(UroToday.com) The 2024 American Society for Radiation Oncology (ASTRO) Annual Meeting held in Washington, DC between September 29^th and October 2^nd, 2024, was host to a presidential symposium of innovations in genitourinary cancers, specifically addressing the ‘renaissance’ of radiotherapy for renal cell carcinoma (RCC). Dr. Shankar Siva discussed whether stereotactic ablative radiotherapy (SABR) for the treatment of primary RCC is ready for ‘primetime’.

(UroToday.com) The 2024 American Society for Radiation Oncology (ASTRO) annual meeting held in Washington D.C. was host to the session GU Quick Pitch (GU 4). Dr. Qi Xin presented the 5-Year Results of the Prolong Study, evaluating Radiotherapy of the Primary Tumor and All Metastatic Lesions in Oligometastatic Prostate Cancer.

(UroToday.com) The 2024 American Society for Radiation Oncology (ASTRO) annual meeting held in Washington D.C. was host to the session GU Quick Pitch (GU 4). Dr. Chia-Lin Tseng presented the results of a prospective trial exploring Post-Prostatectomy Linac-Based Ultrahypofractionated Radiotherapy for Patients with Localized Prostate Cancer: Toxicity and Quality-of Life Results.

(UroToday.com) The 2024 American Society for Radiation Oncology (ASTRO) annual meeting held in Washington D.C., between September 29 and October 2 was host to the session GU Quick Pitch (GU 4). Dr. Omar Azem discussed the impact of prior local therapy on treatment response and survival of men with metastatic castrate resistant prostate cancer (mCRPC) in a secondary analysis of the COU-AA-302 and ACIS Trials.

(UroToday.com) The 2024 IBCN annual meeting included a session on the current status and future directions of antibody-drug conjugates, featuring a presentation by Dr. Markus Eckstein discussing mechanisms of resistance to antibody-drug conjugates.

(UroToday.com) The 2024 IBCN annual meeting included a session on treatment response correlates, featuring a presentation by Dr. Aymeric Zadoroznyj discussing the systematic evaluation of differentially expressed genes associated with response to neoadjuvant chemotherapy in muscle invasive bladder cancer. Neoadjuvant cisplatin-based combination chemotherapy is standard of care for patients with muscle-invasive bladder cancer. Around one-third of patients achieve a pathologic complete response (ypT0N0) and have excellent survival after radical cystectomy. Predicting pathologic complete response based at TURBT would enable selective administration of neoadjuvant chemotherapy, sparing patients from side effects and exposure to ineffective therapy. At IBCN 2024, Dr. Zadoroznyj and colleagues aimed to identify genes that robustly predict pathologic complete response in published transcriptomes and integrate data from several studies to prioritize genes for experimental validation.

(UroToday.com) The 2024 IBCN annual meeting included a session on treatment response correlates, featuring a presentation by Dr. Jacqueline Fontugne discussing the quantification of intra-tumoral molecular subtype heterogeneity in muscle invasive bladder cancer from histological slides using a deep learning approach in the VESPER trial.^1,2 Dr. Fontugne and colleagues have previously demonstrated in the VESPER trial that muscle invasive bladder cancer patients with molecular subtype intra-tumoral heterogeneity show poor prognosis in a cohort of chemotherapy-treated patients:

(UroToday.com) The 2024 IBCN annual meeting included a session on treatment response correlates, featuring a presentation by Dr. Hardev Pandha discussing oncolytic virotherapy expressing a novel TLR agonist and IL-15 for the treatment of NMIBC. The efficacy of BCG therapy in NMIBC results from direct interaction of BCG with urothelial and bladder cancer cells, and activation of innate and adaptive immune responses. The crucial role of TLR activation by BCG has been highlighted previously. Using an NF-KB reporter system coupled to the appropriate TLR receptors, Dr. Pandha and colleagues screened microbial ligands of a range of TLRs to identify a very highly potent ligand (superior to lipopolysaccharide) for expression in their backbone recombinant oncolytic herpesvirus. This has been engineered to be immunostimulatory and tumor-selective, and expresses IL-15 for proliferation of B lymphocytes and NK cells and activates CD4+ and CD8+ T cells:

The resultant virus, HSV5-15, was tested using in vitro and in vivo models. The hypothesis was that oncolytic HSV1 would be very efficient in killing cells, viral DNA activates the cGAS/STING pathway, subsequently modulating the exhausted/suppressive tumor microenvironment for delivery of key cytokines and activating/sustaining innate and adaptive immune cells.

Construction of viruses were undertaken to create variants expressing a cytokine with or without a TLR agonist, NF-κB activity assays, viral growth curves, cellular death/immunogenic cell death assays, THP-1 macrophage response assays, and an in vivo subcutaneous model of bladder cancer: 

HSV5-15 had potent antitumor effects across a range of murine and human bladder cancer cell lines:

In vivo, using the subcutaneous MB49 bladder cancer model, HSV5-15 virus expressing both the cytokine and TLR agonist demonstrated selective cytotoxicity towards cancer cells while simultaneously triggering potent anti-cancer immunity to prevent recurrence: 

HSV5-15 cured 40-50% of the mice, and 100% of these animals resisted rechallenge with MB49. Moreover, the virus elicited efficient cytotoxicity and activation of both innate and adaptive immune responses, with activation of TNF-α.

Dr. Pandha concluded his presentation discussing oncolytic virotherapy expressing a novel TLR agonist and IL-15 for the treatment of NMIBC with the following take-home points:

• There is a resurgent interest in oncolytic virotherapy
• The CG Oncology program confirms feasibility, safety and efficacy, which led to FDA fast track and breakthrough (BOND-003) of cretostimogene
• HSV-1 is already licensed and validated in melanoma
• oHSV-IL15-TLR5 has cytotoxic and immunomodulatory activity and was well tolerated in a murine model

Presented by: Hardev Pandha, MD, University of Surry, Guilford, UK

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2024 International Bladder Cancer Network (IBCN) Annual Meeting, Bern, Switzerland, Thurs, Sept 19 – Sat, Sept 21, 2024

(UroToday.com) The 2024 IBCN annual meeting included a session on treatment response correlates, featuring a presentation by Dr. Trine Strandgaard discussing spatial proteomics and transcriptomics in patients unresponsive to BCG treatment. Patients with high-risk non-muscle invasive bladder cancer (NMIBC) are recommended treatment with BCG. The therapeutic effect of BCG is highly dependent on the host immune system and the tumor microenvironment. Previously, the cellular composition and the functional status of the tumor microenvironment have been shown to play crucial roles in BCG treatment efficacy: 

From bulk to single cell analyses, understanding biomarkers is important given that characteristics of the tumor microenvironment are not available from bulk analyses. Moreover, there is increasing granularity given potential interactions, phenotypes, and mechanisms of resistance. Using spatial proteomics and transcriptomics, Dr. Strandgaard and colleagues investigated the immune cell landscape in a cohort of BCG-treated patients.

A total of 183 tumors from 111 patients with NMIBC treated with BCG were included on a tissue microarray, which included paired pre- and post-BCG tumors. They analyzed the tumor tissue using Imaging Mass Cytometry for simultaneous detection of 36 immune and tumor-related proteins. Ilastik was used to generate probability maps, and DeepCell Mesmer was used for cell segmentation. Markers were quantified for the mean intensity per cell. The GeoMx Digital Spatial Profiler was used for spatial proteomics and transcriptomics profiling of tumor and stromal areas.

After computing a neighborhood graph using the log normalized and z-scaled signal and embedding it using UMAP, Leiden clustering was performed on 360,673 cells to detect communities of unique cell types by interrogating the presence of phenotypic markers:

The investigators observed more macrophages (p = 0.02), CD4 T cells (p < 0.001), and CD8 T cells (p = 0.004) after BCG:

Similarly, they found enrichment of cellular neighborhoods composed of immune cells after treatment. Patients who progressed to muscle invasive bladder cancer after BCG had higher numbers of CD4 T cells (p = 0.034), CD8 T cells (p = 0.023), and NK cells (p < 0.001) prior to BCG. Additionally, Dr. Strandgaard found high pretreatment expression of interferon signaling pathways in tumor regions from patients with a signature of CD8 T cell exhaustion after BCG using GeoMx Digital Spatial Profiler transcriptomic analysis:

These data suggest that immune phenotypes are important for response. Dr. Strandgaard concluded her presentation discussing spatial proteomics and transcriptomics in patients unresponsive to BCG treatment with the following take-home points:

• The composition and functional status of the tumor microenvironment is associated with clinical and biological features such as immune cell abundance, CD8 T cell exhaustion, and progression
• A greater understanding of the tumor microenvironment may help identify patients unresponsive to BCG and improve the understanding of biological differences in tumor development and aggressiveness, ultimately improving patient outcomes

Presented by: Trine Strandgaard, MD, MS, PhD, Aarhus University, Aarhus, Denmark

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2024 International Bladder Cancer Network (IBCN) Annual Meeting, Bern, Switzerland, Thurs, Sept 19 – Sat, Sept 21, 2024

(UroToday.com) The 2024 IBCN annual meeting included a session on molecular subtyping in the 2024, featuring a presentation by Dr. Yves Allory discussing the VESPER trial. The GETUG-AFU V05 VESPER trial is a randomized phase III trial of 500 patients with cT2-4aN0M0 urothelial carcinoma of the bladder receiving neoadjuvant chemotherapy or pT3-4 or pT_anyN+M_any receiving adjuvant chemotherapy.

(UroToday.com) The 2024 IBCN annual meeting included a session on molecular subtyping in the 2024, featuring a presentation by Dr. Saum Ghodoussipour discussing the LUMBER-NAC trial in progress. A standard treatment of muscle-invasive bladder cancer is neoadjuvant chemotherapy followed by radical cystectomy with pelvic lymph node dissection.

(UroToday.com) The 2024 IBCN annual meeting included a session on molecular subtyping in 2024, featuring a presentation by Dr. Jon Griffin discussing the trial in progress, GUSTO. The key question to be answered in GUSTO is: Will gene expression subtype guided neoadjuvant chemotherapy and/or immunotherapy better than unselected neoadjuvant treatment in patients with bladder cancer eligible for radical cystectomy? Additionally, there are several other outstanding questions:

(UroToday.com) The 2024 IBCN annual meeting included a session on the current status and future directions of antibody drug conjugates, featuring a presentation by Dr. Srikala Sridhar discussing antibody drug conjugate toxicity, management and clinical trial updates. The clinical trial updates portion of Dr. Sridhar’s talk was given on behalf of Dr. Matt Milowsky who was unable to attend the meeting. Bladder cancer is the 9^th most common cancer in the world, with >600,000 new cases worldwide. Patients present with an average age at diagnosis of 73 years, men are more frequently affected than women (3:1), with the key risk factor being smoking. The main histology is urothelial (pure or mixed), with some patients having variant histology. Depth of invasion into the bladder wall is important, and metastatic disease remains incurable. Until recently, life expectancy for metastatic disease was only 14 months, however new advances, including immune checkpoint inhibitors and antibody drug conjugates, have led to a nearly doubling of survival, thus it is a very exciting time in the field.

(UroToday.com) The 2024 IBCN annual meeting included a session on novel therapies and outcome measures in clinical trials, featuring a presentation by Dr. Gautier Marcq discussing the benefit of whole-pelvis radiation for patients with muscle-invasive bladder cancer. The value of pelvic lymph node irradiation is debated for patients with muscle-invasive bladder cancer undergoing curative-intent radiation therapy.

(UroToday.com) The 2024 IBCN annual meeting included a bladder cancer session, featuring a presentation by Dr. Amy Chan discussing influence of immortal time bias and conditional survival on the comparison of radical cystectomy versus trimodality therapy for muscle invasive bladder cancer. Dr. Chan and colleagues recently demonstrated, in a multi-institutional propensity score matched and weighted analysis study, similar oncological outcomes between radical cystectomy and trimodality therapy for select patients with muscle-invasive bladder cancer [1]. Despite using propensity score matching and inverse probability treatment weighting (IPTW) to balance groups when a randomized study is not available, inherent confounding variables and biases can persist. At IBCN 2024, Dr. Chan investigated the impact of immortal time bias as well as conditional survival on outcomes.

(UroToday.com) The 2024 IBCN annual meeting included a session on novel therapies and outcome measures in clinical trials, featuring a presentation by Dr. Colin Dinney discussing results from a comprehensive analysis from BOND-003 assessing translational correlates using urinary genomic disease burden to assess cretostimogene grenadenorepvec. Cretostimogene grenadenorepvec is a serotype-5 oncolytic adenovirus designed to selectively replicate in bladder cancer cells with alterations in the Retinoblastoma-E2F pathway. Additionally, the virus is engineered to express the GM-CSF transgene, resulting in a potent oncolytic immunotherapy mechanism of action. Pretreatment is required with the detergent dodecyl maltoside (DDM) to enhance gene transfer across the urothelium. The presumed mechanisms of action include lysis of Rb-deficient or E2F expressing tumor cells and immune activation by GM-CSF and neoantigens.

(UroToday.com) The 2024 IBCN annual meeting included a session on novel therapies and outcome measures in clinical trials, featuring a presentation by Dr. James Sullivan discussing preclinical characterization and translation to the clinic of EG-70. EG-70 (detalimogene voraplasmid) is an investigational, non-viral gene therapy designed to elicit local stimulation of anti-tumor immune response in the bladder and drive durable efficacy in patients with BCG-unresponsive high-risk NMIBC while mitigating the risk of systemic toxicities from immune stimulation:

(UroToday.com) The 2024 IBCN annual meeting included a session on emerging technologies in bladder cancer, featuring a presentation by Dr. Joseph Liao discussing augmented cystoscopy with deep learning. Dr. Liao notes that early diagnosis and accurate staging for bladder cancer is critical, with current strategies for risk stratification based on clinicopathological factors. Precision oncology relies on diagnostics, surgery, and therapy. Artificial intelligence is an enabling tool for clinical decision support and integrated risk stratification.

(UroToday.com) The 2024 IBCN annual meeting included a session on emerging technologies in bladder cancer, featuring a presentation by Dr. Andrea Necchi discussing the value of mpMRI in assisting decision-making in muscle-invasive bladder cancer.

(UroToday.com) The 2024 IBCN annual meeting included a session on novel therapies and outcome measures in clinical trials, featuring a presentation by Dr. Michiel van der Heijden discussing results from SunRISe-1, assessing TAR-200 + cetrelimab, TAR-200 alone, or cetrilumab alone in patients with BCG unresponsive high-risk non muscle invasive bladder cancer (NMIBC).