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PD1/PDL1 inhibitors for the treatment of advanced urothelial bladder cancer.

ABSTRACT: Introduction:Until recently, systemic chemotherapy was the only option for treating bladder cancer and outcomes remained dismal. After a long gap of no progress for 40 years, immuno-therapy with checkpoint inhibitors (PDL1 and PD1) has revolutionized the treatment paradigm of bladder cancer, with five approved agents to treat platinum-refractory bladder cancer since the first approval of atezolizumab in May 2016. Methods:This review summarizes the most recent data on approved checkpoint inhibitors currently used in management of advanced bladder cancer. Early- and late-phase trials of the five checkpoint inhibitors (pembrolizumab, nivolumab, atezolizumab, durvalumab, and avelumab) in advanced bladder cancer are reviewed in detail. This review also describes the potential application of PD1/PDL1 inhibitors in adjuvant and neoadjuvant settings and non-muscle-invasive bladder cancer, as well as with radiation in muscle-invasive bladder cancer treatment. The role of PDL1 and tumor-mutation burden and clinical considerations in choosing a particular immunotherapy are also discussed. Results:The approved checkpoint inhibitors (PD1 and PDL1 inhibitors) have similar efficacy and safety profiles in metastatic platinum-refractory bladder cancer, but they vary in dose and frequency and cost burden. However, only pembrolizumab has shown superiority over standard chemotherapy in a randomized Phase III setting so far. In addition, in the first-line setting for cisplatin-ineligible patients, both pembrolizumab and atezolizumab are US Food and Drug Administration-approved and well tolerated. There is a lack of consensus on the utility of testing for PDL1 as a predictive biomarker, as patients with no PDL1 expression also derive some clinical benefit. Tumor-mutation burden is another predictive biomarker, but needs further validation. Conclusion:Immunotherapy has offered a glimmer of hope to patients with bladder cancer. The current landscape is rapidly evolving, with novel immunotherapy-combination trials to improve outcomes further and evaluate predictive biomarkers to help identify patients most likely to benefit from such therapies.

SUBMITTER: Stenehjem DD

PROVIDER: S-EPMC6157986 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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PD1/PDL1 inhibitors for the treatment of advanced urothelial bladder cancer.

Stenehjem David D DD Tran Dao D Nkrumah Michael A MA Gupta Shilpa S

OncoTargets and therapy 20180919

<h4>Introduction</h4>Until recently, systemic chemotherapy was the only option for treating bladder cancer and outcomes remained dismal. After a long gap of no progress for 40 years, immuno-therapy with checkpoint inhibitors (PDL1 and PD1) has revolutionized the treatment paradigm of bladder cancer, with five approved agents to treat platinum-refractory bladder cancer since the first approval of atezolizumab in May 2016.<h4>Methods</h4>This review summarizes the most recent data on approved chec ...[more]

PMID: 30275703

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Project description:Objective:MLN4924, a pharmacological inhibitor of cullin neddylation, resulted in glioma cell apoptosis, deregulation of the S-phase of DNA synthesis and thus, offers great potential for the treatment of brain tumours. However, targeting the neddylation pathway with an MLN4924 treatment stabilized the hypoxia-inducible factor 1A (HIF1A), which is one of the main transcriptional enhancers of the immune checkpoint molecule PDL1 (programmid death ligand-1) in cancer cells. The influence of immune checkpoint molecules on glioma progression has recently been discovered; PDL1 overexpression in gliomas corresponds to a significant shortening of patient survival and a decrease of the anti-tumour immune response. We hypothesize that i) PDL1 is up-regulated in gliomas after treatment with MLN4924 and induces T-cell energy; ii) co-utilization of the PD1/PDL1 blockage with MLN4924 therapy may reduce T-cell energy and may engage MLN4924-induced tumour disruption with the immune response. Methods:PDL1 expression and its immunosuppressive role in gliomas, glioma microenvironments, and after treatments with MLN4924 were assessed by utilizing methods of immunohistochemistry, molecular biology, and biochemistry. Results:We confirmed PDL1 overexpression in clinical brain tumour samples, PDGx and established glioma cell lines, extracellular media from glioma cells, and CSF (cerebrospinal fluid) samples from tumour-bearing mice. Our primary T-cell based assays verified that the up-regulation of PDL1 in tumour cells protects gliomas from T-cell treatment and reduces T-cell activation. We found that a pharmacological inhibitor of cullin neddylation, MLN4924, exhibited strong cytotoxicity towards PDGx and established glioma cell lines, in vitro, with an IC50's range from 0.2 to 3 uM. However, we observed a significant increase of HIF1A and PDL1 in mRNA and protein levels in all glioma cell lines after treatment with MLN4924. The MLN4924-dependent induction of PDL1 in gliomas resulted in T-cell energy, which was blocked by a blockage of the PD1/PDL1 interaction. Conclusion:We conclude that i) PDL1 up-regulation in gliomas and the glioma microenvironment is an important chemotherapeutic target; ii) MLN4924 therapy, combined with a blockage of the PD1/PDL1 pathway, should be considered as a potential strategy for glioma treatment.

Project description:ObjectiveTo describe the current treatment landscape in advanced urothelial cancer (aUC)/metastatic urothelial cancer and in particular to review the relevant literature highlighting recent advances in the treatment of patients with aUC after progression on chemotherapy and immune checkpoint inhibitor (ICI).BackgroundaUC is a very aggressive disease with poor outcomes. Over the past several years, its treatment landscape has seen significant advances with the approval of ICI and targeted agents, which have led to improved outcomes. The current standard of care for most patients with aUC involves platinum-based chemotherapy followed by ICI after progression or as switch maintenance therapy (if no progression after chemotherapy). Treatment of patients following progression on ICI is more challenging, but novel therapies have been approved, such as erdafitinib for tumors with fibroblast growth factor receptor 2 (FGFR2) or FGFR3 activating mutation or fusion (can also be used following progression on platinum-based chemotherapy), enfortumab vedotin (EV) and sacituzumab govitecan (SG) in an unselected patient population. Many other trials in this space are currently ongoing and other promising agents may also potentially become available in the future.MethodsNarrative overview of the recent literature relevant to the treatment of advanced/metastatic urothelial cancer following progression on chemotherapy and ICI was undertaken. Relevant literature was obtained from review of computerized databases including pubmed.gov and proceedings of major conferences including American Society of clinical Oncology (ASCO) Meetings, GU ASCO Symposia and European Society of Medical Oncology (ESMO) Meetings.ConclusionsIn this narrative review, we highlight the current dynamic treatment landscape in aUC, emphasizing the recent important developments and a few examples of ongoing clinical trials. In particular, we focus on therapy options available following progression on platinum-based chemotherapy and ICI, a treatment space where until recently there had been no FDA-approved treatment options. The recent pivotal trials of antibody drug conjugates (ADCs) that led to FDA approvals in this space are highlighted, as are other agents currently in development. We conclude by discussing future directions and ongoing challenges in this evolving disease space.

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PD1/PDL1 inhibitors for the treatment of advanced urothelial bladder cancer.

Publications

PD1/PDL1 inhibitors for the treatment of advanced urothelial bladder cancer.

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