune checkpoint blockade as a single agent before radical cystectomy reported a rate of pathological complete response (CR), ranging from 31% with an anti-PD-L1 monoclonal antibody (mAb) atezolizumab (n = 27/88) to 37% with anti-PD-1 mAb pembrolizumab (n = 42/114). Overall, 92% (n = 87/95) and 98% (n = 112/114) of the patients underwent radical cystectomy. Neoadjuvant immune checkpoint blockade did not delay planned surgery. Checkpoint inhibitor monotherapy was well tolerated, with no unexpected toxicity in the presurgical setting. Early phase I/II trials investigating neoadjuvant combination chemotherapy strategies with immune checkpoint blockers reported enhanced antitumor efficacy, with a pathological CR ranging from 33% to 50%. Although limited clinical data are available on long-term survival, neoadjuvant immune checkpoint blockade demonstrated effective antitumor efficacy for localized muscle-invasive bladder cancer. Phase III trials are currently investigating this strategy in the presurgical setting. Immunotherapy prior to surgery has been evaluated for patients with muscle-invasive bladder cancer. Although long-term survival benefit is unknown, such treatment strategy revealed a promising antitumor response rate for patients who underwent radical cystectomy. Ongoing prospective clinical trials will define the potential advantage of this approach over current cisplatin-based chemotherapeutic regimens alone or in combination.

Rouanne M ，Bajorin DF ，Hannan R ，Galsky MD ，Williams SB ，Necchi A ，Sharma P ，Powles T ... -  《European Urology Oncology》

TOX-expressing terminally exhausted tumor-infiltrating CD8(+) T cells are reinvigorated by co-blockade of PD-1 and TIGIT in bladder cancer.

Exhausted T cells in the tumor microenvironment are major targets of immunotherapies. However, the exhaustion status of CD8+ tumor-infiltrating lymphocytes (TILs) in bladder cancer has not been comprehensively evaluated. Herein, we examined distinct exhaustion status of CD8+ TILs based on the level of programmed cell death-1 (PD-1) and thymocyte selection-associated high mobility group box protein (TOX) expression in urothelial bladder cancer. We also evaluated the reinvigoration of exhausted CD8+ TILs upon ex vivo treatment with inhibitory checkpoint blockers. TOX-expressing PD-1highCD8+ TILs had the highest expression of immune checkpoint receptors (ICRs), the most terminally exhausted features, and the highest tumor antigen reactivity among PD-1+CD8+ TILs. Bladder cancer patients with a high percentage of PD-1highTOX+CD8+ TILs had more progressed T-cell exhaustion features and higher programmed death-ligand 1 expression in tumor tissues. TIGIT was the most frequent co-expressed ICR on PD-1+CD8+ TILs, and TIGIT blockade enhanced the PD-1 blockade-mediated cytokine production by CD8+ TILs from bladder cancer patients. Our findings provide an improved understanding of the heterogeneous exhaustion status of CD8+ TILs and additional immunotherapy strategies to improve outcomes of bladder cancer patients.

Han HS ，Jeong S ，Kim H ，Kim HD ，Kim AR ，Kwon M ，Park SH ，Woo CG ，Kim HK ，Lee KH ，Seo SP ，Kang HW ，Kim WT ，Kim WJ ，Yun SJ ，Shin EC ... -  《-》

Neoadjuvant PARPi for urothelial carcinoma: between lifeline and desperation.

Tayeh GA ，Alkassis M ，Semaan A ，Khalil N ，Nemr E ，Waked C ... -  《-》

[Immunotherapy in bladder cancer-quo vadis? Update on current trials and developments].

Todenhöfer T ，Boegemann M 《-》