Frequent amplification of HDAC genes and efficacy of HDAC inhibitor chidamide and PD-1 blockade combination in soft tissue sarcoma

BackgroundThe advent of immune checkpoint therapy has been a tremendous advance in cancer treatment. However, the responses are still insufficient in patients with soft tissue sarcoma (STS). We aimed to identify rational combinations to increase the response to immune checkpoint therapy and improve survival.MethodsWhole-exome sequencing (WES) was performed in 11 patients with liposarcoma. Somatic copy number alterations (SCNAs) were analyzed at the gene level to identify obvious amplification patterns in drug-target genes. The expression and prognostic value of class I histone deacetylases (HDACs) was evaluated in 49 patients with sarcoma in our center and confirmed in 263 sarcoma samples from The Tumor Cancer Genome Atlas (TCGA) database. Q-PCR, flow cytometry and RNA-seq were performed to determine the correlations between class I HDACs, chidamide and PD-L1 in vitro and in vivo. The efficacy of combining chidamide with PD-1 blockade was explored in an immunocompetent murine model and a small cohort of patients with advanced sarcoma. Western blot, ChIP assay and dual luciferase assessment were applied in the mechanistic study.ResultsThe HDAC gene family was frequently amplified in STS. SCNAs in the HDAC gene family were extensively amplified in 8 of 11 (73%) patients with liposarcoma, based on a drug-target gene set, and we verified amplification in 76.65% (197/257) of cases by analyzing TCGA sarcoma cohort. Class I HDAC expression is associated with a poor prognosis for patients with STS, and its inhibition is responsible for promoting apoptosis and upregulating of programmed cell death ligand 1 (PD-L1). The HDAC class I inhibitor chidamide significantly increases PD-L1 expression, increased the infiltration of CD8+ T cells and reduced the number of MDSCs in the tumor microenvironment. The combination of chidamide with an anti-PD-1 antibody significantly promotes tumor regression and improves survival in a murine model. Moreover, chidamide combined with the anti-PD-1 antibody toripalimab is effective in patients with advanced and metastatic sarcoma, and the side effects are tolerable. Mechanistically, chidamide increases histone acetylation at the PD-L1 gene through the activation of the transcriptional factor STAT1.ConclusionsThe combination of chidamide and anti-programmed cell death 1 (PD-1) therapy represents a potentially important strategy for STS.

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

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0284 ◽

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.

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Immune Checkpoint Inhibition in Oesophago-Gastric Carcinoma

Pharmaceuticals ◽

10.3390/ph14020151 ◽

2021 ◽

Vol 14 (2) ◽

pp. 151

Author(s):

Anica Högner ◽

Peter Thuss-Patience

Keyword(s):

Cell Death ◽

Gastric Carcinoma ◽

Programmed Cell Death ◽

Immune Checkpoint ◽

Disease Free Survival ◽

Line Treatment ◽

Second Line ◽

First Line ◽

The Usa ◽

First Line Treatment

Immune checkpoint inhibitors enrich the therapeutic landscape in oesophago-gastric carcinoma. With regard to oesophageal squamous cell carcinoma (ESCC), the selective PD-1 (programmed cell death receptor 1)-inhibitor nivolumab improves disease-free survival in the adjuvant therapy setting (CHECKMATE-577). In first-line treatment, ESCC patients (pts) benefit in overall survival (OS) from the PD-1-inhibitor pembrolizumab in combination with chemotherapy (KEYNOTE-590). In the second-line setting, nivolumab (ATTRACTION-03) and pembrolizumab (KEYNOTE-181) demonstrate a benefit in OS compared with chemotherapy. These data resulted in the approval of nivolumab for the second-line treatment of advanced ESCC pts regardless of PD-L1 (programmed cell death ligand 1) status in Europe, Asia, and the USA, and pembrolizumab for pts with PD-L1 CPS (combined positivity score) ≥ 10 in Asia and the USA. Further approvals can be expected. In gastro-oesophageal junction and gastric cancer, the addition of nivolumab to chemotherapy in first-line treatment improves OS in pts with advanced disease with PD-L1 CPS ≥ 5 (CHECKMATE-649). Additionally, pembrolizumab was non-inferior to chemotherapy for OS in PD-L1 CPS ≥ 1 pts (KEYNOTE-062). In third-line treatment, nivolumab shows benefits in OS regardless of PD-L1 expression (ATTRACTION-02) with approval in Asia, and pembrolizumab prolonged the duration of response in PD-L1 positive pts (KEYNOTE-059) with approval in the USA. We discuss the recent results of the completed phase II and III clinical trials.

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Human Herpesvirus and the Immune Checkpoint PD-1/PD-L1 Pathway: Disorders and Strategies for Survival

Microorganisms ◽

10.3390/microorganisms9040778 ◽

2021 ◽

Vol 9 (4) ◽

pp. 778

Author(s):

Takayuki Murata

Keyword(s):

Cell Death ◽

Immune System ◽

Programmed Cell Death ◽

Immune Checkpoint ◽

Human Herpesvirus ◽

Barr Virus ◽

Programmed Cell Death 1 ◽

Epstein Barr ◽

Simplex Virus ◽

Human Herpesviruses

The immune system has evolved as a complex and efficient means of coping with extrinsic materials, such as pathogens and toxins, as well as intrinsic abnormalities, such as cancers. Although rapid and timely activation of the immune system is obviously important, regulated downregulation of the system is almost as significant as activation to prevent runaway immunity, such as allergies and hypercytokinemia. Therefore, the immune checkpoint programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway is beneficial for the host. On the other hand, pathogens have evolved to evade host immunity by taking advantage of the PD-1/PD-L1 pathway. This review is focused on human herpesviruses, such as herpes simplex virus (HSV), cytomegalovirus (CMV), and Epstein–Barr virus (EBV), which cause various types of disorders, and their relationships with the PD-1/PD-L1 pathway. Understanding such relationships will be useful for developing preventative and therapeutic methods for disorders caused by herpesviruses.

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Radiotherapy with the anti-programmed cell death ligand-1 immune checkpoint blocker avelumab: acute toxicities in triple-negative breast cancer

Medical Oncology ◽

10.1007/s12032-018-1228-y ◽

2018 ◽

Vol 36 (1) ◽

Cited By ~ 4

Author(s):

Eliana La Rocca ◽

Michela Dispinzieri ◽

Laura Lozza ◽

Gabriella Mariani ◽

Serena Di Cosimo ◽

...

Keyword(s):

Breast Cancer ◽

Cell Death ◽

Programmed Cell Death ◽

Triple Negative Breast Cancer ◽

Immune Checkpoint ◽

Triple Negative

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Expression of programmed cell death ligand 1 and immune checkpoint markers in residual tumors after neoadjuvant chemotherapy for advanced high-grade serous ovarian cancer

Gynecologic Oncology ◽

10.1016/j.ygyno.2018.08.023 ◽

2018 ◽

Vol 151 (3) ◽

pp. 414-421 ◽

Cited By ~ 14

Author(s):

Hyun-Soo Kim ◽

Ji-Ye Kim ◽

Yong Jae Lee ◽

So Hee Kim ◽

Jung-Yun Lee ◽

...

Keyword(s):

Ovarian Cancer ◽

Cell Death ◽

Neoadjuvant Chemotherapy ◽

Programmed Cell Death ◽

Immune Checkpoint ◽

High Grade ◽

Serous Ovarian Cancer

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Management of Hematologic Adverse Events Associated With Immune Checkpoint Inhibitors

Journal of the Advanced Practitioner in Oncology ◽

10.6004/jadpro.2021.12.4.4 ◽

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.

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Speed of Adoption of Immune Checkpoint Inhibitors of Programmed Cell Death 1 Protein and Comparison of Patient Ages in Clinical Practice vs Pivotal Clinical Trials

JAMA Oncology ◽

10.1001/jamaoncol.2018.0798 ◽

2018 ◽

Vol 4 (8) ◽

pp. e180798 ◽

Cited By ~ 34

Author(s):

Jeremy M. O’Connor ◽

Kristen L. Fessele ◽

Jean Steiner ◽

Kathi Seidl-Rathkopf ◽

Kenneth R. Carson ◽

...

Keyword(s):

Clinical Trials ◽

Cell Death ◽

Clinical Practice ◽

Programmed Cell Death ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Programmed Cell Death 1

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Cancer Immunotherapy-Immune Checkpoint Inhibitors in Hepatocellular Carcinoma

Recent Patents on Anti-Cancer Drug Discovery ◽

10.2174/1574892816666210212145107 ◽

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.

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Abstract 254: Predictors of Immune Checkpoint Inhibitor Associated Cardiotoxicity

Circulation Cardiovascular Quality and Outcomes ◽

10.1161/hcq.13.suppl_1.254 ◽

2020 ◽

Vol 13 (Suppl_1) ◽

Author(s):

Danette L Flint ◽

Lauren Gilstrap ◽

Ashley Baronner ◽

Krina Patel

Keyword(s):

Heart Failure ◽

Cell Death ◽

Programmed Cell Death ◽

Beta Blocker ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitor ◽

Checkpoint Inhibitor ◽

Initial Exposure ◽

History Of ◽

Pre Treatment

Background: Immune checkpoint inhibitors (ICIs), including programmed cell death-1 (PD-1), programmed cell death ligand-1 (PD-L1) and cytotoxic lymphocyte antigen-4 (CTLA-4) inhibitors, are increasingly used in treatment of advanced stage cancers due to a well-established mortality benefit. ICI therapy is associated with immune mediated toxicity which may impact any organ system. Cardiovascular toxicities are rare based on existing data, but associated with high mortality rates. Objectives: The aim of this study is to determine whether preexisting cardiac conditions and/or cardiac therapies are associated with an increased or decreased risk of developing cardiotoxicity after ICI exposure. Methods: All patients treated with ICI therapy from March 2011 through October 2019 at our institution were identified. Demographic information, treatment dates, pre-treatment cardiac conditions and comorbidities, cancer types, pre-treatment cardiac biomarkers, and pre-treatment cardio-protective medication use were determined for each patient. New cardiac diagnoses after ICI exposure were identified in the medical record. Multivariate logistic regression was used determine the association between preexisting cardiac conditions and/or cardiac therapies and the development of cardiotoxicity after ICI exposure. Results: There were 902 patients identified with 1071 ICI exposures. The majority of exposures were to a PD-1 inhibitor (70%), with the most common drugs being pembrolizumab (42.8%) and nivolumab (26.5%). Eighty-nine new cardiac diagnoses were coded after initiation of ICI therapy. Sixteen events occurred within 30 days of initial exposure to an ICI and likely represent new cases of immune checkpoint inhibitor associated cardiotoxicity (incidence 1.5%). Of these events, one was confirmed as myocarditis, seven were heart failure without confirmation of myocarditis, three were arrhythmia, one was pericarditis, three were myocardial infarction and one was ventricular tachyarrhythmia/sudden cardiac death, without confirmed myocarditis or heart failure. There was an additional case of myocarditis identified within 90 days of initial exposure to ICI therapy, and a third case identified 115 days following exposure. All three patients who developed myocarditis died, consistent with the known high mortality rate of ICI associated myocarditis. One of the patients who developed myocarditis received pembrolizumab, one nivolumab and one cemiplimab (all PD-1 inhibitors). A history of heart failure increased the odds of developing a cardiac toxicity by 2.3 fold (95% CI 1.4 to 3.3, p<0.001) and prior beta-blocker exposure decreased the odds by 1.8 fold (95% -2.9 to -0.7, p=0.002). Conclusion: A history of heart failure is associated with an increased odds of developing cardiotoxicity after ICI exposure while prior beta blocker exposure appears to be protective.

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