Biomarkers guiding the neoadjuvant use of immune-checkpoint blockers (ICB) are needed for patients with localized muscle-invasive bladder cancers (MIBC). Profiling tumor and blood samples, we found that follicular helper CD4+ T cells (TFH) are among the best therapeutic targets of pembrolizumab correlating with progression-free survival. TFH were associated with tumoral CD8 and PD-L1 expression at baseline and the induction of tertiary lymphoid structures after pembrolizumab. Blood central memory TFH accumulated in tumors where they produce CXCL13, a chemokine found in the plasma of responders only. IgG4+CD38+ TFH residing in bladder tissues correlated with clinical benefit. Finally, TFH and IgG directed against urothelium-invasive Escherichia coli dictated clinical responses to pembrolizumab in three independent cohorts. The links between tumor infection and success of ICB immunomodulation should be prospectively assessed at a larger scale. Significance: In patients with bladder cancer treated with neoadjuvant pembrolizumab, E. coli–specific CXCL13 producing TFH and IgG constitute biomarkers that predict clinical benefit. Beyond its role as a biomarker, such immune responses against E. coli might be harnessed for future therapeutic strategies. This article is highlighted in the In This Issue feature, p. 2221

Radiation cystitis is a potential complication following the therapeutic irradiation of pelvic cancers. Its clinical management remains unclear, and few preclinical data are available on its underlying pathophysiology. The therapeutic strategy is difficult to establish because few prospective and randomized trials are available. In this review, we report on the clinical presentation and pathophysiology of radiation cystitis. Then we discuss potential therapeutic approaches, with a focus on the immunopathological processes underlying the onset of radiation cystitis, including the fibrotic process. Potential therapeutic avenues for therapeutic modulation will be highlighted, with a focus on the interaction between mesenchymal stromal cells and macrophages for the prevention and treatment of radiation cystitis.

Purpose: The androgen receptor axis inhibitors (ARPI; e.g., enzalutamide, abiraterone acetate) are administered in daily practice for men with metastatic castration-resistant prostate cancer (mCRPC). However, not all patients respond, and mechanisms of both primary and acquired resistance remain largely unknown. Experimental Design: In the prospective trial MATCH-R (NCT02517892), 59 patients with mCRPC underwent whole-exome sequencing (WES) and/or RNA sequencing (RNA-seq) of samples collected before starting ARPI. Also, 18 patients with mCRPC underwent biopsy at time of resistance. The objectives were to identify genomic alterations associated with resistance to ARPIs as well as to describe clonal evolution. Associations of genomic and transcriptomic alterations with primary resistance were determined using Wilcoxon and Fisher exact tests. Results: WES analysis indicated that no single-gene genomic alterations were strongly associated with primary resistance. RNA-seq analysis showed that androgen receptor (AR) gene alterations and expression levels were similar between responders and nonresponders. RNA-based pathway analysis found that patients with primary resistance had a higher Hedgehog pathway score, a lower AR pathway score and a lower NOTCH pathway score than patients with a response. Subclonal evolution and acquisition of new alterations in AR-related genes or neuroendocrine differentiation are associated with acquired resistance. ARPIs do not induce significant changes in the tumor transcriptome of most patients; however, programs associated with cell proliferation are enriched in resistant samples. Conclusions: Low AR activity, activation of stemness programs, and Hedgehog pathway were associated with primary ARPIs’ resistance, whereas most acquired resistance was associated with subclonal evolution, AR-related events, and neuroendocrine differentiation. See related commentary by Slovin, p. 4323

Anti-PD-1 antibodies prolong survival of performance status (PS) 0–1 advanced non-small-cell lung cancer (aNSCLC) patients. Their efficacy in PS 3–4 patients is unknown. Conse- cutive PS 3–4 aNSCLC patients receiving compassionate nivolumab were accrued by 12 French thoracic oncology departments, over 24 months. Overall survival (OS) was calculated using the Kaplan-Meier method. Prognostic variables were assessed using Cox proportional hazards models. Overall, 35 PS 3–4 aNSCLC patients (median age 65 years) received a median of 4 nivolumab infusions (interquartile range [IQR], 1–7) as first- (n = 6) or second-line (n = 29) therapy. At a median of 52-month follow-up (95%CI, 41–63), 32 (91%) patients had died. Median progression-free survival was 2.1 months (95%CI, 1.1–3.2). Median OS was 4.4 months (95%CI, 0.5–8.2). Overall, 20% of patients were alive at 1 year, and 14% at 2 years. Treatment-related adverse events occurred in 8/35 patients (23%), mostly of low-grade. After adjustment, brain metastases (HR = 5.2; 95%CI, 9–14.3, p = 0.001) and <20 pack-years (HR = 4.8; 95%CI, 1.7–13.8, p = 0.003) predicted worse survival. PS improvement from 3–4 to 0–1 (n = 9) led to a median 43-month (95%CI, 0–102) OS. Certain patients with very poor general condition could derive long-term benefit from nivolumab salvage therapy.

Background: Telemedicine is currently being adopted for the management of patients in routine care. However, its use remains limited in the context of clinical trials. Objective: This study aimed to demonstrate the feasibility of telemonitoring and patient-reported outcomes collection in the context of clinical trials. Methods: The patients who were included in an interventional oncology clinical trial were eligible. The patients were registered with a digital tool to respond to a patient-reported outcomes questionnaire (ePRO) based on CTCAE (The Common Terminology Criteria for Adverse Events, National Cancer Institute), version 5.0, personalized to their pathology and treatment. An algorithm evaluated the health status of the patient based on the reported adverse events, with a classification in 4 different states (correct, compromise, state to be monitored, or critical state). The main objective was to evaluate the feasibility of remote monitoring via a connected platform of patients included in a clinical trial. Results: From July 1, 2020, to March 31, 2021, 39 patients were included. The median age was 71 years (range 41-94); 74% (n=29) were male, and 59% (n=23) had metastatic disease. Out of the 969 ePRO questionnaires completed over the course of the study, 77.0% (n=746) were classified as “correct,” 10.9% (n=106) as “compromised,” and 12.1% (n=117) as “to be monitored” or “critical.” The median response time was 7 days (IQR 7-15.5), and 76% (25/33) of the patients were compliant. Out of the 35 patients who answered a satisfaction questionnaire, 95% (n=33) were satisfied or very satisfied with the tool, and 85% (n=30) were satisfied with their relationship with the health care team. There were 5 unscheduled hospitalizations during the study period. Conclusions: Remote monitoring in clinical trials is feasible, with a high level of patient participation and satisfaction. It benefits patients, but it also ensures the high quality of the trial through the early management of adverse events and better knowledge of the tolerance profile of experimental treatments. This e-technology will likely be deployed more widely in our clinical trials.

Background: Radiation cystitis (RC) results from chronic inflammation, fibrosis, and vascular damage. The urinary symptoms it causes have a serious impact on patients’ quality of life. Despite the improvement in irradiation techniques, the incidence of radiation cystitis remains stable over time, and the therapeutic possibilities remain limited. Mesenchymal stem/stromal cells (MSC) appear to offer² a promising therapeutic approach by promoting tissue repair through their paracrine action via extracellular vesicles (MSC-EVs) or conditioned medium from human mesenchymal stromal cells (MSC-CM). We assess the therapeutic potential of MSC-EVs or MSC-CM in an in vitro model of RC. Methods:in vitro RC was induced by irradiation of human bladder fibroblasts (HUBF) with the small-animal radiation research platform (SARRP). HUBF were induced towards an RC phenotype after 3 × 3.5 Gy irradiation in the presence of either MSC-EVs or MSC-CM, to assess their effect on fibrosis, angiogenesis, and inflammatory markers. Results: Our data revealed in vitro a higher therapeutic potential of MSC-EVs and MSC-CM in prevention of RC. This was confirmed by down-regulation of α-SMA and CTGF transcription, and the induction of the secretion of anti-fibrotic cytokines, such as IFNγ, IL10 and IL27 and the decrease in the secretion of pro-fibrotic cytokines, IGFBP2, IL1β, IL6, IL18, PDGF, TNFα, and HGF, by irradiated HUBFs, conditioned with MSC-EVs or MSC-CM. The secretome of MSC (MSC-CM) or its subsecretome (MSC-EVs) are proangiogenic, with the ability to induce vessels from HUVEC cells, ensuring the management of bladder vascular lesions induced by irradiation. Conclusion: MSC-EVs and MSC-CM appear to have promising therapeutic potential in the prevention of RC in vitro, by targeting the three main stages of RC: fibrosis, inflammation and vascular damage.