Expression-Based Subtypes Define Pathologic Response to Neoadjuvant Immune-Checkpoint Inhibitors in Muscle-Invasive Bladder Cancer
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PROVIDER: EGAS00001005549 | EGA |
REPOSITORIES: EGA
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Project description:Checkpoint immunotherapy (CPI) has increased survival for some patients with advanced-stage bladder cancer (BCa). However, most patients do not respond. Here, we characterized the tumor and immune microenvironment in pre- and post-treatment tumors from the PURE01 neoadjuvant pembrolizumab immunotherapy trial, using a consolidative approach that combined transcriptional and genetic profiling with digital spatial profiling. We identify five distinctive genetic and transcriptomic programs and validate these in an independent neoadjuvant CPI trial to identify the features of response or resistance to CPI. By modeling the regulatory network, we identify the histone demethylase KDM5B as a repressor of tumor immune signaling pathways in one resistant subtype (S1, Luminal-excluded) and demonstrate that inhibition of KDM5B enhances immunogenicity in FGFR3-mutated BCa cells. Our study identifies signatures associated with response to CPI that can be used to molecularly stratify patients and suggests therapeutic alternatives for subtypes with poor response to neoadjuvant immunotherapy.
| S-EPMC10140274 | biostudies-literature
Project description:Bladder cancer is the ninth most common cancer worldwide. Over 75% of non-muscle invasive cancer patients require conservative local treatment, while the remaining 25% of patients undergo radical cystectomy or radiotherapy. Immune checkpoint inhibitors represent a novel class of immunotherapy drugs that restore natural antitumoral immune activity via the blockage of inhibitory receptors and ligands expressed on antigen-presenting cells, T lymphocytes and tumour cells. The use of immune checkpoint inhibitors in bladder cancer has been expanded from the neoadjuvant setting, i.e., after radical cystectomy, to the adjuvant setting, i.e., before the operative time or chemotherapy, in order to improve the overall survival and to reduce the morbidity and mortality of both the disease and its treatment. However, some patients do not respond to checkpoint inhibitors. As result, the capability for identifying patients that are eligible for this immunotherapy represent one of the efforts of ongoing studies. The aim of this systematic review is to summarize the most recent evidence regarding the use of immune checkpoint inhibitors, in a neoadjuvant and adjuvant setting, in the treatment of muscle-invasive bladder cancer.
| S-EPMC9139497 | biostudies-literature
Project description:Data Access Committee EGAC00001002276
| EGAC00001002276 | EGA
Project description:ObjectiveWe aim to describe and highlight the current use of immune checkpoint inhibitors (ICIs) in the muscle invasive bladder cancer (MIBC) treatment landscape, particularly focusing on the perioperative setting. We provide a comprehensive review of key trials of the use of ICI in the perioperative setting, discussing trial outcomes and limitations and reviewing the role of biomarkers.IntroductionICIs have recently been integrated into the treatment algorithm for metastatic urothelial carcinoma. More than 30 published studies have investigated the role of these agents in the radical treatment of MIBC. Some studies have demonstrated conflicting results, affecting widespread adoption in clinical practice.MethodsWe performed a narrative overview of the literature from databases including PubMed, MEDLINE, Embase, European society of Medical Oncology/American Society of Clinical Oncology Annual Proceedings, and clinicaltrials.gov databases up until December 2021.DiscussionWe described the results of key trials in the neoadjuvant and adjuvant setting, some of the reasons for conflicting study results, and the implications for clinical practice. Relevant biomarkers in the field are discussed, alongside a brief overview of the immune microenvironment in bladder cancer.ConclusionsPerioperative ICIs have shown promising efficacy with low toxicity in the neoadjuvant setting. The two large trials in the adjuvant setting have been contradictory. The efficacy of perioperative ICIs combined with favorable tolerability and better toxicity profile compared with chemotherapy, with the potential for biomarker-driven patient selection, may lead to a change in future practice. There is, however, a lack of long-term survival and toxicity data for those treated with ICIs, and this needs to be developed further to demonstrate an added survival benefit by using ICIs.
| S-EPMC9935774 | biostudies-literature
Project description:BackgroundMultiple single-arm clinical trials showed promising pathologic complete response rates with neoadjuvant immune checkpoint inhibitors (ICIs) in muscle-invasive bladder cancer. We conducted a cost-effectiveness analysis comparing neoadjuvant ICIs with cisplatin-based chemotherapy (CBC).MethodsWe applied a decision analytic simulation model with a health care payer perspective to compare neoadjuvant ICIs vs. CBC. For the primary analysis we compared pembrolizumab with ddMVAC. We performed a secondary analysis with gemcitabine/cisplatin as CBC and exploratory analyses with atezolizumab or nivolumab/ipilimumab as ICI. We input pathologic complete response rates from trials or meta-analysis and costs from average sales price. Outcomes of interest included costs, 2-year recurrence-free survival (RFS), and incremental cost-effectiveness ratio (ICER) of cost per 2-year RFS. A threshold analysis estimated a price reduction for ICI to be cost-effective and one-way and probabilistic sensitivity analyses were performed.ResultsThe incremental cost of pembrolizumab compared with ddMVAC was $8,041 resulting in an incremental improvement of 1.5% in 2-year RFS for an ICER of $522,143 per 2-year RFS. A 21% reduction in cost of pembrolizumab would render it more cost-effective with an ICER of $100,000 per 2-year RFS. GC required an 89% pembrolizumab cost reduction to achieve an ICER of $100,000 per 2-year RFS. Atezolizumab appeared to be more cost-effective than ddMVAC.ConclusionsICIs were not cost-effective as neoadjuvant therapies, except when atezolizumab was compared with ddMVAC. Randomized clinical trials, larger sample sizes and longer follow-up are required to better understand the value of ICIs as neoadjuvant treatments.
| S-EPMC8455700 | biostudies-literature
Project description:Neoadjuvant immune checkpoint blockade (ICB) has shown unprecedented activity in mismatch repair deficient (MMRd) colorectal cancers, but its effectiveness in MMRd endometrial cancer (EC) remains unknown. In this investigator-driven, phase I, feasibility study (NCT04262089), 10 women with MMRd EC of any grade, planned for primary surgery, received two cycles of neoadjuvant pembrolizumab (200 mg IV) every three weeks. All patients completed treatment without severe toxicity. A partial radiologic response was observed in 3/10 patients, 5/10 patients had stable disease and 2/10 patients were non-evaluable on Magnetic Resonance Imaging (MRI). Pathologic response was observed in 5/10 patients, with 2 patients showing a major pathologic response. No patient achieved a complete pathologic response. At median duration of follow-up of 22.5 months, two non-responders experienced disease recurrence. Monoclonal T cell expansion significantly correlated with treatment response. Tumour-draining lymph nodes displayed clonal overlap with intra-tumoural T cell expansion. All pre-specified endpoints were reached. Neoadjuvant ICB with pembrolizumab proved safe and induced pathologic, radiologic, and immunologic responses in MMRd EC, warranting further exploration of extended neoadjuvant treatment.
2024-07-19 | GSE268903 | GEO
Project description:Purpose: Neoadjuvant cisplatin-based Chemotherapy (NAC) followed by cystectomy is the standard of care for patients with muscle-invasive bladder cancer (MIBC). Unfortunately, only a third of patients achieve pathologic complete response (pCR). The aim of this study is to deeply investigate the role played by peripheral immunogenicity and the Tumor and Immune Microenvironment (TIME) in patients undergoing NAC to identify predictive and pharmacodynamic biomarkers associated with treatment response or treatment resistance. Experimental design: N= 19 patients with MIBC received NAC and were classified as pCR (n=10) or non-pCR (n=9). Bulk RNA-seq was performed on 13 formalin-fixed paraffin-embedded (FFPE) tumor biopsies collected before treatment with NAC and immune protein evaluations using GeoMx Digital Spatial Profiling (DSP) technology were performed on matched FFPE tumor biopsies collected before and after treatment with NAC. Matching Peripheral blood collected prior treatment initiation and during cystectomy was assessed for lymphocytes and neutrophils counts. Kaplan–Meier analyses and Cox PH regression models were used for survival analyses (OS). Results: Genes associated with immune signaling and DNA repair signaling correlated with treatment outcome of patients with MIBC undergoing NAC. At baseline, gene expression analysis and digital special profile highlighted an abundance of B cells and a reduced neuroendocrine phenotype in the TME of pCR vs. no-pCR. Increased protein expression of immune checkpoints molecules (e.g. LAG3, ICOS, PD-L1) was also observed in the TME of patients with no-pCR. In peripheral blood, a significant increase of lymphocytes and decrease of neutrophils counts, respectively, was observed in pCR vs no-pCR following NAC. Conclusions: When confirmed on a larger cohort, our results might lead to novel therapeutic strategies and to novel biomarkers predicting patients likely to respond to NAC.
2024-08-16 | GSE247185 | GEO
Project description:Immunological classifiers that predict patient outcome and therapeutic responses have been constructed through targeted immune gene expression profiling of pre-treatment bone marrow samples from patients with acute myeloid leukaemia treated with pembrolizumab and hypomethylating agent azacytidine (clinicaltrials.gov identifier: NCT02845297).
2022-09-16 | GSE178926 | GEO
Project description:Non-muscle-invasive bladder cancer (NMIBC) is characterized by a high rate of cure, but also by a non-negligible probability of recurrence and risk progression to muscle-invasive disease. NMIBC management requires a proper local resection and staging, followed by a risk-based treatment with intravesical agents. For many years, the current gold standard treatment for patients with intermediate or high-risk disease is transurethral resection of the bladder (TURB) followed by intravesical bacillus Calmette-Guérin (BCG) instillations. Unfortunately, in about half of high-risk patients, intravesical BCG treatment fails and NMIBC persists or recurs early. While radical cystectomy remains the gold standard for these patients, new therapeutic targets are being individuated and studied. Radical cystectomy in fact can provide an excellent long-term disease control, but can deeply interfere with quality of life. In particular, the enhanced immune checkpoints expression shown in BCG-unresponsive patients and the activity of immune checkpoints inhibitors (ICIs) in advanced bladder cancer provided the rationale for testing ICIs in NMIBC. Recently, pembrolizumab has shown promising activity in BCG-unresponsive NMIBC patients, obtaining FDA approval. Meanwhile multiple novel drugs with alternative mechanisms of action have proven to be safe and effective in NMIBC treatment and others are under investigation. The aim of this review is to analyse and describe the clinical activity of new emerging drugs in BCG-unresponsive NMIBC focusing on immunotherapy results.
| S-EPMC8834622 | biostudies-literature
Project description:The success of immunotherapy and targeted therapy for metastatic melanoma has generated considerable interest in the adjuvant setting, even though high-risk stage III melanoma (with or without in-transit metastases) still holds a substantial probability of relapse, despite surgical resection and available adjuvant treatments. Based on preclinical and clinical trials in resectable melanoma, immune checkpoint inhibitors can enhance anti-tumor immunity by activating antigen-specific T cells found in the primary site. These tumor-reactive T cells continue to exert their anti-tumor effects on remaining neoplastic cells after resection of the primary tumor, potentially preventing relapses from reoccurring. Several trials in the neoadjuvant setting have been conducted for melanoma patients using checkpoint inhibitors with promising early data, showing an improvement of operability and clinical outcomes. Hence, in this study, we review and discuss the available published and ongoing clinical trials to explore the scientific background behind immunotherapy in the neoadjuvant context.
| S-EPMC9122306 | biostudies-literature