scholarly journals Development of Indole Alkaloid-Type Dual Immune Checkpoint Inhibitors Against CTLA-4 and PD-L1 Based on Diversity-Enhanced Extracts

2021 ◽  
Vol 9 ◽  
Author(s):  
Yoshihide Suzuki ◽  
Keisuke Ichinohe ◽  
Akihiro Sugawara ◽  
Shinya Kida ◽  
Shinya Murase ◽  
...  
Keyword(s):  
Gene Expression ◽  
Small Molecules ◽  
Small Molecule ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Indole Alkaloid ◽  
Cell Penetration ◽  
Manufacturing Costs ◽  
Blocking Antibodies

Cancer immunotherapy involves the use of the immune system for cancer treatment. Recently, immune checkpoint-blocking antibodies have become integral for the treatment of some cancers. However, small molecules exhibit advantages over monoclonal antibody drugs, such as cell penetration, long half-life, and low manufacturing costs, and the possibility of oral administration. Thus, it is imperative to develop small-molecule immune checkpoint inhibitors. Previously, we have screened a library of synthetic indole-alkaloid-type compounds, which are produced by diversity-enhanced extracts of Japanese cornelian cherry, and reported that an unnatural pentacyclic compound inhibits CTLA-4 gene expression. In this study, immune checkpoint inhibitors with increased potency were developed by introducing substituents and conversion of functional groups based on the unnatural pentacyclic compound. The developed compounds suppressed not only CTLA-4 and PD-L1 gene expression but also protein expression on the cell surface. Their efficacy was not as potent as that of the existing small-molecule immune checkpoint inhibitors, but, to the best of our knowledge, the developed compounds are the first reported dual small-molecule inhibitors of CTLA-4 and PD-L1.

scholarly journals The Efficacy of Anti-PD-L1 Treatment in Melanoma Is Associated with the Expression of the ECM Molecule EMILIN2

2021 ◽  
Vol 22 (14) ◽  
pp. 7511
Author(s):  
Albina Fejza ◽  
Maurizio Polano ◽  
Lucrezia Camicia ◽  
Evelina Poletto ◽  
Greta Carobolante ◽  
...  
Keyword(s):  
Gene Expression ◽  
Effective Treatment ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Tumor Hypoxia ◽  
Melanoma Cells ◽  
Vessel Normalization ◽  
Melanoma Patients

The use of immune checkpoint inhibitors has revolutionized the treatment of melanoma patients, leading to remarkable improvements in the cure. However, to ensure a safe and effective treatment, there is the need to develop markers to identify the patients that would most likely respond to the therapies. The microenvironment is gaining attention in this context, since it can regulate both the immunotherapy efficacyand angiogenesis, which is known to be affected by treatment. Here, we investigated the putative role of the ECM molecule EMILIN-2, a tumor suppressive and pro-angiogenic molecule. We verified that the EMILIN2 expression is variable among melanoma patients and is associated with the response to PD-L1 inhibitors. Consistently, in preclinical settings,the absence of EMILIN-2 is associated with higher PD-L1 expression and increased immunotherapy efficacy. We verified that EMILIN-2 modulates PD-L1 expression in melanoma cells through indirect immune-dependent mechanisms. Notably, upon PD-L1 blockage, Emilin2−/− mice displayed improved intra-tumoral vessel normalization and decreased tumor hypoxia. Finally, we provide evidence indicating that the inclusion of EMILIN2 in a number of gene expression signatures improves their predictive potential, a further indication that the analysis of this molecule may be key for the development of new markers to predict immunotherapy efficacy.

Conjugation of biphenyl groups with poly(ethylene glycol) to enhance inhibitory effects on the PD-1/PD-L1 immune checkpoint interaction

2020 ◽  
Vol 8 (44) ◽  
pp. 10162-10171
Author(s):  
Eun-Hye Kim ◽  
Boyang Ning ◽  
Masuki Kawamoto ◽  
Hideyuki Miyatake ◽  
Eiry Kobatake ◽  
...  
Keyword(s):  
Ethylene Glycol ◽  
Small Molecule ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Inhibitory Effect ◽  
Inhibitory Effects ◽  
Poly Ethylene Glycol ◽  
Poly Ethylene ◽  
Multivalent Effect

Inhibitory effect of small molecule immune checkpoint inhibitors on the PD-1/PD-L1 immune checkpoint interaction was enhanced by the multivalent effect through the conjugation of branched PEG.

T-cell inflamed gene expression to predict prognosis and response to immune checkpoint inhibitors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15264-e15264
Author(s):  
Yao Yu ◽  
Jingjiao Ma ◽  
Jie Chen ◽  
Ning He ◽  
Xiaohong Xu ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cell ◽  
Real World ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Cox Regression ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Small Sample ◽  
Youden Index

e15264 Background: To prove that T-cell-inflamed gene-expression profile (GEP) can predict prognosis and response to immune checkpoint inhibitors (ICIs) in the real-world study. Methods: 36 patients admitted from January 2018 to December 2018 were enrolled, including 15 patients with advanced NSCLC, 12 with advanced bladder cancer and 9 with advanced liver cancer. All patients were treated with nivolumab or pembrolizumab and provided informed written consent for analysis. Tumor total RNA was isolated from pretreatment FFPE samples and RNA-seq was performed on the Illumina NovaSeq 6000 system. GEP was calculated as a weighted sum of normalized expression values for 18 genes, as described in the article written by Ayer M, et al. in 2017. The data cutoff date was July 30, 2019. Primary end points were objective response rate (ORR) and disease control rate (DCR). Secondary end point was progression-free survival (PFS) assessed per RECIST v1.1. 95% CIs and P values for ORR and DCR were evaluated by the binomial exact method. Correlation between GEP and ORR, DCR and PFS was assessed by Wilcoxon rank sum test and Cox regression model, respectively. Survival curves were estimated by Kaplan-Meier methods. Cut-off value of GEP was confirmed by the Youden Index. The comparisons of DCR and PFS were performed by Fisher’s exact test and log-rank test, respectively. Results: ORR was 30.6% (95% CI, 16.3%-48.1%) and DCR was 50.0% (95% CI, 32.9%-67.1%). Median PFS was 3.9 months (95% CI, 0.8-NR). We found that GEP was higher in patients who achieved DCR and had longer PFS. And then GEP was significantly associated with DCR (p = 0.019) and PFS (p = 0.005), but not significantly with ORR (p = 0.42). Based on Youden Index, cut-off value of GEP was confirmed as -0.368, with 94.4% of sensitivity and 66.7% of specificity. According to cut-off value, 23 patients were evaluated as GEP-H. GEP-H group had higher DCR and longer PFS (DCR: 73.9% vs 7.69%, p = 0.0003; mPFS: 7.0m vs 2.1m, p = 0.00049). Conclusions: GEP can predict prognosis and response to ICIs in multiple cancers in our real-world study. Interpretation of these data may be limited by small sample sizes. Further studies are being conducted.

scholarly journals Treating tumors with immune checkpoint inhibitors: Rationale and limitations

2017 ◽  
Vol 1 (1) ◽  
pp. 2 ◽  
Author(s):  
Judith Anna Seidel ◽  
Atsushi Otsuka ◽  
Kenji Kabashima
Keyword(s):  
Immune Responses ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoints ◽  
Programmed Cell Death 1 ◽  
Human Use ◽  
Blocking Antibodies ◽  
Medical Advances

Immune checkpoints are essential for preventing immunopathology but can also obstruct anti-tumor immune responses. Recent medical advances in blocking these mechanisms have therefore opened promising avenues in the treatment of cancer.  Various blocking antibodies targeting the immune checkpoints programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) are now approved for human use. This review summarizes the properties of PD-1 and CTLA-4 in physiological and tumor settings, and examines the treatment efficacy, side effects and biomarkers of their inhibitors. Future avenues in the application and development of immune checkpoint inhibitors for the treatment of cancer are also explored.

scholarly journals Immune Checkpoint Inhibitors in the Treatment of Renal Cancer: Current State and Future Perspective

2020 ◽  
Vol 21 (13) ◽  
pp. 4691
Author(s):  
Daniele Lavacchi ◽  
Elisa Pellegrini ◽  
Valeria Emma Palmieri ◽  
Laura Doni ◽  
Marinella Micol Mela ◽  
...  
Keyword(s):  
Gene Expression ◽  
Renal Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Gene Expression Pattern ◽  
Gene Expression Signature ◽  
Future Perspective ◽  
Immune Gene

Systemic treatment of renal cancer (RCC) has undergone remarkable changes over the past 20 years with the introduction of immunotherapeutic agents targeting programmed cell death (PD-1)/programmed death-ligand 1 (PD-L1) axis, as a single-agent or combined with anti-CTLA-4 monoclonal antibodies (MoAbs) or a multi-target vascular endothelial growth factor-(VEGF) tyrosine kinase inhibitor (TKI). In this paper, we review the main evidence on the use of Immune Checkpoint Inhibitors (ICIs) for RCC treatment from the first demonstration of activity of a nivolumab single agent in a phase I trial to the novel combination strategies (anti-PD-1 plus anti-CTLA4 or anti-PD-1 plus TKI). In addition, we discuss the use of anti-PD-1/PD-L1 agents in patients with non-clear cells and rare histological subtype RCC. Then, we critically examine the current findings in biomarkers that have been proposed to be prognostic or predictive to the response of immunotherapy including immune gene expression signature, B7-H1 expression, PBRM1 loss of function, PD-L1 expression, frame shift indel count, mutations in bromodomain-containing genes in patients with MiT family translocation RCC (tRCC), high expression of the T-effector gene signature, and a high myeloid inflammation gene expression pattern. To date, a single biomarker as a predictor of response has not been established. Since the dynamic behavior of the immune response and the different impact of ICI treatment on patients with specific RCC subtypes, the integration of multiple biomarkers and further validation in clinical trials are needed.

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