scholarly journals Advances in Immunotherapy and the TGF-β Resistance Pathway in Metastatic Bladder Cancer

Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5724
Author(s):  
David J. Benjamin ◽  
Yung Lyou
Keyword(s):  
Bladder Cancer ◽  
Clinical Trials ◽  
Checkpoint Inhibitors ◽  
Locally Advanced ◽  
Resistance Mechanism ◽  
Small Subset ◽  
Advanced Tumor ◽  
Resistance Pathway ◽  
Promising Therapeutic Approach ◽  
Line Setting

Bladder cancer accounts for nearly 200,000 deaths worldwide yearly. Urothelial carcinoma (UC) accounts for nearly 90% of cases of bladder cancer. Cisplatin-based chemotherapy has remained the mainstay of treatment in the first-line setting for locally advanced or metastatic UC. More recently, the treatment paradigm in the second-line setting was drastically altered with the approval of several immune checkpoint inhibitors (ICIs). Given that only a small subset of patients respond to ICI, further studies have been undertaken to understand potential resistance mechanisms to ICI. One potential resistance mechanism that has been identified in the setting of metastatic UC is the TGF-β signaling pathway. Several pre-clinical and ongoing clinical trials in multiple advanced tumor types have evaluated several therapies that target the TGF-β pathway. In addition, there are ongoing and planned clinical trials combining TGF-β inhibition with ICI, which may provide a promising therapeutic approach for patients with advanced and metastatic UC.

scholarly journals The dynamics of the inflammatory response during BBN-induced bladder carcinogenesis in mice

2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Marina Degoricija ◽  
Jelena Korac-Prlic ◽  
Katarina Vilovic ◽  
Tonci Ivanisevic ◽  
Benedikt Haupt ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Inflammatory Response ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Locally Advanced ◽  
Histopathological Analysis ◽  
Tumor Escape ◽  
Induced Tumors ◽  
Frequent Mutations ◽  
Muscle Invasive

Abstract Background Bladder cancer (BC) is the most common malignant disease of the urinary tract. Recurrent high grade non muscle invasive BC carries a serious risk for progression and subsequent metastases. The most common preclinical mouse model for bladder cancer relies on administration of N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) to mice. BBN-induced tumors in mice recapitulate the histology of human BC and were characterized with an overexpression of markers typical for basal-like cancer subtype in addition to a high mutational burden with frequent mutations in Trp53, similar to human muscle invasive BC. Methods Bladder cancer was induced in C57BL/6J male mice by administering the BBN in the drinking water. A thorough histopathological analysis of bladder specimen during and post BBN treatment was performed at 2, 4, 16, 20 and 25 weeks. RNA sequencing and qPCR was performed to assess the levels of expression of immunologically relevant genes at 2 weeks and 20 weeks during and post BBN treatment. Results We characterized the dynamics of the inflammatory response in the BBN-induced BC in mice. The treatment with BBN had gradually induced a robust inflammation in the first 2 weeks of administration, however, the inflammatory response was progressively silenced in the following weeks of the treatment, until the progression of the primary carcinoma. Tumors at 20 weeks were characterized with a marked upregulation of IL18 when compared to premalignant inflammatory response at 2 weeks. In accordance with this, we observed an increase in expression of IFNγ-responsive genes coupled to a pronounced lymphocytic infiltrate during the early stages of malignant transformation in bladder. Similar to human basal-like BC, BBN-induced murine tumors displayed an upregulated expression of immunoinhibitory molecules such as CTLA-4, PD-L1, and IDO1 which can lead to cytotoxic resistance and tumor escape. Conclusions Despite the recent advances in bladder cancer therapy which include the use of checkpoint inhibitors, the treatment options for patients with locally advanced and metastatic BC remain limited. BBN-induced BC in mice displays an immunological profile which shares similarities with human MIBC thus representing an optimal model for preclinical studies on immunomodulation in management of BC.

Updates in the management and future landscape of urothelial carcinoma

2020 ◽  
pp. 107815522097102
Author(s):  
Kirollos S Hanna ◽  
Maren Campbell ◽  
Adam Kolling ◽  
Alex Husak ◽  
Sabrina Sturm ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Urothelial Carcinoma ◽  
Metastatic Disease ◽  
Checkpoint Inhibitors ◽  
Early Stage ◽  
Locally Advanced ◽  
The United States ◽  
Cancer Type ◽  
Antibody Drug Conjugate ◽  
Early Stage Disease

Urothelial carcinoma is the sixth most common cancer type in the United States. Although most patients present with early stage disease which is associated with improved outcomes, many will progress to locally advanced or metastatic disease. Immune checkpoint inhibitors have significantly impacted the treatment paradigm for patients and have resulted in improved survival rates. Despite their proven efficacy, many ongoing clinical trials continue to refine combinations with chemotherapy, sequencing of therapies and the role of ligand expression. Additionally, novel targets have been identified for advanced urothelial carcinoma and have led to the approval of the antibody-drug conjugate, enfortumab vedotin, and the fibroblast growth factor receptor-targeted, erdafitinib. Enrollment in a clinical trial is strongly encouraged for all stages of advanced or metastatic disease. Numerous ongoing clinical trials are likely to impact the treatment armamentarium for patients. In this manuscript, we highlight key updates in the clinical management for patients and outline ongoing trials.

Analysis of real-world data (RWD) on treatment (tx) sequencing in patients with advanced non-small cell lung cancer (aNSCLC).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e20642-e20642
Author(s):  
Meng Ma ◽  
Xiang Zhou ◽  
Howard Goldsweig ◽  
Nicholas Hahner ◽  
Dianwei Han ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Targeted Therapy ◽  
Kinase Inhibitors ◽  
Checkpoint Inhibitors ◽  
Rank Test ◽  
Real World Data ◽  
Therapeutic Modalities ◽  
Platinum Based Chemotherapy ◽  
Line Of Therapy ◽  
Line Setting

e20642 Background: While optimal sequencing of systemic therapy in aNSCLC is critical to achieve maximal clinical benefit, it is practically challenging to study tx sequencing through clinical trials. RWD allow retrospective, observational studies to examine tx patterns and associated clinical outcomes. Methods: 1,609 aNSCLC patients who received systemic therapies at Mount Sinai hospitals were analyzed for the number of line of therapy (LOT), therapeutic modalities (chemotherapy, targeted therapy and immunotherapy), and the sequence in which treatments were given when LOT > 1. Time to tx discontinuation (TTD) was used as a surrogate clinical endpoint for outcomes. Results: 578 of the 1,609 (36%) patients received more than one LOT. 356 (22%) received tyrosine kinase inhibitors (TKIs), and 297 (16%) received immune checkpoint inhibitors (CPIs). Kaplan-Meier analysis revealed that among 297 patients who received CPIs, median TTD was longer in the 1st line setting (295 days, 95% CI 169 to 523; n=132) than when LOT > 1 (169 days, 95% CI 113 to 269; n=165), although the difference was not statistically significant (P=0.092, log-rank test). No difference of TTD on TKIs was observed between LOT = 1 and LOT > 1 (P=0.51). With respect to tx sequencing, when patients (n=94) received TKIs as the 1st LOT, 60%, 35%, and 5% of them received another TKI, chemotherapy, or a CPI-containing regimen, respectively, as the 2nd LOT. Among patients (n=370) who progressed on 1st line platinum-based chemotherapy, 52%, 32%, and 16% received another chemo regimen, a CPI-containing regimen, or a targeted therapy, respectively, as the 2nd LOT; these percentages shifted significantly toward more CPIs (24%, 66%, 10% for chemo, CPI, targeted, respectively) when only 2016-2018 data were examined. In the 2nd line setting after platinum therapy, TTD was significantly longer in the CPI group (332 days, 95% CI 169-484) compared to the chemo group (88 days, 95% CI 65-100; P<0.0001), consistent with results from pivotal clinical trials. Conclusions: As the tx algorithm of aNSCLC has been evolving rapidly, we observed diverse tx patterns in RWD. Various tx sequences may impact patient outcomes, and therefore warrant further investigation.

A phase II, randomized study of nivolumab (nivo) or nivo plus BMS-986205 with or without intravesical Bacillus Calmette-Guerin (BCG) in BCG-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC): CheckMate 9UT.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. TPS493-TPS493 ◽  
Author(s):  
Noah M. Hahn ◽  
Sam S. Chang ◽  
Maxwell Meng ◽  
Neal D. Shore ◽  
Badrinath R. Konety ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
High Risk ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Locally Advanced ◽  
Unmet Need ◽  
Clinical Activity ◽  
Free Survival ◽  
Bcg Therapy ◽  
Intravesical Bcg

TPS493 Background: Immune checkpoint inhibitors, including nivo (anti–PD-1), have demonstrated favorable tolerability and efficacy profiles, ushering in a new treatment (tx) paradigm for advanced bladder cancer (advBC). However, an unmet need exists for new effective tx options in earlier stages of disease, specifically for patients (pts) with BCG-unresponsive, high-risk NMIBC. Increased IDO and PD-L1 expression in NMIBC tumors (Inman, et al. Cancer 2007; Hudolin, et al. Anticancer Res 2017), support the combination of anti–PD-1 and IDO1 inhibition in NMIBC. BMS-986205, a selective, potent, once-daily IDO1 inhibitor that works early in the IDO1 pathway, has demonstrated clinical activity in combination with nivo in pts with immunotherapy-naive advBC who received ≥ 1 prior line of therapy (objective response rate, 37%; Tabernero, et al. J Clin Oncol 2018;36(suppl) [abstr 4512]). These findings provide a rationale for investigation of nivo + BMS-986205 ± intravesical BCG therapy in BCG-unresponsive high-risk NMIBC. Here we describe a phase 2, randomized, open-label study assessing the safety and efficacy of nivo ± BMS-986205 ± intravesical BCG in pts with BCG-unresponsive, high-risk NMIBC. Methods: Pts aged ≥ 18 years with BCG-unresponsive (per February 2018 FDA guidance), high-risk NMIBC, defined as carcinoma-in-situ (CIS) with or without papillary component, any T1, or Ta high-grade lesions, will be enrolled. Pts must have urothelial carcinoma as the predominant histological component (>50%). Key exclusion criteria include locally advanced or metastatic BC, upper urinary tract disease within 2 years, prostatic urethral disease within 1 year, and prior immunotherapy. Using a novel adaptive-type design, pts will be randomized to 1 of 4 tx arms with nivo ± BMS-986205 ± BCG. Primary endpoints include proportion of pts with CIS with complete response (CR), duration of CR in pts with CIS, and event-free survival for all pts without CIS. Secondary endpoints are progression-free survival and safety. This global study in 13 countries is underway, with a target enrollment of 436 pts. ( Clinical trial information: NCT03519256.

scholarly journals Advances and Controversies With Checkpoint Inhibitors in Bladder Cancer

2021 ◽  
Vol 15 ◽  
pp. 117955492110449
Author(s):  
Logan P Rhea ◽  
Jeanny B Aragon-Ching
Keyword(s):  
Bladder Cancer ◽  
Checkpoint Inhibitors ◽  
Phase Iii ◽  
First Line ◽  
Disease States ◽  
Metastatic Setting ◽  
Phase Iii Trials ◽  
Line Setting ◽  
Almost All ◽  
Confirmatory Phase

Immune checkpoint inhibitors have revolutionized the treatment of bladder urothelial cancers and have wide application in almost all disease states. Although several drugs have initially been shown to be beneficial in the second-line metastatic setting, there are still ongoing controversies and debate, including voluntary withdrawals of durvalumab and atezolizumab, along with the approval of agents in the first-line setting in the cisplatin-ineligible state based on inconsistent confirmatory phase III trials. As novel immunotherapy drugs are discovered and studied in various phases of clinical trials, these agents will continue to change the treatment landscape for bladder cancer patients. This review will discuss current available evidence and information and key pivotal trials using checkpoint inhibitors in bladder cancer.

Repurposing infectious diseases vaccines against cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e14564-e14564
Author(s):  
Gauthier Bouche ◽  
Liese Vandeborne ◽  
Pan Pantziarka ◽  
An M. T. Van Nuffel
Keyword(s):  
Bladder Cancer ◽  
Clinical Trials ◽  
Infectious Diseases ◽  
Nk Cell ◽  
Checkpoint Inhibitors ◽  
Research Area ◽  
Future Research ◽  
Varicella Zoster ◽  
Research Activities ◽  
Immunological Mechanisms

e14564 Background: Vaccines used to prevent infection have long been known to stimulate immune responses to cancer as illustrated by the approval of the Bacillus Calmette–Guérin (BCG) vaccine to treat bladder cancer since the 1970s. The recent approval of immunotherapies has rejuvenated this research area with reports of anti-tumour responses with existing infectious diseases vaccines used as such, either alone or in combination with approved immune checkpoint inhibitors. This prompted us to review recent research activities using approved vaccines to treat cancer. Methods: PubMed and clinicaltrials.gov databases were queried for all 31 infectious diseases having at least one preventive vaccine approved, and all hits were reviewed for relevance. Only articles and trial registrations about infectious diseases vaccines used in an unmodified form as treatment for cancer, were included. The search was restricted in time, capturing articles from the year 2000 until November 2020. Results: A total of 1,754 PubMed abstracts and 549 trial registrations were screened. Data supporting a cancer therapeutic use was found for 16 of the 31 infectious diseases vaccines. For 10 (BCG, diphtheria, tetanus, human papillomavirus (HPV), influenza, measles, pneumococcus, smallpox, typhoid and varicella-zoster), clinical trials have been conducted or are ongoing. Within the remaining 6, preclinical evidence supports further evaluation of the rotavirus, yellow fever and pertussis vaccine in carefully designed clinical trials. The mechanistic evidence for the cholera vaccine, combined with the observational data in colorectal cancer, is also supportive of clinical translation. There is limited data for the hepatitis B vaccine and for the mumps vaccine alone. Four findings are worth highlighting: first, the superiority of intra-vesical typhoid vaccine instillations over BCG instillations in a preclinical bladder cancer model, which is now the subject of a phase I trial; second, the perioperative use of the influenza vaccine to limit and prevent the NK cell dysfunction induced by cancer surgery; third, objective responses following intra-tumoral injections of the measles vaccine in cutaneous T-cell lymphoma; fourth, objective responses induced by the HPV vaccine in skin squamous cell carcinoma. Conclusions: Sixteen infectious diseases vaccines have been or are currently being explored for repurposing in oncology. All vaccines are intended to induce or improve an anti-tumour (immune) response. Next to biological and immunological mechanisms, that are very different from one vaccine to another, also the mode of administration and combinations and sequence with other (immuno-)therapies deserve more attention in future research.

scholarly journals Antibody Targeting of B7-H4 Enhances the Immune Response in Urothelial Carcinoma

2019 ◽  
Author(s):  
Joseph R. Podojil ◽  
Alexander P. Glaser ◽  
Dylan Baker ◽  
Elise T. Courtois ◽  
Damiano Fantini ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
T Cell ◽  
Urothelial Carcinoma ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Locally Advanced ◽  
Human Monocyte ◽  
Tumor Stage ◽  
Immune Checkpoints ◽  
Ifn Γ

AbstractLocally advanced urothelial carcinoma has a poor survival despite a response to immunotherapy in approximately 25% of patients. To develop new therapies targeting other immune checkpoints, we identified increased expression of the T cell inhibitor protein, B7-H4 (VTCN1, B7S1, B7X), during tumor development of murine bladder cancer. Evaluation of B7-H4 in human bladder cancer by single-cell RNA-Seq and immune mass cytometry showed that B7-H4 is expressed by luminal tumors that are not normally responsive to PD-1 inhibitors. Additionally, overexpression B7-H4 was associated with significantly worse patient survival. In support of clinical translation, treatment of human monocyte and T cell co-cultures with a B7-H4 blocking antibody resulted in enhanced IFN-γ secretion by CD4+ and CD8+ T cell. While the study of B7-H4 in mouse cancer models has been difficult using tumor cell lines, our findings show that B7-H4 expression increased at 3 months after exposure to BBN on CD11b+ monocytes/macrophages and delivery of anti-B7-H4 antibody resulted in decreased tumor size and increased CD8 immune cell infiltration with increased CD8+/IFN-γ-producing T cells and a complimentary decrease in tumor infiltrating T regulatory cells (Tregs). Furthermore, treatment with a combination of anti-PD-1 and anti-B7-H4 antibodies resulted in a significant reduction in tumor stage. This data suggests that novel anti-B7-H4 antibodies maybe a viable target for bladder cancers unresponsive to PD-1 checkpoint inhibitors.

scholarly journals Novel Options in Metastatic and Non-surgically Curable Bladder Cancer

2018 ◽  
Vol 14 (2) ◽  
pp. 87
Author(s):  
Elise Vong ◽  
Jens Samol ◽  
◽  
Keyword(s):  
Bladder Cancer ◽  
Checkpoint Inhibitors ◽  
Locally Advanced ◽  
Standard Of Care ◽  
Current Evidence ◽  
Predictors Of Response ◽  
Programmed Death ◽  
Platinum Based Chemotherapy ◽  
Programmed Cell Death 1 ◽  
Urothelial Bladder

For over two decades, the prognosis of patients with metastatic or locally advanced non-resectable bladder cancer has remained poor, with no significant advances in life-prolonging treatment, especially following progression on platinum-based chemotherapy or for cisplatin-ineligible patients. In recent years, immunotherapy has changed the standard of care for an increasing number of tumour types, including bladder cancer. Here, we will review the current evidence of the clinical usage of immune checkpoint inhibitors with a focus on programmed cell death-1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors, as well as their toxicities, potential biomarkers and predictors of response, and provide an outline of future directions in the treatment of patients with metastatic and/or non-surgically curable urothelial bladder cancer.

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