scholarly journals A review on the role of gut microbiota in immune checkpoint blockade therapy for cancer

2021 ◽  
Author(s):  
Esther Kim ◽  
Hyeok Ahn ◽  
Hansoo Park
Keyword(s):  
Gut Microbiota ◽  
Immune Checkpoint ◽  
Molecular Mechanisms ◽  
Cytotoxic T Lymphocyte ◽  
Response Prediction ◽  
Immune Checkpoint Blockade ◽  
Immune Checkpoints ◽  
Bacterial Strains ◽  
Programmed Cell Death 1 ◽  
Health And Disease

AbstractGut microbiota has been studied in relation to human health and disease prediction for decades. Also, immune checkpoints (ICPs) are enthusiastically investigated for anti-tumor immunotherapy. Recent studies show potential of gut microbiome and gut cytokines as biomarkers for carcinogenesis and response prediction of immune checkpoint inhibitor (ICI) response. Evidence has revealed that intestinal microorganisms play a major role in the effectiveness of programmed cell death 1 (PD-1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) blockade. In this review, we have focused on how microbiome and microbiome-generated cytokines affect immune checkpoints. We have also described the molecular mechanisms behind this interplay and the bacterial strains that have a potential role in immunotherapy.

scholarly journals Immunotherapy Associated Pulmonary Toxicity: Biology Behind Clinical and Radiological Features

Cancers ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 305 ◽  
Author(s):  
Michele Porcu ◽  
Pushpamali De Silva ◽  
Cinzia Solinas ◽  
Angelo Battaglia ◽  
Marina Schena ◽  
...  
Keyword(s):  
Early Diagnosis ◽  
Immune Checkpoint ◽  
Pulmonary Toxicity ◽  
Clinical Symptoms ◽  
Cytotoxic T Lymphocyte ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Multidisciplinary Teams ◽  
Programmed Cell Death 1 ◽  
Radiological Patterns

The broader use of immune checkpoint blockade in clinical routine challenges clinicians in the diagnosis and management of side effects which are caused by inflammation generated by the activation of the immune response. Nearly all organs can be affected by immune-related toxicities. However, the most frequently reported are: fatigue, rash, pruritus, diarrhea, nausea/vomiting, arthralgia, decreased appetite and abdominal pain. Although these adverse events are usually mild, reversible and not frequent, an early diagnosis is crucial. Immune-related pulmonary toxicity was most frequently observed in trials of lung cancer and of melanoma patients treated with the combination of the anti-cytotoxic T lymphocyte antigen (CTLA)-4 and the anti-programmed cell death-1 (PD-1) antibodies. The most frequent immune-related adverse event in the lung is represented by pneumonitis due to the development of infiltrates in the interstitium and in the alveoli. Clinical symptoms and radiological patterns are the key elements to be considered for an early diagnosis, rendering the differential diagnosis crucial. Diagnosis of immune-related pneumonitis may imply the temporary or definitive suspension of immunotherapy, along with the start of immuno-suppressive treatments. The aim of this work is to summarize the biological bases, clinical and radiological findings of lung toxicity under immune checkpoint blockade, underlining the importance of multidisciplinary teams for an optimal early diagnosis of this side effect, with the aim to reach an improved patient care.

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 In Situ Crosslinked Hydrogel Depot for Sustained Antibody Release Improves Immune Checkpoint Blockade Cancer Immunotherapy

Nanomaterials ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 471
Author(s):  
Jihoon Kim ◽  
David M. Francis ◽  
Susan N. Thomas
Keyword(s):  
Cancer Immunotherapy ◽  
Immune Checkpoint ◽  
Cytotoxic T Lymphocyte ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
High Rate ◽  
Immune Checkpoints ◽  
Safe Delivery ◽  
Therapeutic Class

The therapeutic inhibition of immune checkpoints, including cytotoxic T lymphocyte-associated protein (CTLA)-4 and programmed cell death 1 (PD-1), through the use of function blocking antibodies can confer improved clinical outcomes by invigorating CD8+ T cell-mediated anticancer immunity. However, low rates of patient responses and the high rate of immune-related adverse events remain significant challenges to broadening the benefit of this therapeutic class, termed immune checkpoint blockade (ICB). To overcome these significant limitations, controlled delivery and release strategies offer unique advantages relevant to this therapeutic class, which is typically administered systemically (e.g., intravenously), but more recently, has been shown to be highly efficacious using locoregional routes of administration. As such, in this paper, we describe an in situ crosslinked hydrogel for the sustained release of antibodies blocking CTLA-4 and PD-1 signaling from a locoregional injection proximal to the tumor site. This formulation results in efficient and durable anticancer effects with a reduced systemic toxicity compared to the bolus delivery of free antibody using an equivalent injection route. This formulation and strategy thus represent an approach for achieving the efficient and safe delivery of antibodies for ICB cancer immunotherapy.

A highly stable multifunctional aptamer for enhancing antitumor immunity against hepatocellular carcinoma by blocking dual immune checkpoints

2021 ◽  
Author(s):  
Yanlin Du ◽  
Da Zhang ◽  
Yiru Wang ◽  
Ming Wu ◽  
Cuilin Zhang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Immune Checkpoint ◽  
Antitumor Immunity ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Immune Checkpoints

A highly stable multifunctional aptamer was prepared for strengthening antitumor immunity through a dual immune checkpoint blockade of CTLA-4 and PD-L1.

scholarly journals Recent Advances and Future Prospects in Immune Checkpoint (ICI)-Based Combination Therapy for Advanced HCC

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1949
Author(s):  
Yawen Dong ◽  
Jeffrey Sum Lung Wong ◽  
Ryohichi Sugimura ◽  
Ka-On Lam ◽  
Bryan Li ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoints ◽  
Advanced Hcc ◽  
Oncogenic Pathways ◽  
Vegf Pathway ◽  
And Function ◽  
Endothelial Growth Factor

Advanced, unresectable hepatocellular carcinoma has a dismal outcome. Multiple immune checkpoint inhibitors (ICIs) targeting the programmed-cell death 1 pathway (PD-1/L1) have been approved for the treatment of advanced HCC. However, outcomes remain undesirable and unpredictable on a patient-to-patient basis. The combination of anti-PD-1/L1 with alternative agents, chiefly cytotoxic T-lymphocyte antigen-4 (CTLA-4) ICIs or agents targeting other oncogenic pathways such as the vascular endothelial growth factor (VEGF) pathway and the c-MET pathway, has, in addition to the benefit of directly targeting alterative oncogenic pathways, in vitro evidence of synergism through altering the genomic and function signatures of T cells and expression of immune checkpoints. Several trials have been completed or are underway evaluating such combinations. Finally, studies utilizing transcriptomics and organoids are underway to establish biomarkers to predict ICI response. This review aims to discuss the biological rationale and clinical advances in ICI-based combinations in HCCs, as well as the progress and prospects of the search for the aforementioned biomarkers in ICI treatment of HCC.

scholarly journals 836 Releasing the restraints of Vγ9Vδ2 T-cells in cancer immunotherapy

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A888-A888
Author(s):  
Laura Ridgley ◽  
Angus Dalgleish ◽  
Mark Bodman-Smith
Keyword(s):  
T Cells ◽  
Cancer Immunotherapy ◽  
Tumour Cell ◽  
Immune Checkpoint ◽  
Expansion Method ◽  
Immune Checkpoint Blockade ◽  
Immune Checkpoints ◽  
Inhibitory Receptors ◽  
Healthy Donors ◽  
Vγ9vδ2 T Cells

BackgroundVγ9Vδ2 T-cells are a subset of cells with a crucial role in immunosurveillance which can be activated and expanded by multiple means to stimulate effector responses, often exploited in cancer immunotherapy. Little is known about the expression of checkpoint molecules on this cell population and whether the ligation of these molecules can regulate their activity. The aim of this study was to assess the expression of activatory and inhibitory markers on Vγ9Vδ2 T-cells to assess potential avenues of regulation to target with immunotherapy.MethodsPBMCs were isolated from healthy donors and the expression of activatory and inhibitory receptors was assessed on Vγ9Vδ2 T-cells by flow cytometry at baseline, following 24 hours activation and 14 days expansion using zoledronic acid (ZA) and Bacillus Calmette-Guerin (BCG), both with IL-2. Activation and expansion of Vδ2 cells was assessed by expression of CD69 and by frequency of Vδ2 cells, respectively. Production of effector molecules was also assessed following coculture with various tumour cell targets. The effect of immune checkpoint blockade on Vγ9Vδ2 T-cells was also assessed.ResultsVγ9Vδ2 T-cells constitutively expressed high levels of NK-associated activatory markers NKG2D and DNAM1 which remained high following stimulation with ZA and BCG. Vγ9Vδ2 T-cells expressed variable levels of checkpoint inhibitor molecules at baseline with high levels of BTLA, KLRG1 and NKG2A and intermediate levels of PD1, TIGIT and VISTA. Expression of checkpoint receptors were modulated following activation and expansion with ZA and BCG with decreased expression of BTLA and upregulation of numerous markers including PD1, TIGIT, TIM3, LAG3 and VISTA. Expression of these markers is further modulated upon coculture with tumour cell lines with changes reflecting activation of these cells with Vγ9Vδ2 T-cells expressing inhibitory receptors PD1 and NKG2A producing the highest level of TNF.ConclusionsOur data reveals unique characteristics of Vδ2 in terms of their expression of immune checkpoints, which provide a mechanism which may be utilised by tumour cells to subvert Vγ9Vδ2 T-cell cytotoxicity. Our work suggests different profiles of immune checkpoints dependent on the method of stimulation. This highlights importance of expansion method in the function of Vγ9Vδ2 T-cells. Furthermore, this work suggests important candidates for blockade by immune checkpoint therapy in order to increase the successful use of Vγ9Vδ2 T-cells in cancer immunotherapy.

scholarly journals Cancer Immunotherapy by Blocking Immune Checkpoints on Innate Lymphocytes

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3504
Author(s):  
Silvia Pesce ◽  
Sara Trabanelli ◽  
Clara Di Vito ◽  
Marco Greppi ◽  
Valentina Obino ◽  
...  
Keyword(s):  
Immune System ◽  
Immune Checkpoint ◽  
Nk Cell ◽  
Current Knowledge ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoint Blockade ◽  
Lymphoid Cells ◽  
Immune Checkpoints ◽  
Tissue Damages ◽  
Innate Lymphocytes

Immune checkpoints refer to a plethora of inhibitory pathways of the immune system that play a crucial role in maintaining self-tolerance and in tuning the duration and amplitude of physiological immune responses to minimize collateral tissue damages. The breakdown of this delicate balance leads to pathological conditions, including cancer. Indeed, tumor cells can develop multiple mechanisms to escape from immune system defense, including the activation of immune checkpoint pathways. The development of monoclonal antibodies, targeting inhibitory immune checkpoints, has provided an immense breakthrough in cancer therapy. Immune checkpoint inhibitors (ICI), initially developed to reverse functional exhaustion in T cells, recently emerged as important actors in natural killer (NK)-cell-based immunotherapy. Moreover, the discovery that also helper innate lymphoid cells (ILCs) express inhibitory immune checkpoints, suggests that these molecules might be targeted on ILCs, to modulate their functions in the tumor microenvironment. Recently, other strategies to achieve immune checkpoint blockade have been developed, including miRNA exploiting systems. Herein, we provide an overview of the current knowledge on inhibitory immune checkpoints on NK cells and ILCs and we discuss how to target these innate lymphocytes by ICI in both solid tumors and hematological malignancies.

scholarly journals Management of pulmonary toxicity associated with immune checkpoint inhibitors

2019 ◽  
Vol 28 (154) ◽  
pp. 190012 ◽  
Author(s):  
Myriam Delaunay ◽  
Grégoire Prévot ◽  
Samia Collot ◽  
Laurent Guilleminault ◽  
Alain Didier ◽  
...  
Keyword(s):  
Adverse Events ◽  
Immune Checkpoint ◽  
Pulmonary Toxicity ◽  
Immune Checkpoint Inhibitors ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Standard Of Care ◽  
Serious Adverse Events ◽  
Programmed Cell Death 1 ◽  
Life Threatening

Immunotherapy has become a standard of care in oncology, following the recent approvals of cytotoxic T-lymphocyte-associated protein-4 and programmed cell death-1 inhibitors in lung cancer, melanoma, renal cell carcinoma, Hodgkin's lymphoma, bladder, head and neck cancers. Besides their efficacy, these agents also generate specific immune-related adverse events. Due to the increasing prescription of immune-checkpoint inhibitors, the incidence of immune toxicity will continue to rise. The awareness of immune-related adverse events is key to ensuring both diagnosis and management of the possible serious adverse events. Although severe immune-related adverse events remain rare, they can lead to discontinued treatment or to death if they are not forecasted and managed properly. Even if lung toxicity is not the most frequent adverse event, it remains critical as it can be life-threatening. Herein, the main aspects of pulmonary toxicity are reviewed and guidelines are also proposed in order to manage the possible side-effects.

scholarly journals Transcriptional Regulation of Cancer Immune Checkpoints: Emerging Strategies for Immunotherapy

Vaccines ◽  
2020 ◽  
Vol 8 (4) ◽  
pp. 735
Author(s):  
Simran Venkatraman ◽  
Jarek Meller ◽  
Suradej Hongeng ◽  
Rutaiwan Tohtong ◽  
Somchai Chutipongtanate
Keyword(s):  
Immune Checkpoint ◽  
Cancer Genomics ◽  
Checkpoint Inhibitors ◽  
Acquired Resistance ◽  
Immune Checkpoint Blockade ◽  
Immune Checkpoints ◽  
Master Regulators ◽  
New Class ◽  
Public Datasets ◽  
Molecular Expression

The study of immune evasion has gained a well-deserved eminence in cancer research by successfully developing a new class of therapeutics, immune checkpoint inhibitors, such as pembrolizumab and nivolumab, anti-PD-1 antibodies. By aiming at the immune checkpoint blockade (ICB), these new therapeutics have advanced cancer treatment with notable increases in overall survival and tumor remission. However, recent reports reveal that 40–60% of patients fail to benefit from ICB therapy due to acquired resistance or tumor relapse. This resistance may stem from increased expression of co-inhibitory immune checkpoints or alterations in the tumor microenvironment that promotes immune suppression. Because these mechanisms are poorly elucidated, the transcription factors that regulate immune checkpoints, known as “master regulators”, have garnered interest. These include AP-1, IRF-1, MYC, and STAT3, which are known to regulate PD/PD-L1 and CTLA-4. Identifying these and other potential master regulators as putative therapeutic targets or biomarkers can be facilitated by mining cancer literature, public datasets, and cancer genomics resources. In this review, we describe recent advances in master regulator identification and characterization of the mechanisms underlying immune checkpoints regulation, and discuss how these master regulators of immune checkpoint molecular expression can be targeted as a form of auxiliary therapeutic strategy to complement traditional immunotherapy.

scholarly journals Overview of Immune Checkpoint Inhibitors Therapy for Hepatocellular Carcinoma, and The ITA.LI.CA Cohort Derived Estimate of Amenability Rate to Immune Checkpoint Inhibitors in Clinical Practice

Cancers ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 1689 ◽  
Author(s):  
Edoardo Giannini ◽  
Andrea Aglitti ◽  
Mauro Borzio ◽  
Martina Gambato ◽  
Maria Guarino ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Clinical Practice ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Critical Evaluation ◽  
Real Life ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Immune Checkpoints

Despite progress in our understanding of the biology of hepatocellular carcinoma (HCC), this tumour remains difficult-to-cure for several reasons, starting from the particular disease environment where it arises—advanced chronic liver disease—to its heterogeneous clinical and biological behaviour. The advent, and good results, of immunotherapy for cancer called for the evaluation of its potential application also in HCC, where there is evidence of intra-hepatic immune response activation. Several studies advanced our knowledge of immune checkpoints expression in HCC, thus suggesting that immune checkpoint blockade may have a strong rationale even in the treatment of HCC. According to this background, initial studies with tremelimumab, a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor, and nivolumab, a programmed cell death protein 1 (PD-1) antibody, showed promising results, and further studies exploring the effects of other immune checkpoint inhibitors, alone or with other drugs, are currently underway. However, we are still far from the identification of the correct setting, and sequence, where these drugs might be used in clinical practice, and their actual applicability in real-life is unknown. This review focuses on HCC immunobiology and on the potential of immune checkpoint blockade therapy for this tumour, with a critical evaluation of the available trials on immune checkpoint blocking antibodies treatment for HCC. Moreover, it assesses the potential applicability of immune checkpoint inhibitors in the real-life setting, by analysing a large, multicentre cohort of Italian patients with HCC.

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