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The combination of targeted therapy with immune checkpoint inhibition (ICI) is an area of intense interest. We studied the interaction of fibroblast growth factor receptor (FGFR) inhibition with ICI in urothelial carcinoma (UC) of the bladder, in which FGFR3 is altered in 50% of cases. Using an FGFR3-driven, Trp53-mutant genetically engineered murine model (UPFL), we demonstrate that UPFL tumors recapitulate the histology and molecular subtype of their FGFR3-altered human counterparts. Additionally, UPFL1 allografts exhibit hyperprogression to ICI associated with an expansion of T regulatory cells (Tregs). Erdafitinib blocked Treg proliferation in vitro, while in vivo ICI-induced Treg expansion was fully abrogated by FGFR inhibition. Combined erdafitinib and ICI resulted in high therapeutic efficacy. In aggregate, our work establishes that, in mice, co-alteration of FGFR3 and Trp53 results in high-grade, non-muscle-invasive UC and presents a previously underappreciated role for FGFR inhibition in blocking ICI-induced Treg expansion.

The APOBEC3 family of RNA and single stranded DNA cytidine deaminases contribute prominently to the mutagenesis of certain cancers including urothelial carcinoma of the bladder (UC). Remarkably, up to 70% of mutations in UC are attributable to the mutagenic activity of the APOBEC3 deaminases. Despite this strong association, few functional studies have investigated APOBEC3’s role in bladder cancer. We report a genetically engineered murine model with conditional knock out of Pten and Trp53 in addition to overexpression of mouse Apobec3 (UPPA). Analysis of bladder tumors from UPPA mice demonstrates that mA3 promotes tumor progression and squamous trans-differentiation. We establish that APOBEC3 promotes squamous differentiation through IL-1α and downstream activation of the AP-1 transcription factor. Bulk RNA-sequencing from human UC shows APOBEC3A as the only human APOBEC3 family member to correlate with squamous differentiation. Furthermore, single cell and spatial transcriptomics reinforces the role of APOBEC3A in fostering squamous trans-differentiation and promoting the emergence of a subpopulation of highly squamous epithelial cells. Our results demonstrate that mouse Apobec3 and human APOBEC3A promote squamous differentiation in urothelial carcinoma and that this trans-differentiation phenotype is mediated through IL-1α signaling, a target of FDA approved therapies for rheumatologic disease. Deaminases of the APOBEC3 family contribute to the mutagenesis of various cancers, including urothelial carcinoma (UC) of the bladder. Here, the authors use functional studies and transcriptomics to demonstrate that APOBEC3 promotes tumour progression and squamous trans-differentiation in UC through IL-1α and downstream activation of the AP-1 transcription factor.

Over the past decade, the use of immune checkpoint inhibitors and antibody–drug conjugates has led to longer survival in patients with metastatic bladder cancer. Platinum-based chemotherapy had been the standard of care for decades. The combination of enfortumab vedotin, an antibody–drug conjugate directed against nectin-4, and pembrolizumab, a programmed death 1 (PD-1) inhibitor, has dramatically improved survival as compared with platinum-based chemotherapy. 1 The integration of platinum-based chemotherapy with immune checkpoint inhibitors has been evaluated in several trials, including CheckMate 901, wherein nivolumab, a PD-1 inhibitor, plus gemcitabine–cisplatin led to longer survival than chemotherapy alone, despite negative findings of earlier trials . . .

[This corrects the article DOI: 10.1371/journal.pone.0253021.].

Radium-223, abiraterone, and enzalutamide have each been shown to significantly improve survival as monotherapy in patients with metastatic castration-resistant prostate cancer. However, effects of combination radium-223 plus abiraterone or enzalutamide on survival and safety remain unclear. This single-center retrospective cohort study used electronic health record data of patients with metastatic castration-resistant prostate cancer and bone metastases who were treated with radium-223 between April 1, 2014 and February 19, 2019. Patients who received radium-223 monotherapy were compared to patients who received a combination of radium-223 plus either abiraterone or enzalutamide. The primary endpoint was overall survival. Secondary endpoints included progression-free survival, time to symptomatic skeletal event, symptomatic skeletal event-free survival, and incidence of drug-related adverse events. Time-to-event analyses were estimated by log rank tests using Kaplan-Meier curves. Hazard ratios and 95% confidence intervals were derived from Cox proportional hazards models. Chi-square tests evaluated difference in serious adverse events between the two arms. A total of 60 patients met inclusion criteria (n = 41 in the monotherapy arm, n = 19 in the combination arm). Differences in median overall survival were not observed (12.7 vs. 12.8 months; HR 1.15, 95% CI 0.59-2.23; P = 0.68), but median progression-free survival was significantly longer in the combination arm (7.6 vs. 4.9 months; HR 1.94, 95% CI 1.11-3.40; P = 0.02). Significant differences were not observed in time to first SSE (P = 0.97), SSE-free survival (P = 0.16), or in the overall incidence of serious adverse events (P = 0.45). Combination radium-223 plus abiraterone or enzalutamide did not improve overall survival, but prolonged progression-free survival without increasing the incidence of serious adverse events in metastatic castration-resistant prostate cancer patients with bone metastases. However, these results are limited by small numbers and patient selection inherent in retrospective analysis.

The standard of care for most patients with non-muscle-invasive bladder cancer (NMIBC) is immunotherapy with intravesical Bacillus Calmette-Guérin (BCG), which activates the immune system to recognize and destroy malignant cells and has demonstrated durable clinical benefit. Urologic best-practice guidelines and consensus reports have been developed and strengthened based on data on the timing, dose, and duration of therapy from randomized clinical trials, as well as by critical evaluation of criteria for progression. However, these reports have not penetrated the community, and many patients do not receive appropriate therapy. Additionally, several immune checkpoint inhibitors have recently been approved for treatment of metastatic disease. The approval of immune checkpoint blockade for patients with platinum-resistant or -ineligible metastatic bladder cancer has led to considerations of expanded use for both advanced and, potentially, localized disease. To address these issues and others surrounding the appropriate use of immunotherapy for the treatment of bladder cancer, the Society for Immunotherapy of Cancer (SITC) convened a Task Force of experts, including physicians, patient advocates, and nurses, to address issues related to patient selection, toxicity management, clinical endpoints, as well as the combination and sequencing of therapies. Following the standard approach established by the Society for other cancers, a systematic literature review and analysis of data, combined with consensus voting was used to generate guidelines. Here, we provide a consensus statement for the use of immunotherapy in patients with bladder cancer, with plans to update these recommendations as the field progresses.