scholarly journals Antitumor efficacy of combined CTLA4/PD-1 blockade without intestinal inflammation is achieved by elimination of FcγR interactions

2020 ◽  
Vol 8 (2) ◽  
pp. e001584
Author(s):  
David Bauché ◽  
Smita Mauze ◽  
Christina Kochel ◽  
Jeff Grein ◽  
Anandi Sawant ◽  
...  
Keyword(s):  
Cell Death ◽  
Animal Models ◽  
Intestinal Inflammation ◽  
Antibody Therapy ◽  
Effector Function ◽  
Checkpoint Blockade ◽  
Prolonged Administration ◽  
Clinical Events ◽  
Increased Risk ◽  
Cell Death Protein

BackgroundProgrammed cell death protein 1 (PD-1) and CTLA4 combination blockade enhances clinical efficacy in melanoma compared with targeting either checkpoint alone; however, clinical response improvement is coupled with increased risk of developing immune-related adverse events (irAE). Delineating the mechanisms of checkpoint blockade-mediated irAE has been hampered by the lack of animal models that replicate these clinical events.MethodsWe have developed a mouse model of checkpoint blockade-mediated enterocolitis via prolonged administration of an Fc-competent anti-CTLA4 antibody.ResultsSustained treatment with Fc-effector, but not Fc-mutant or Fc-null, anti-CTLA4 antagonist for 7 weeks resulted in enterocolitis. Moreover, combining Fc-null or Fc-mutant CTLA4 antagonists with PD-1 blockade results in potent antitumor combination efficacy indicating that Fc-effector function is not required for combination benefit.ConclusionThese data suggest that using CTLA4 antagonists with no Fc-effector function can mitigate gut inflammation associated with anti-CTLA4 antibody therapy yet retain potent antitumor activity in combination with PD-1 blockade.

scholarly journals Immune-Checkpoint Blockade Therapy in Lymphoma

2020 ◽  
Vol 21 (15) ◽  
pp. 5456 ◽  
Author(s):  
Ayumi Kuzume ◽  
SungGi Chi ◽  
Nobuhiko Yamauchi ◽  
Yosuke Minami
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Malignant Lymphoma ◽  
Hodgkin Lymphoma ◽  
Immune Checkpoint ◽  
Immune Cell ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Host Immune System ◽  
Cell Death Protein

Tumor cells use immune-checkpoint pathways to evade the host immune system and suppress immune cell function. These cells express programmed cell-death protein 1 ligand 1 (PD-L1)/PD-L2, which bind to the programmed cell-death protein 1 (PD-1) present on cytotoxic T cells, trigger inhibitory signaling, and reduce cytotoxicity and T-cell exhaustion. Immune-checkpoint blockade can inhibit this signal and may serve as an effective therapeutic strategy in patients with solid tumors. Several trials have been conducted on immune-checkpoint inhibitor therapy in patients with malignant lymphoma and their efficacy has been reported. For example, in Hodgkin lymphoma, immune-checkpoint blockade has resulted in response rates of 65% to 75%. However, in non-Hodgkin lymphoma, the response rate to immune-checkpoint blockade was lower. In this review, we evaluate the biology of immune-checkpoint inhibition and the current data on its efficacy in malignant lymphoma, and identify the cases in which the treatment was more effective.

Hyperprogression of a Sinonasal Squamous Cell Carcinoma Following Programmed Cell Death Protein-1 Checkpoint Blockade

2020 ◽  
Vol 146 (12) ◽  
pp. 1176
Author(s):  
Said Izreig ◽  
Faisal Alzahrani ◽  
Joseph Earles ◽  
Saral Mehra ◽  
Benjamin L. Judson ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Checkpoint Blockade ◽  
Cell Death Protein

Die Systemtherapie des fortgeschrittenen Melanoms im Jahr 2016

2017 ◽  
Vol 5 (3) ◽  
pp. 126-133
Author(s):  
Markus Vincent Heppt ◽  
Cecilia Dietrich ◽  
Saskia Graf ◽  
Thomas Ruzicka ◽  
Julia Tietze ◽  
...  
Keyword(s):  
Cell Death ◽  
Protein Kinase ◽  
Programmed Cell Death ◽  
T Lymphocyte ◽  
Checkpoint Blockade ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein ◽  
Cell Death Protein

Das Melanom ist eine häufige Form von Hautkrebs mit hoher Tendenz zur Metastasenbildung. Tyrosinkinase-Inhibitoren, die zielgerichtet in den MAPK (mitogen-activated protein kinase)-Signaltransduktionsweg eingreifen, sowie die Immun-Checkpoint-Blockade haben in jüngster Zeit die Behandlung des nicht-resezierbaren und des metastasierten Melanoms revolutioniert. Doch erworbene Resistenzen und primäres Nichtansprechen auf diese Therapien machen neuartige Behandlungsstrategien und Kombinationsansätze erforderlich. Das Ziel dieser Übersichtsarbeit ist es, einen kurzen und aktuellen Überblick über das klinische Management des Melanoms und die gegenwärtige Studiensituation zu geben. Die Arbeit enthält Zusammenfassungen der relevantesten Studien zu BRAF- und MEK-Inhibitoren sowie zu Antikörpern gegen CTLA-4 (T-lymphocyte-associated protein 4) und PD-1 (programmed cell death protein 1). Während die meisten Wirkstoffe schon in Monotherapie eine gute antitumorale Wirksamkeit zeigen, sind durch Kombinationstherapien mit zugelassenen und in der Entwicklung befindlichen Wirkstoffen weitere Verbesserungen erzielt worden. Wir besprechen hier laufende Studien und evaluieren Ansätze, die künftig eine noch höhere Wirksamkeit bei geringerer Toxizität gewährleisten könnten. Übersetzung aus Oncol Res Treat 2016;39:635-642 (DOI:10.1159/000448904)

scholarly journals Genetic variants of programmed cell death 1 are associated with HBV infection and liver disease progression

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Nghiem Xuan Hoan ◽  
Pham Thi Minh Huyen ◽  
Mai Thanh Binh ◽  
Ngo Tat Trung ◽  
Dao Phuong Giang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Death ◽  
Liver Disease ◽  
Programmed Cell Death ◽  
Disease Progression ◽  
Infection Risk ◽  
Hbv Infection ◽  
Liver Disease Progression ◽  
Increased Risk ◽  
Programmed Cell Death 1

AbstractThe inhibitory effects of programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) modulates T-cell depletion. T-cell depletion is one of the key mechanisms of hepatitis B virus (HBV) persistence, in particular liver disease progression and the development of hepatocellular carcinoma (HCC). This case–control study aimed to understand the significance of PD-1 polymorphisms (PD-1.5 and PD-1.9) association with HBV infection risk and HBV-induced liver disease progression. Genotyping of PD-1.5 and PD-1.9 variants was performed by direct Sanger sequencing in 682 HBV-infected patients including chronic hepatitis (CHB, n = 193), liver cirrhosis (LC, n = 183), hepatocellular carcinoma (HCC, n = 306) and 283 healthy controls (HC). To analyze the association of PD-1 variants with liver disease progression, a binary logistic regression, adjusted for age and gender, was performed using different genetic models. The PD-1.9 T allele and PD-1.9 TT genotype are significantly associated with increased risk of LC, HCC, and LC + HCC. The frequencies of PD-1.5 TT genotype and PD-1.5 T allele are significantly higher in HCC compared to LC patients. The haplotype CT (PD-1.5 C and PD-1.9 T) was significantly associated with increased risk of LC, HCC, and LC + HCC. In addition, the TC (PD-1.5 T and PD-1.9 C) haplotype was associated with the risk of HCC compared to non-HCC. The PD-1.5 CC, PD-1.9 TT, genotype, and the CC (PD-1.5 C and PD-1.9) haplotype are associated with unfavorable laboratory parameters in chronic hepatitis B patients. PD-1.5 and PD1.9 are useful prognostic predictors for HBV infection risk and liver disease progression.

scholarly journals Predicting Responses to Checkpoint Inhibitors in Lymphoma: Are We Up to the Standards of Solid Tumors?

2020 ◽  
Vol 14 ◽  
pp. 117955492097636
Author(s):  
Ah-Reum Jeong ◽  
Edward D Ball ◽  
Aaron Michael Goodman
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
B Cell ◽  
Solid Tumors ◽  
Cell Lymphoma ◽  
Checkpoint Inhibitors ◽  
B Cell Lymphoma ◽  
Hematologic Malignancies ◽  
Checkpoint Blockade ◽  
Programmed Cell Death 1

Treatment of cancer has transformed with the introduction of checkpoint inhibitors. However, the majority of solid tumor patients do not respond to checkpoint blockade. In contrast, the response rate to programmed cell death 1 (PD-1) blockade in relapsed/refractory classical Hodgkin lymphoma (cHL) is 65% to 84% which is the highest among all cancers. Currently, checkpoint inhibitors are only approved for cHL and primary mediastinal B-cell lymphoma as the responses to single-agent checkpoint blockade in other hematologic malignancies is disappointingly low. Various established biomarkers such as programmed cell death 1 ligand 1 (PD-L1) protein surface expression, mismatch repair (MMR) status, and tumor mutational burden (TMB) are routinely used in clinical decision-making in solid tumors. In this review, we will explore these biomarkers in the context of hematologic malignancies. We review characteristic 9p24.1 structural alteration in cHL and primary mediastinal B-cell lymphoma (PMBCL) as a basis for response to PD-1 inhibition, as well as the role of antigen presentation pathways. We also explore the reported frequencies of MMR deficiency in various hematologic malignancies and investigate TMB as a predictive marker.

Fragmented QRS, a predictor of clinical events in patients on cardiac resynchronization therapy

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
J Martinez Milla ◽  
C Garcia-Talavera ◽  
B Arroyo ◽  
A Camblor ◽  
A Garcia-Ropero ◽  
...  
Keyword(s):  
Cardiac Resynchronization Therapy ◽  
Cardiovascular Events ◽  
Hospital Admissions ◽  
Multivariate Logistic Regression Analysis ◽  
Cardiac Resynchronization ◽  
Resynchronization Therapy ◽  
Coronary Syndrome ◽  
Clinical Events ◽  
Increased Risk

Abstract Introduction Cardiac resynchronization therapy with defrilator (CRT-D) has been shown to reduce mortality in HFrEF. The width and morphology of the QRS are essential when deciding on the implantation of these devices. QRS fragmentation (fQRS) has been shown to be a good predictor of cardiovascular events in certain patients, but its role in patients with CRT-D has not been studied. The aim of this study is to determine whether the presence of a fQRS at the time of CRT-D implantation can predict clinical events. Methods All patients who underwent CRT-D implantation from 2010 to 2017 were included. Patients' ECG were evaluated at the time of implantation, and the incidence of clinical events during follow-up was also assessed. fQRS was defined as the presence of an RSR' pattern with a notch in the R wave or in the ascending or descending branch of the S wave in two continuous leads on the ECG. Results We studied 131 patients (mean age 73 years, 76.5% male). The mean follow-up period was 37±26 months. No difference in baseline characteristics was found (Table 1); the proportion of fQRS was 48.9%. 25 patients (19.1%) had hospital admissions secondary to cardiovascular causes (heart failure, arrhythmic events, acute coronary syndrome, and death from other causes). We performed a multivariate logistic regression analysis aiming at an association between the presence of fQRS and the increased risk of hospital admissions due to cardiovascular causes OR 2.92 (95% CI: 1.04–8.21, P=0.04). Conclusion The presence of a fQRS at the time of implantation of a CRT-D is an independent predictor of hospital admissions due to cardiovascular causes. Therefore this could be a useful marker to identify the population at high risk of cardiovascular events, for this we consider necessary to conduct future studies and thus assess the value of the fQRS for the selection of patients requiring closer monitoring thus avoiding further hospital admissions. Funding Acknowledgement Type of funding source: None

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