Potential immunotherapy for Alzheimer disease and age-related dementia

2019 ◽  
Vol 21 (1) ◽  
pp. 21-25 ◽  
Keyword(s):  
Immune System ◽  
Alzheimer Disease ◽  
Cross Talk ◽  
Immune Checkpoint ◽  
Short Review ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
New Approach ◽  
Age Related ◽  
The Brain

Emerging results support the concept that Alzheimer disease (AD) and age-related dementia are affected by the ability of the immune system to contain the brain’s pathology. Accordingly, well-controlled boosting, rather than suppression of systemic immunity, has been suggested as a new approach to modify disease pathology without directly targeting any of the brain’s disease hallmarks. Here, we provide a short review of the mechanisms orchestrating the cross-talk between the brain and the immune system. We then discuss how immune checkpoint blockade directed against the PD-1/PD-L1 pathways could be developed as an immunotherapeutic approach to combat this disease using a regimen that will address the needs to combat AD.

Potential immunotherapy for Alzheimer disease and age-related dementia

2019 ◽  
Vol 21 (1) ◽  
pp. 21-25 ◽  
Keyword(s):  
Immune System ◽  
Alzheimer Disease ◽  
Cross Talk ◽  
Immune Checkpoint ◽  
Short Review ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
New Approach ◽  
Age Related ◽  
The Brain

Emerging results support the concept that Alzheimer disease (AD) and age-related dementia are affected by the ability of the immune system to contain the brain's pathology. Accordingly, well-controlled boosting, rather than suppression of systemic immunity, has been suggested as a new approach to modify disease pathology without directly targeting any of the brain's disease hallmarks. Here, we provide a short review of the mechanisms orchestrating the cross-talk between the brain and the immune system. We then discuss how immune checkpoint blockade directed against the PD-1/PD-L1 pathways could be developed as an immunotherapeutic approach to combat this disease using a regimen that will address the needs to combat AD.

scholarly journals Potential immunotherapy for Alzheimer disease and age-related dementia

2019 ◽  
Vol 21 (1) ◽  
pp. 21-25 ◽  
Keyword(s):  
Immune System ◽  
Alzheimer Disease ◽  
Cross Talk ◽  
Immune Checkpoint ◽  
Short Review ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
New Approach ◽  
Age Related ◽  
The Brain

Emerging results support the concept that Alzheimer disease (AD) and age-related dementia are affected by the ability of the immune system to contain the brain's pathology. Accordingly, well-controlled boosting, rather than suppression of systemic immunity, has been suggested as a new approach to modify disease pathology without directly targeting any of the brain's disease hallmarks. Here, we provide a short review of the mechanisms orchestrating the cross-talk between the brain and the immune system. We then discuss how immune checkpoint blockade directed against the PD-1/PD-L1 pathways could be developed as an immunotherapeutic approach to combat this disease using a regimen that will address the needs to combat AD.

scholarly journals Rethinking immune checkpoint blockade: ‘Beyond the T cell’

2021 ◽  
Vol 9 (1) ◽  
pp. e001460 ◽  
Author(s):  
Xiuting Liu ◽  
Graham D Hogg ◽  
David G DeNardo
Keyword(s):  
Immune System ◽  
T Cell ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Antitumor Immunity ◽  
Checkpoint Inhibitors ◽  
Clinical Success ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade

The clinical success of immune checkpoint inhibitors has highlighted the central role of the immune system in cancer control. Immune checkpoint inhibitors can reinvigorate anti-cancer immunity and are now the standard of care in a number of malignancies. However, research on immune checkpoint blockade has largely been framed with the central dogma that checkpoint therapies intrinsically target the T cell, triggering the tumoricidal potential of the adaptive immune system. Although T cells undoubtedly remain a critical piece of the story, mounting evidence, reviewed herein, indicates that much of the efficacy of checkpoint therapies may be attributable to the innate immune system. Emerging research suggests that T cell-directed checkpoint antibodies such as anti-programmed cell death protein-1 (PD-1) or programmed death-ligand-1 (PD-L1) can impact innate immunity by both direct and indirect pathways, which may ultimately shape clinical efficacy. However, the mechanisms and impacts of these activities have yet to be fully elucidated, and checkpoint therapies have potentially beneficial and detrimental effects on innate antitumor immunity. Further research into the role of innate subsets during checkpoint blockade may be critical for developing combination therapies to help overcome checkpoint resistance. The potential of checkpoint therapies to amplify innate antitumor immunity represents a promising new field that can be translated into innovative immunotherapies for patients fighting refractory malignancies.

New Strategies for Therapeutic Cancer Vaccines

2019 ◽  
Vol 19 (2) ◽  
pp. 213-221 ◽  
Author(s):  
Hanjiao Qin ◽  
Jiyao Sheng ◽  
Dan Zhang ◽  
Xuewen Zhang ◽  
Linlin Liu ◽  
...  
Keyword(s):  
Stem Cell ◽  
Immune System ◽  
Cancer Stem Cell ◽  
Continuous Improvement ◽  
Immune Checkpoint ◽  
Cancer Vaccines ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Therapeutic Effects ◽  
Therapeutic Cancer Vaccines

Background: Patients with low response rates to cancer vaccines, short duration of anti-tumor response after vaccination, and relatively weak curative effects are problems that have not been resolved effectively during the development and application of cancer vaccines. With the continuous improvement of knowledge and awareness regarding the immune system and cancer cells, many researches have helped to explain the reasons for poor vaccine efficacy. Input from researchers accompanied by some newly emerged strategies could bring hope to improve the therapeutic effects of vaccines. Methods: Data were collected from Web of Science, Medline, Pubmed, through searching of these keywords: “cancer vaccine”, “cancer stem cell”, “targeted agent”, “immune checkpoint blockade” and “neoantigen”. Results: It may be more effective in immunotherapy of human cancers, including cancer stem cell vaccines, combination vaccines with targeted agents or immune checkpoint blockade, and neoantigen-based vaccines. Conclusion: Personalized vaccines will become the mainstream solution of cancer treatment program with the continuous improvement of human understanding of the immune system and the progress of related experiments.

scholarly journals The proposed promiscuity value of an HLA can vary significantly depending on the source data used

2021 ◽  
Author(s):  
Jordan Anaya ◽  
Alexander S. Baras
Keyword(s):  
T Cells ◽  
Immune System ◽  
Cancer Cells ◽  
Immune Checkpoint ◽  
Peptide Binding ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Data Types ◽  
Patient Response ◽  
Source Data

ABSTRACTImmune checkpoint blockade, a form of immunotherapy, mobilizes a patient’s own immune system against cancer cells by releasing some of the natural brakes on T cells. Although our understanding of this process is evolving, it is thought that a patient response to immunotherapy requires tumor presentation of neoantigens to T cells and patients whose tumors present a wider array of neoantigens are more likely to derive benefit from immune checkpoint blockade1–4. Manczinger et al.5 recently reported findings that would appear contrarian to this notion in that they suggested patients with HLA alleles which bind more diverse peptides (higher promiscuity) are less likely to respond to immunotherapy. To estimate HLA promiscuity they looked at the HLA-peptide binding repertoires for class I alleles contained in the IEDB6, and obtained consistent results when performing robustness checks and subsequent analyses. Here we show that the proposed HLA promiscuity values can vary significantly across source data types and individual experiments.

scholarly journals 62 Identify immune cell types and biomarkers associated with immune-related adverse events using single cell RNA sequencing

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A67-A67
Author(s):  
Jiamin Chen ◽  
Lance Pflieger ◽  
Sue Grimes ◽  
Tyler Baker ◽  
Michael Brems ◽  
...  
Keyword(s):  
Colon Cancer ◽  
T Cells ◽  
Immune System ◽  
Adverse Events ◽  
Single Cell ◽  
Immune Checkpoint ◽  
Inflammatory Responses ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Single Cell Rna Sequencing

BackgroundRecent advancements in immunotherapy are revolutionizing the landscape of clinical immuno-oncology and have significantly increased patient survival in a range of cancers. Notably, immune checkpoint blockade therapies have induced durable responses and provided tremendous clinical benefits to previously untreatable patients. However, unleashing immune system against cancer also disrupts the immunologic homeostasis and induce inflammatory responses, resulting immune-related adverse events. The precise mechanisms underlying immune-related adverse events (irAEs) remain unknown. Furthermore, it is unclear why immune checkpoint blockade therapies only induce irAEs in some patients but not the others. In this study, we systematically characterize the functional impacts of immune checkpoint blockade on the patient immune system at single-cell resolution.MethodsThe peripheral blood mononuclear cells (PBMCs) from seven cancer patients with melanoma, non-small cell lung cancer, or colon cancer (MSI-H) receiving immune checkpoint inhibitors (CPIs), i.e. anti–PD-1+anti-CTLA4 combo or anti-PD-1 single agent, were collected at three serial time points (T1, T2, and T3). During the immunotherapy, four patients developed irAEs, including colitis (2X), pneumonitis (1), hyper/hypothyroidism (1), while three patients showed no signs of irAEs. In total, we generated and characterized single cell gene expression profiles for more than 65,000 cells from 21 PBMC libraries. Furthermore, we simultaneously measured TCR and BCR from nine selected samples, thus generating a comprehensive profile of Immune repertoire upon CPIs.ResultsWe systematically characterized T cells, B cells, monocytes, NK cells, and platelets from PBMCs. Both checkpoint blockade and patient comorbidity affect PBMC populations. We found that irAEs are often associated with an acute increase in monocytes and decrease in T cells. After repeated CPI treatment, PBMC populations remained relatively stable. We characterized specific subsets within each cell type that are associated with CPI treatment as well as patient clinical conditions, and identified signature genes for each subset. For example, Mucosal-Associated Invariant CD8 T cells were strongly enriched in the PBMC population of the colon cancer patient. In the melanoma patient who received anti–PD-1+anti-CTLA4 combo but didn’t develop colitis, we found enriched NK cell subsets expressing chemokine such as XCL1 and CCL4. Furthermore, we found prominent T cell clonal expansion in this patient compared to the two melanoma patients who developed colitis. The administration of steroids after irAEs led to massive anti-inflammatory responses in PMBCs, often characterized by the prominent expression of AREG.ConclusionsOur study characterized the functional impact of CPIs on patient PBMCs. Our data demonstrated that single cell RNA sequencing provides a powerful tool to dissect and identify clinically actionable biomarkers for response prediction and side effects alleviation in patients receiving immunotherapy in the era of precision medicine.Ethics ApprovalThis study was approved by the Institutional Review Board (#1050678) at Intermountain Healthcare (Salt Lake City, UT USA)

scholarly journals Emerging dynamics pathways of response and resistance to PD-1 and CTLA-4 blockade: tackling uncertainty by confronting complexity

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Allan Relecom ◽  
Maysaloun Merhi ◽  
Varghese Inchakalody ◽  
Shahab Uddin ◽  
Darawan Rinchai ◽  
...  
Keyword(s):  
Immune System ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Therapeutic Benefit ◽  
Immune Checkpoint Blockade ◽  
Mechanisms Of Action ◽  
Checkpoint Blockade ◽  
Adaptive Resistance ◽  
Insight Into

AbstractImmune checkpoint inhibitors provide considerable therapeutic benefit in a range of solid cancers as well as in a subgroup of hematological malignancies. Response rates are however suboptimal, and despite considerable efforts, predicting response to immune checkpoint inhibitors ahead of their administration in a given patient remains elusive. The study of the dynamics of the immune system and of the tumor under immune checkpoint blockade brought insight into the mechanisms of action of these therapeutic agents. Equally relevant are the mechanisms of adaptive resistance to immune checkpoint inhibitors that have been uncovered through this approach. In this review, we discuss the dynamics of the immune system and of the tumor under immune checkpoint blockade emanating from recent studies on animal models and humans. We will focus on mechanisms of action and of resistance conveying information predictive of therapeutic response.

scholarly journals Age-Related Differences in Molecular Profiles for Immune Checkpoint Blockade Therapy

2021 ◽  
Vol 12 ◽  
Author(s):  
Qi-jie Zhang ◽  
Jiao-chen Luan ◽  
Le-bin Song ◽  
Rong Cong ◽  
Cheng-jian Ji ◽  
...  
Keyword(s):  
Elderly Patients ◽  
Immune Checkpoint ◽  
Treatment Efficacy ◽  
Young Patients ◽  
The Elderly ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Age Related ◽  
Cancer Types ◽  
Molecular Profiles

Immune checkpoint blockade (ICB) therapies have significantly improved the prognosis and shown considerable promise for cancer therapy; however, differences in ICB treatment efficacy between the elderly and young are unknown. We analyzed the studies enrolled in the meta-analysis using the deft approach, and found no difference in efficacy except melanoma patients receiving anti–PD-1 therapy. Similarly, higher treatment response rate and more favorable prognosis were observed in elderly patients in some cancer types (e.g., melanoma) with data from published ICB treatment clinical trials. In addition, we comprehensively compared immunotherapy-related molecular profiles between elderly and young patients from public trials and The Cancer Genome Atlas (TCGA), and validated these findings in several independent datasets. We discovered a divergent age-biased immune profiling, including the properties of tumors (e.g., tumor mutation load) and immune features (e.g., immune cells), in a pancancer setting across 27 cancer types. We believe that ICB treatment efficacy might vary depending on specific cancer types and be determined by both the tumor internal features and external immune microenvironment. Considering the high mutational properties in elderly patients in many cancer types, modulating immune function could be beneficial to immunotherapy in the elderly, which requires further investigation.

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