scholarly journals An Immunotherapy Strategy Targeting Programmed Cell Death Ligand 1 and CD73 with Macrophage-Derived Mimetic Nanovesicles to Treat Bladder Cancer

2021 ◽  
Author(s):  
Qidong Zhou ◽  
Weihong Ding ◽  
Zhiyu Qian ◽  
Quangang Zhu ◽  
Chuanyu Sun ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Inhibitory Effect ◽  
Immunotherapy Strategy ◽  
Multiple Drugs

Abstract BackgroundThe tumor microenvironment in bladder cancer exerts an inhibitory effect on immune effector cells. Thus, removing this inhibitory effect could help improve the efficacy of immune checkpoint inhibitors, and combination immunotherapy is a promising strategy for increasing the proportion of patients with bladder cancer who benefit from immune checkpoint inhibitors. However, it is difficult to effectively and simultaneously deliver multiple drugs to the tumor tissue. In this study, we describe the design and in vivo validation of macrophage-derived exosome-mimetic nanovesicles (EMVs) as a nanoplatform for coloading and targeted delivery of a CD73 inhibitor (AB680) and monoclonal antibodies targeting programmed cell death ligand 1 (aPDL1). ResultsOur results indicated that these nanocomplexes (AB680@EMVs-aPDL1) were highly stable, provided adequate biosafety in vivo, and exhibited enhanced targeting in a mouse model of bladder cancer. Moreover, the CD73 inhibitor reduced extracellular adenosine production, and the combination therapy significantly promoted activation of cytotoxic T lymphocytes, resulting in suppression of tumor growth in vivo. ConclusionsTherefore, using EMVs to deliver a combination of aPDL1 and a CD73 inhibitor may be an effective combined immunotherapy strategy for treating bladder cancer.

scholarly journals The Impact of Immune Checkpoint-Inhibitors Therapy in Urinary Bladder Cancer

Onco ◽  
2021 ◽  
Vol 1 (1) ◽  
pp. 3-22
Author(s):  
Ana Lúcia Silva ◽  
Pedro Abreu-Mendes ◽  
Diana Martins ◽  
Fernando Mendes
Keyword(s):  
Bladder Cancer ◽  
Cell Death ◽  
Tumor Microenvironment ◽  
Programmed Cell Death ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Cytotoxic T Cells ◽  
The Impact ◽  
Cell Death Protein

Bladder cancer (BC) is one of the most common cancers in the world. From an early age, it was observed that chronic inflammation is associated with conditions favorable to the development of tumors, as well as the tumor microenvironment. Moreover, regulating tumor progression also interferes with the therapy’s response. The interaction between the tumor and the immune system led to the development of new immune therapies, the immune checkpoint inhibitors. Immunotherapy has shown a better safety profile, survival, and tolerance compared to standard chemotherapy. This therapy offers an effective alternative to patients who are ineligible for cisplatin and patients with advanced disease progression after platinum-based therapy. The first immunotherapy approved for BC was intravesical instillation with Bacillus Calmette–Guérin, for tumors at early stages. Later, immunotherapy focused on immune checkpoint inhibitors, namely, anti-programmed cell death protein 1 (PD1), anti-programmed cell death protein ligand 1(PD-L1), and anti-antigen 4 associated with cytotoxic T cells (CTLA-4). Currently, five immune checkpoint inhibitors for advanced BC are approved by the Food and Drug Administration (FDA): Atezolizumab, Durvalumab, Avelumab, Pembrolizumab, and Nivolumab. This review addresses the correlation between inflammation, tumor microenvironment, and cancer; various studies regarding immune checkpoint inhibitors, either in monotherapy or in combination therapy, are also addressed.

284 Real World Data of Sequencing Immune Checkpoint Inhibitors (ICI) after Initial ICI

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A310-A310
Author(s):  
Krishna Gunturu ◽  
Muhammad Awidi ◽  
Rojer Ranjit ◽  
Brendan Connell ◽  
Rachel Carrasquillo ◽  
...  
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Real World ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Medical Center ◽  
Clear Understanding ◽  
Real World Data ◽  
World Data

BackgroundICI revolutionized modern Oncology landscape and being utilized in metastatic to adjuvant and neo-adjuvant settings. As Oncologists, we are treating cancer patients with ICI every day, yet there is still a lot that is unknown about these drugs. We don’t have clear understanding of the efficacy and toxicity when sequencing one ICI for another. We conducted a retrospective review of real world data at Lahey Hospital and Medical Center to understand further and to pave path for prospective studies to understand this issue further to improve patient care.MethodsWe retrospectively reviewed Oncology patient charts who received ICI between January1, 2014 to December 18, 2018. Total 483 patients received ICI during this time frame and 22 of these patients received a second ICI either as monotherapy or in combination with other ICI or chemotherapy.ResultsA total of 22 patients received subsequent ICI after the initial ICI as showed in table 1. 15 of the 22 (68%) patients were transitioned from one ICI to another monotherapy. 11 of these patients were transitioned secondary to disease progression (73%), three had immune related adverse events and one was switched per standard of care. One patient had ICI re-challenge. Three patients had a transition from ICI monotherapy to combination ICI therapy. One patient went onto chemo-immunotherapy and 2 patients transitioned from combination ICI to chemo-immunotherapy.Abstract 284 Table 1Real world data of sequencing immune checkpoint inhibitors (ICI) after initial ICIConclusionsICI therapy is evolving and patients are being treated with multiple lines of ICI. In current practices, ICI is frequently being transitioned from cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death 1 (PD-1) or its ligand, programmed cell death ligand 1 (PD-L1) classes or combined with chemotherapy or targeted therapy. It would be prudent to explore the effects of sequencing these medications either as a monotherapy or in combination with other therapies to better serve our patients and to prevent financial toxicity.

scholarly journals Management of Hematologic Adverse Events Associated With Immune Checkpoint Inhibitors

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Barbara Barnes Rogers, CRNP, MN, AOCN, ANP-BC ◽  
Carolyn Zawislak, MPAS, PA-C ◽  
Victoria Wong, PA-C
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Adverse Events ◽  
Immune Checkpoint ◽  
Blood Cells ◽  
Immune Checkpoint Inhibitors ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
White Blood Cells ◽  
Activated T Cells

Immune checkpoint inhibitors target suppressor receptors, including cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1), and programmed cell death ligand 1 (PD-L1). The activated T cells are not antigen specific; therefore, the blockade of the immune checkpoint may result in the development of autoimmune adverse events. The most common immune-related adverse events (irAEs) are rash, colitis, and endocrinopathies. However, irAEs that affect the hematologic system are rare and can affect red blood cells (e.g., autoimmune hemolytic anemia), white blood cells, and platelets (e.g., immune thrombocytopenia). Usually one cell line is affected; however, in some cases, multiple cell lines can be affected. Other changes in the hematologic system can also be affected (e.g., cryoglobulinemia, cytokine release syndrome). Due to the rarity and lack of recognition of these AEs, the timing, spectrum of events, and clinical presentation are poorly understood. Management of hematologic irAEs usually involves the use of steroids; however, other agents (e.g., IVIG, cyclosporine, rituximab) or procedures (e.g., plasma exchange, transfusions) can also be used.

Cancer Immunotherapy-Immune Checkpoint Inhibitors in Hepatocellular Carcinoma

2021 ◽  
Vol 16 ◽  
Author(s):  
Jing Bai ◽  
Ping Liang ◽  
Qian Li ◽  
Rui Feng ◽  
Jiang Liu
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Cancer Immunotherapy ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Treatment Strategies ◽  
Locoregional Therapy ◽  
Incidence And Mortality

: Hepatocellular Carcinoma (HCC) is one of the most common malignancies, the incidence and mortality of which are increasing worldwide. Cancer immunotherapy has revolutionized cancer treatment in recent years. In particular, Immune Checkpoint Inhibitors (ICIs) as new therapeutic tools have demonstrated encouraging antitumor activity and manageable tolerability in HCC. Immunologic checkpoint blockade with antibodies targeting Programmed cell Death-1 (PD-1), Programmed cell Death Ligand-1 (PD-L1), and Cytotoxic T Lymphocyte-Associated protein-4 (CTLA-4) strengthens tumor immunity by restoring exhausted T cells. Although the efficacy of combination treatment strategies using ICIs combined with other ICIs, molecular targeted agents, systemic therapy, or locoregional therapy has been well documented in numerous preclinical and clinical studies on several types of cancers, most HCC patients do not benefit from ICI treatment. This review highlights recent developments and potential opportunities related to ICIs and their combination in the management of HCC. The present article also includes recent patent review coverage on this topic.

scholarly journals Immune Thrombocytopenia Induced by Immune Checkpoint Inhibitors in Solid Cancer: Case Report and Literature Review

2020 ◽  
Vol 10 ◽  
Author(s):  
Xiaolin Liu ◽  
Xiuju Liang ◽  
Jing Liang ◽  
Yan Li ◽  
Jun Wang
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Immune Checkpoint ◽  
Immune Thrombocytopenia ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Cancer Case ◽  
Solid Cancer ◽  
Severe Thrombocytopenia ◽  
Advanced Cancer Patients

Immune checkpoint inhibitors, including antibodies targeting programmed cell death protein-1 (PD-1) and its receptor programmed cell death ligand-1 (PD-L1), represent promising therapeutic strategies for advanced human malignancies. However, a subgroup of patients experiences various autoimmune toxicities, termed immune-related adverse events (irAEs), that occur as a result of on-target and off-tumor autoimmune responses. Although irAEs are generally confirmed to be less severe than toxicities caused by conventional chemotherapy and targeted therapy, uncommon irAEs, such as immune thrombocytopenia, may occur with a very low incidence and sometimes be severe or fatal. This review focuses on the epidemiology, clinical presentation, and prognosis of immune thrombocytopenia occurring in advanced cancer patients induced by immune checkpoint inhibitors, especially in those with PD-1 or PD-L1 inhibitor treatment. We also first present one patient with non-small cell lung cancer who received the PD-L1 inhibitor durvalumab and developed severe thrombocytopenia.

scholarly journals Tumour Microenvironment and Immune Evasion in EGFR Addicted NSCLC: Hurdles and Possibilities

Cancers ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1419 ◽  
Author(s):  
Antonio Santaniello ◽  
Fabiana Napolitano ◽  
Alberto Servetto ◽  
Pietro De Placido ◽  
Nicola Silvestris ◽  
...  
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Growth Factor Receptor ◽  
Tumour Microenvironment ◽  
Almost All ◽  
Nsclc Patients

In the last few years, the treatment strategy in Non-Small Cell Lung Cancer (NSCLC) patients has been heavily modified by the introduction of the immune-checkpoint inhibitors. Anti-programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) therapy has improved both progression-free and the overall survival in almost all subgroups of patients, with or without PDL1 expression, with different degrees of responses. However, there are patients that are not benefitting from this treatment. A defined group of immune-checkpoint inhibitors non-responder tumours carry EGFR (epidermal growth factor receptor) mutations: nowadays, anti-PD-1/PD-L1 clinical trials often do not involve this type of patient and the use of immune-checkpoint inhibitors are under evaluation in this setting. Our review aims to elucidate the mechanisms underlying this resistance: we focused on evaluating the role of the tumour microenvironment, including infiltrating cells, cytokines, secreted factors, and angiogenesis, and its interaction with the tumour tissue. Finally, we analysed the possible role of immunotherapy in EGFR mutated tumours.

scholarly journals PD-L1, an Important Immune Checkpoint Regulator, Is Suppressed by miR-34a in Head and Neck Squamous Cell Carcinoma

2020 ◽  
Author(s):  
Kenjiro Higashi ◽  
Takenori Ogawa ◽  
Yuriko Saiki ◽  
Tomohiko Ishikawa ◽  
Yuta Kobayashi ◽  
...  
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Head And Neck ◽  
Cell Lines ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Expression Levels ◽  
Programmed Cell Death 1 ◽  
Hnscc Cell

Abstract Background: Key molecules regulating the immune checkpoint have shed light on the efforts to control several cancers. Recently, immune checkpoint inhibitors for cancer therapy such as antibodies against programmed cell death 1 (PD-1), programmed cell death 1 ligand 1 (PD-L1), and cytotoxic T-lymphocyte associated protein 4 (CTLA4) have been developed. In head and neck squamous cell carcinomas (HNSCCs), such immune checkpoint inhibitors have come into clinical use and are expected to improve patients’ prognoses. Recently, miR-34a has been shown to be a downstream micro RNA of TP53 that regulates PD-L1 in several types of cancer. To reveal the correlations between miR-34a and PD-L1 in HNSCCs in terms of clinical significance, we analyzed 19 HNSCC cell lines.Methods: We measured the expression levels of miR-34a and PD-L1 in 10 HNSCC cell lines as well as in 9 of their derived acquired cisplatin (CDDP) resistant cell lines by qRT-PCR and Western blotting. Results were further analyzed by their TP53 statuses. We also investigated the changes in PD-L1 expression levels after miR-34a precursor- or inhibitor-mediated forced expression or suppression in HNSCC cell lines. Results: We observed inverse correlations between both mRNA and protein expression levels of miR-34a and PD-L1. No significant differences in miR-34a levels were observed with regard to TP53 status. Forced expression of miR-34a decreased PD-L1 expression, and suppression of miR-34a increased PD-L1 expression. Conclusion: Our present results suggest that miR-34a negatively regulates PD-L1 expression, possibly in a TP53 independent manner in HNSCC.

scholarly journals Anti–PD-L1 Treatment Induced Central Diabetes Insipidus

2017 ◽  
Vol 103 (2) ◽  
pp. 365-369 ◽  
Author(s):  
Chen Zhao ◽  
Sri Harsha Tella ◽  
Jaydira Del Rivero ◽  
Anuhya Kommalapati ◽  
Ifechukwude Ebenuwa ◽  
...  
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Diabetes Insipidus ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Central Diabetes Insipidus ◽  
Early Screening ◽  
Cell Death Protein

Abstract Context Immune checkpoint inhibitors, including anti–programmed cell death protein 1 (PD-1), anti–programmed cell death protein ligand 1 (PD-L1), and anti–cytotoxic T-lymphocyte antigen 4 (anti-CTLA4) monoclonal antibodies, have been widely used in cancer treatment. They are known to cause immune-related adverse events (irAEs), which resemble autoimmune diseases. Anterior pituitary hypophysitis with secondary hypopituitarism is a frequently reported irAE, especially in patients receiving anti–CTLA4 treatment. In contrast, posterior pituitary involvement, such as central diabetes insipidus (DI), is relatively rare and is unreported in patients undergoing PD-1/PD-L1 blockade. Case Description We describe a case of a 73-year-old man with Merkel cell carcinoma who received the anti–PD-L1 monoclonal antibody avelumab and achieved partial response. The patient developed nocturia, polydipsia, and polyuria 3 months after starting avelumab. Further laboratory testing revealed central DI. Avelumab was held and he received desmopressin for the management of central DI. Within 6 weeks after discontinuation of avelumab, the patient’s symptoms resolved and he was eventually taken off desmopressin. The patient remained off avelumab and there were no signs or symptoms of DI 2 months after the discontinuation of desmopressin. Conclusion To our knowledge, this is the first report of central DI associated with anti–PD-L1 immunotherapy. The patient’s endocrinopathy was successfully managed by holding treatment with the immune checkpoint inhibitor. This case highlights the importance of early screening and appropriate management of hormonal irAEs in subjects undergoing treatment with immune checkpoint inhibitors to minimize morbidity and mortality.

Sign in / Sign up

Export Citation Format

Share Document