scholarly journals A Novel Epitope Quality-Based Immune Escape Mechanism Reveals Patient’s Suitability for Immune Checkpoint Inhibition

2020 ◽  
Vol Volume 12 ◽  
pp. 7881-7890
Author(s):  
Michael Wessolly ◽  
Susann Stephan-Falkenau ◽  
Anna Streubel ◽  
Robert Werner ◽  
Sabrina Borchert ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Escape ◽  
Checkpoint Inhibition ◽  
Immune Checkpoint Inhibition ◽  
Escape Mechanism ◽  
Immune Escape Mechanism

scholarly journals Combination of epigenetic regulation with gene therapy-mediated immune checkpoint blockade induces anti-tumour effects and immune response in vivo

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Huapan Fang ◽  
Zhaopei Guo ◽  
Jie Chen ◽  
Lin Lin ◽  
Yingying Hu ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Immune Response ◽  
Epigenetic Regulation ◽  
Immune Checkpoint ◽  
Immune Escape ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Immune Memory ◽  
Escape Mechanism ◽  
Immune Escape Mechanism

AbstractImmunotherapy has become a powerful cancer treatment, but only a small fraction of patients have achieved durable benefits due to the immune escape mechanism. In this study, epigenetic regulation is combined with gene therapy-mediated immune checkpoint blockade to relieve this immune escape mechanism. PPD (i.e., mPEG-b-PLG/PEI-RT3/DNA) is developed to mediate plasmid-encoding shPD-L1 delivery by introducing multiple interactions (i.e., electrostatic, hydrogen bonding, and hydrophobic interactions) and polyproline II (PPII)-helix conformation, which downregulates PD-L1 expression on tumour cells to relieve the immunosuppression of T cells. Zebularine (abbreviated as Zeb), a DNA methyltransferase inhibitor (DNMTi), is used for the epigenetic regulation of the tumour immune microenvironment, thus inducing DC maturation and MHC I molecule expression to enhance antigen presentation. PPD plus Zeb combination therapy initiates a systemic anti-tumour immune response and effectively prevents tumour relapse and metastasis by generating durable immune memory. This strategy provides a scheme for tumour treatment and the inhibition of relapse and metastasis.

scholarly journals Immune Checkpoint Inhibition in Classical Hodgkin Lymphoma: From Early Achievements towards New Perspectives

2019 ◽  
Vol 2019 ◽  
pp. 1-16 ◽  
Author(s):  
Diego De Goycoechea ◽  
Gregoire Stalder ◽  
Filipe Martins ◽  
Michel A. Duchosal
Keyword(s):  
Hodgkin Lymphoma ◽  
Immune Checkpoint ◽  
Immune Escape ◽  
Response Rates ◽  
Genetic Alterations ◽  
Immune Checkpoints ◽  
Checkpoint Inhibition ◽  
Immune Checkpoint Inhibition ◽  
Classical Hodgkin Lymphoma ◽  
Immune Escape Mechanisms

Immune checkpoint inhibition (ICI) became one of the major breakthroughs in cancer treatment over the past decade and entered into therapy within standard oncohematology practice. ICI has demonstrated impressive response rates as salvage therapy in relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL) and is now being tested as an adjunction to chemotherapy in the frontline settings. CHL exquisite sensitivity to PD-1/PD-L1 axis inhibition relies on a particular biological background. By contrast, non-Hodgkin lymphomas (NHL) have demonstrated heterogeneous response rates using ICI. These observations highlight discrepancies between various types of lymphomas in terms of genetic alterations, immune microenvironment interactions, and disease phenotype. This review aims to focus on cHL immune escape mechanisms, focusing on cHL biological sensitivity to PD-1 blockade. We will summarize the available data issued from clinical trials on ICI in cHL and its safety profile. Going beyond the current use of monoclonal antibodies (mAb) targeting immune checkpoints in clinical practice, we will offer an overview of new combinatory therapeutic perspectives where cHL immunotherapy may be considered.

Locoregional treatment of ‘immune escape' metastatic melanoma in the setting of immune checkpoint inhibition for widespread disease.

2016 ◽  
Vol 34 (15_suppl) ◽  
pp. e14544-e14544
Author(s):  
Maria Frances Coakley ◽  
David Cormican ◽  
Cynthia Heffron ◽  
Richard Martin Bambury ◽  
Deirdre O'Mahony ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Immune Checkpoint ◽  
Immune Escape ◽  
Checkpoint Inhibition ◽  
Immune Checkpoint Inhibition ◽  
Locoregional Treatment

Sinonasal Mucosal Melanoma: A Comparison of Outcomes between Surgical Resection and Immune Checkpoint Inhibition

2020 ◽  
Author(s):  
Shivangi Lohia ◽  
Stephanie Flukes ◽  
Alexander N. Shoushtari ◽  
Akash D. Shah ◽  
Ian Ganly ◽  
...  
Keyword(s):  
Surgical Resection ◽  
Immune Checkpoint ◽  
Mucosal Melanoma ◽  
Checkpoint Inhibition ◽  
Immune Checkpoint Inhibition

scholarly journals PD-L1 lncRNA splice isoform promotes lung adenocarcinoma progression via enhancing c-Myc activity

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Shuang Qu ◽  
Zichen Jiao ◽  
Geng Lu ◽  
Bing Yao ◽  
Ting Wang ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Lung Adenocarcinoma ◽  
Solid Tumors ◽  
Immune Checkpoint ◽  
Checkpoint Inhibition ◽  
Immune Checkpoint Inhibition ◽  
Non Coding Rna ◽  
Adenocarcinoma Cells ◽  
Lung Adenocarcinoma Cells ◽  
Long Non Coding Rna

Abstract Background Although using a blockade of programmed death-ligand 1 (PD-L1) to enhance T cell immune responses shows great promise in tumor immunotherapy, the immune-checkpoint inhibition strategy is limited for patients with solid tumors. The mechanism and efficacy of such immune-checkpoint inhibition strategies in solid tumors remains unclear. Results Employing qRT-PCR, Sanger sequencing, and RNA BaseScope analysis, we show that human lung adenocarcinoma (LUAD) all produce a long non-coding RNA isoform of PD-L1 (PD-L1-lnc) by alternative splicing, regardless if the tumor is positive or negative for the protein PD-L1. Similar to PD-L1 mRNA, PD-L1-lnc in various lung adenocarcinoma cells is significantly upregulated by IFNγ. Both in vitro and in vivo studies demonstrate that PD-L1-lnc increases proliferation and invasion but decreases apoptosis of lung adenocarcinoma cells. Mechanistically, PD-L1-lnc promotes lung adenocarcinoma progression through directly binding to c-Myc and enhancing c-Myc transcriptional activity. Conclusions In summary, the PD-L1 gene can generate a long non-coding RNA through alternative splicing to promote lung adenocarcinoma progression by enhancing c-Myc activity. Our results argue in favor of investigating PD-L1-lnc depletion in combination with PD-L1 blockade in lung cancer therapy.

scholarly journals Thinking Small: Small Molecules as Potential Synergistic Adjuncts to Checkpoint Inhibition in Melanoma

2021 ◽  
Vol 22 (6) ◽  
pp. 3228
Author(s):  
Alexander C. Chacon ◽  
Alexa D. Melucci ◽  
Shuyang S. Qin ◽  
Peter A. Prieto
Keyword(s):  
Skin Cancer ◽  
Small Molecules ◽  
Metastatic Melanoma ◽  
Immune Checkpoint ◽  
Treatment Resistance ◽  
Checkpoint Inhibition ◽  
Immune Checkpoint Inhibition ◽  
Specific Effector ◽  
Melanoma Treatment ◽  
Therapeutic Responses

Metastatic melanoma remains the deadliest form of skin cancer. Immune checkpoint inhibition (ICI) immunotherapy has defined a new age in melanoma treatment, but responses remain inconsistent and some patients develop treatment resistance. The myriad of newly developed small molecular (SM) inhibitors of specific effector targets now affords a plethora of opportunities to increase therapeutic responses, even in resistant melanoma. In this review, we will discuss the multitude of SM classes currently under investigation, current and prospective clinical combinations of ICI and SM therapies, and their potential for synergism in melanoma eradication based on established mechanisms of immunotherapy resistance.

scholarly journals Modulation of temozolomide dose differentially affects T-cell response to immune checkpoint inhibition

2019 ◽  
Vol 21 (6) ◽  
pp. 730-741 ◽  
Author(s):  
Aida Karachi ◽  
Changlin Yang ◽  
Farhad Dastmalchi ◽  
Elias J Sayour ◽  
Jianping Huang ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Checkpoint ◽  
Standard Dose ◽  
Antibody Therapy ◽  
Tumor Infiltrating Lymphocytes ◽  
T Cell Response ◽  
Checkpoint Inhibition ◽  
Immune Checkpoint Inhibition ◽  
Dose Modulation ◽  
Infiltrating Lymphocytes

Abstract Background The changes induced in host immunity and the tumor microenvironment by chemotherapy have been shown to impact immunotherapy response in both a positive and a negative fashion. Temozolomide is the most common chemotherapy used to treat glioblastoma (GBM) and has been shown to have variable effects on immune response to immunotherapy. Therefore, we aimed to determine the immune modulatory effects of temozolomide that would impact response to immune checkpoint inhibition in the treatment of experimental GBM. Methods Immune function and antitumor efficacy of immune checkpoint inhibition were tested after treatment with metronomic dose (MD) temozolomide (25 mg/kg × 10 days) or standard dose (SD) temozolomide (50 mg/kg × 5 days) in the GL261 and KR158 murine glioma models. Results SD temozolomide treatment resulted in an upregulation of markers of T-cell exhaustion such as LAG-3 and TIM-3 in lymphocytes which was not seen with MD temozolomide. When temozolomide treatment was combined with programmed cell death 1 (PD-1) antibody therapy, the MD temozolomide/PD-1 antibody group demonstrated a decrease in exhaustion markers in tumor infiltrating lymphocytes that was not observed in the SD temozolomide/PD-1 antibody group. Also, the survival advantage of PD-1 antibody therapy in a murine syngeneic intracranial glioma model was abrogated by adding SD temozolomide to treatment. However, when MD temozolomide was added to PD-1 inhibition, it preserved the survival benefit that was seen by PD-1 antibody therapy alone. Conclusion The peripheral and intratumoral immune microenvironments are distinctively affected by dose modulation of temozolomide.

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