scholarly journals Chitinase 3-like-1 Stimulates PD-L1 and Other Immune Checkpoint Inhibitors

2021 ◽  
Author(s):  
Bing Ma ◽  
Bedia Akosman ◽  
Suchitra Kamle ◽  
Chang-Min Lee ◽  
Ja Seok Koo ◽  
...  
Keyword(s):  
Pulmonary Metastasis ◽  
Poor Prognosis ◽  
Tumor Metastasis ◽  
Therapeutic Strategy ◽  
Checkpoint Inhibitors ◽  
Innate Immune ◽  
Cytotoxic T Cell ◽  
Tumor Cell Death ◽  
Metastasis Models ◽  
Ifn Γ

ABSTRACTPD-1 and its ligand PD-L1 are major mediators of tumor-induced immunosuppression. Chitinase 3-like-1 (Chi3l1) is induced in many cancers where it portends a poor prognosis and contributes to tumor metastasis. Here we demonstrate that Chi3l1 regulates the expression of PD-L1, PD-L2, PD-1 and LAG3 in melanoma lung metastasis. Chi3l1 stimulates macrophage PD-L1 expression and mediates optimal IFN-γ-stimulated PD-L1 expression via IL-13Rα2. We also demonstrate that RIG-like helicase innate immune activation suppresses Chi3l1, PD-L1, LAG3 and pulmonary metastasis. At least additive antitumor responses were seen in metastasis models treated simultaneously with individual antibodies against PD-1 and Chi3l1. At least additive cytotoxic T cell-induced tumor cell death was also seen in co-cultures of T and tumor cells treated with antibodies that target Chi3l1 and PD-1. Thus, Chi3l1 contributes to pulmonary metastasis by stimulating the PD1-PD-L1 axis and other checkpoint molecules. The simultaneous targeting of Chi3l1 and the PD-1-PD-L1 axis, represents a promising therapeutic strategy for pulmonary metastasis.

Role of Tim-3 in regulating tumorigenesis, inflammation, and antitumor immunity therapy

2021 ◽  
pp. 1-12
Author(s):  
Yuting Cao ◽  
Qiang Li ◽  
Huihui Liu ◽  
Xianglei He ◽  
Fang Huang ◽  
...  
Keyword(s):  
T Cells ◽  
Viral Infections ◽  
Checkpoint Inhibitors ◽  
Innate Immune ◽  
The Past ◽  
Chronic Viral Infections ◽  
Antitumor Potential ◽  
Programmed Cell Death 1 ◽  
Ifn Γ

Over the past decade, cancer immunotherapy, such as immune checkpoint inhibitors (ICRs), has attained considerable progresses in clinical practice. T-cell immunoglobulin and mucin domain-containing protein 3 (Tim-3) act as next ICRs, and originally function as a co-inhibitory receptor expressed on interferon (IFN)-γ producing CD4+ and CD8+ T-cells. Furthermore, Tim-3 has also been found to express on innate immune cells and several types of tumors, signifying the pivotal role that Tim-3 plays in chronic viral infections and cancer. In addition, Tim-3 and multiple ICRs are concurrently expressed and regulated on dysfunctional or exhausted T-cells, leading to improved antitumor immune responses in preclinical or clinical cancer therapy through co-blockade of Tim-3 and other ICRs such as programmed cell death-1 (PD-1). In this review, the biological characteristics of Tim-3 and the function of Tim-3 in regulating tumorigenesis and inflammation have been summarized. The usage of a single blockade of Tim-3 or in combination with multiple immunotherapy regimens have drawn attention to antitumor potential as a target for immunotherapy.

scholarly journals The Innate Immune Signalling Pathways: Turning RIG-I Sensor Activation against Cancer

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3158
Author(s):  
Sandra Iurescia ◽  
Daniela Fioretti ◽  
Monica Rinaldi
Keyword(s):  
T Cell ◽  
Checkpoint Inhibitors ◽  
Adoptive Cell Therapy ◽  
Tumour Microenvironment ◽  
Innate Immune ◽  
Cytotoxic T Cell ◽  
Signalling Pathways ◽  
Type I ◽  
Tumour Immunity

Over the last 15 years, the ability to harness a patient’s own immune system has led to significant progress in cancer therapy. For instance, immunotherapeutic strategies, including checkpoint inhibitors or adoptive cell therapy using chimeric antigen receptor T-cell (CAR-T), are specifically aimed at enhancing adaptive anti-tumour immunity. Several research groups demonstrated that adaptive anti-tumour immunity is highly sustained by innate immune responses. Host innate immunity provides the first line of defence and mediates recognition of danger signals through pattern recognition receptors (PRRs), such as cytosolic sensors of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular pattern (DAMP) signals. The retinoic acid-inducible gene I (RIG-I) is a cytosolic RNA helicase, which detects viral double-strand RNA and, once activated, triggers signalling pathways, converging on the production of type I interferons, proinflammatory cytokines, and programmed cell death. Approaches aimed at activating RIG-I within cancers are being explored as novel therapeutic treatments to generate an inflammatory tumour microenvironment and to facilitate cytotoxic T-cell cross-priming and infiltration. Here, we provide an overview of studies regarding the role of RIG-I signalling in the tumour microenvironment, and the most recent preclinical studies that employ RIG-I agonists. Lastly, we present a selection of clinical trials designed to prove the antitumour role of RIG I and that may result in improved therapeutic outcomes for cancer patients.

Glioblastoma: Prognostic Factors and Predictive Response to Radio and Chemotherapy

2020 ◽  
Vol 27 (17) ◽  
pp. 2814-2825
Author(s):  
Francesco Fiorica ◽  
Maria Colella ◽  
Rosaria Taibi ◽  
Andrea Bonetti ◽  
Jacopo Giuliani ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Glioblastoma Multiforme ◽  
Poor Prognosis ◽  
Therapeutic Strategy ◽  
Biological Factors ◽  
Near Future ◽  
Predictive Response

: Glioblastoma multiforme (GBM) is characterized by poor prognosis despite an aggressive therapeutic strategy. In recent years, many advances have been achieved in the field of glioblastoma biology. : Here we try to summarize the main clinical and biological factors impacting clinical prognostication and therapy of GBM patients. From that standpoint, hopefully, in the near future, personalized therapies will be available.

scholarly journals Evidence for Differential Roles for NKG2D Receptor Signaling in Innate Host Defense against Coronavirus-Induced Neurological and Liver Disease

2007 ◽  
Vol 82 (6) ◽  
pp. 3021-3030 ◽  
Author(s):  
Kevin B. Walsh ◽  
Melissa B. Lodoen ◽  
Robert A. Edwards ◽  
Lewis L. Lanier ◽  
Thomas E. Lane
Keyword(s):  
Liver Disease ◽  
Immune Responses ◽  
Host Defense ◽  
Nk Cell ◽  
Hepatitis Virus ◽  
Innate Immune ◽  
Liver Pathology ◽  
Innate Immune Responses ◽  
Ifn Γ ◽  
The Brain

ABSTRACT Infection of SCID mice with a recombinant murine coronavirus (mouse hepatitis virus [MHV]) expressing the T-cell chemoattractant CXC chemokine ligand 10 (CXCL10) resulted in increased survival and reduced viral burden within the brain and liver compared to those of mice infected with an isogenic control virus (MHV), supporting an important role for CXCL10 in innate immune responses following viral infection. Enhanced protection in MHV-CXCL10-infected mice correlated with increased gamma interferon (IFN-γ) production by infiltrating natural killer (NK) cells within the brain and reduced liver pathology. To explore the underlying mechanisms associated with protection from disease in MHV-CXCL10-infected mice, the functional contributions of the NK cell-activating receptor NKG2D in host defense were examined. The administration of an NKG2D-blocking antibody to MHV-CXCL10-infected mice did not reduce survival, dampen IFN-γ production in the brain, or affect liver pathology. However, NKG2D neutralization increased viral titers within the liver, suggesting a protective role for NKG2D signaling in this organ. These data indicate that (i) CXCL10 enhances innate immune responses, resulting in protection from MHV-induced neurological and liver disease; (ii) elevated NK cell IFN-γ expression in the brain of MHV-CXCL10-infected mice occurs independently of NKG2D; and (iii) NKG2D signaling promotes antiviral activity within the livers of MHV-infected mice that is not dependent on IFN-γ and tumor necrosis factor alpha secretion.

7 Prognostic factors for overall survival in patients with advanced melanoma treated with Anti-PD-1 therapy – the melimmune score

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A7-A7
Author(s):  
Soraia Lobo-Martins ◽  
Diogo Martins-Branco ◽  
Patrícia Miguel Semedo ◽  
Cecília Melo Alvim ◽  
Ana Maria Monteiro ◽  
...  
Keyword(s):  
Risk Factors ◽  
Prognostic Factors ◽  
Poor Prognosis ◽  
Proportional Hazards ◽  
Checkpoint Inhibitors ◽  
Prognostic Score ◽  
Daily Practice ◽  
Cox Proportional Hazards ◽  
Time To Death ◽  
Line Setting

BackgroundImmune checkpoint inhibitors (ICI) have changed the paradigm of advanced malignant melanoma (MM). Several prognostic factors, mostly linked to inflammation, have been under scope to better select patients for such therapies. We aimed to build and apply a prognostic score in this setting.MethodsBaseline characteristics and outcomes on 147 patients with advanced MM treated with an anti-PD1 (nivolumab or pembrolizumab) in monotherapy, between Jan-2016 and Oct-2019, in the 1st, 2nd or 3rd line setting were collected from two centres in Portugal. Data cut-off for follow-up was May-2020. Cox proportional hazards regression was used to identify independent prognostic factors for OS.ResultsWith a median FU of 28.93 months (95% CI [22.52–33.54]), mOS for the whole cohort was 14.75 months (95% CI, [10.80–18.71]). Overall, 43 and 104 patients were treated with nivolumab and pembrolizumab, respectively. We identified four adverse prognostic factors that were independent predictors of bad prognosis: number of metastatic sites >2 (p<0.001), baseline PS-ECOG =1 (p<0.001), presence of baseline lymphopenia (over lower limit of normal) (p=0.002) or very high baseline LDH (>2x upper limit of normal) (p<0.001).Patients were separated into three risk categories according to the number of risk factors present: favourable prognosis (no risk factors; n=34), intermediate prognosis (one risk factor; n=65) and poor prognosis (two or more risk factors; n=48). mOS was 43.41 (95% CI [32.13–54.69], 14.39 (95% CI [6.78–22.01]) and 6.53 months (95% CI [3.61–9.44]), for favourable, intermediate, and poor prognosis group, respectively (p<0.001; figure 1). AUC of ROC curve for OS was 0.737 (95% CI [0.654–0.819], p<0.001).Abstract 7 Figure 1Time to death - Kaplan-Meier survival plotConclusionsUsing easily accessible parameters from our daily practice, we propose the MELImmune prognostic score for advanced MM patients treated with anti-PD1 in monotherapy that could be incorporated to the daily clinical practice and clinical trials. We further aim to validate this score in an independent larger sample.Ethics ApprovalThe study was approved by both institutions’ Ethics Committee.

scholarly journals Clinical Applications of Immunotherapy Combination Methods and New Opportunities for the Future

2017 ◽  
Vol 2017 ◽  
pp. 1-10 ◽  
Author(s):  
Ece Esin
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Checkpoint Inhibitors ◽  
Innate Immune ◽  
Small Subset ◽  
New Class ◽  
Combination Strategies ◽  
Combination Methods ◽  
Immune Editing ◽  
Cell Death Protein

In the last decade, we have gained a deeper understanding of innate immune system. The mechanism of the continuous guarding of progressive mutations happening in a single cell was discovered and the production and the recognition of tumor associated antigens by the T-cells and elimination of numerous tumors by immune-editing were further understood. The new discoveries on immune mechanisms and its relation with carcinogenesis have led to development of a new class of drugs called immunotherapeutics. T lymphocyte-associated antigen 4, programmed cell death protein 1, and programmed cell death protein ligand 1 are the classes drugs based on immunologic manipulation and are collectively known as the “checkpoint inhibitors.” Checkpoint inhibitors have shown remarkable antitumor efficacy in a broad spectrum of malignancies; however, the strongest and most durable immune responses do not last long and the more durable responses only occur in a small subset of patients. One of the solutions which have been put forth to overcome these challenges is combination strategies. Among the dual use of methods, a backbone with either PD-1 or PD-L1 antagonist drugs alongside with certain cytotoxic chemotherapies, radiation, targeted drugs, and novel checkpoint stimulators is the most promising approach and will be on stage in forthcoming years.

scholarly journals Systemic inflammation and pro-inflammatory cytokine profile predict response to checkpoint inhibitor treatment in NSCLC: a prospective study

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Diego Kauffmann-Guerrero ◽  
Kathrin Kahnert ◽  
Rosemarie Kiefl ◽  
Laura Sellmer ◽  
Julia Walter ◽  
...  
Keyword(s):  
Prospective Study ◽  
Systemic Inflammation ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Cytokine Profile ◽  
Second Line ◽  
Cytokine Profiles ◽  
Ifn Γ ◽  
Nsclc Patients

AbstractTreatment with single agent immune checkpoint inhibitors (ICIs) has tremendously changed second line therapy in NSCLC. However, there are still no reliable biomarkers predicting response and survival in this group of patients. PD-L1 revealed to be a correlating, but no perfect marker. Therefore, we sought to investigate in this prospective study, whether inflammation status and cytokine profile could serve as additional biomarkers guiding treatment decision for single agent ICIs in NSCLC. 29 stage IV NSCLC patients receiving single agent PD-1 checkpoint-inhibitor in second line were prospectively enrolled. Inflammatory scores and cytokine profiles (IL-6, IL-8, IL-10, IFN-γ and TNFα) have been obtained before treatment and at the time of the first staging. Cytokine profiles were correlated with response and survival. Patients with signs of pre-therapeutic inflammation (elevated, NLR, SII, IL-6, IL-8) showed significantly lower response to ICI treatment and reduced PFS. Contrary, elevated levels of IFN-γ revealed to characterize a subgroup of patients, who significantly benefits from ICI treatment. Furthermore, low systemic inflammation and high levels of IFN-γ characterized patients with long term-response to ICI treatment. Pre-therapeutic assessment of inflammation and cytokine profiles has the ability to predict response and survival in NSCLC patients treated with single agent ICIs.

Ανοσοθεραπεία ενάντια στον καρκίνο του παγκρέατος

2020 ◽  
Author(s):  
Παύλος Παπακοτούλας
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Tumor Infiltrating Lymphocytes ◽  
Ciclopirox Olamine ◽  
Ifn Γ ◽  
Infiltrating Lymphocytes

Το πιο συχνό είδος καρκίνου του παγκρέατος είναι το αδενοκαρκίνωμα του παγκρέατος. Το παγκρεατικό αδενοκαρκίνωμα είναι η 4η κύρια αιτία των θανάτων από καρκίνο παγκοσμίως. Περίπου 60-80% των ασθενών έχουν τη στιγμή της διάγνωσης προχωρημένη νόσο, επειδή ο καρκίνος εισβάλλει στους περιβάλλοντες ιστούς έξω από το πάγκρεας (τοπικά προχωρημένος), ή έχει δώσει μεταστάσεις έξω από το πάγκρεας (μεταστατικός). Καθώς η νόσος παρουσιάζει πολύ υψηλό ποσοστό θνητότητας, κρίνεται επιτακτική η ανάγκη ανεύρεσης νέων αποτελεσματικότερων θεραπειών. Με τη ανάπτυξη της μοριακής και βιολογικής κατανόησης της ογκογενετικής εξέλιξης, εφαρμόστηκαν νέες στρατηγικές στην αντιμετώπιση του καρκίνου και κατ’ επέκταση σε αυτόν της ανοσοθεραπείας του καρκίνου. Η κατανόηση των μοριακών μηχανισμών που διέπουν την ανοσοδιαφυγή των όγκων, αλλά και την αλληλεπίδραση των καρκινικών κυττάρων με τα κύτταρα του ανοσοποιητικού συστήματος, έχει δώσει τεράστια ώθηση στην ανοσοθεραπεία του καρκίνου την τελευταία δεκαετία. Τα κύτταρα του ανθρώπινου οργανισμού βρίσκονται υπό διαρκή ανοσιακή επιτήρηση και το ανοσοποιητικό σύστημα αποτελεί αποτρεπτικό μηχανισμό στον νεοπλασματικό μετασχηματισμό και τη δημιουργία νεοπλασιών. Κλινικό σημείο που επιβεβαιώνει τη θεωρία της ανοσοεπιτήρησης είναι η διαπίστωση της παρουσίας CD8+ T-λεμφοκυττάρων μέσα στους όγκους (Tumor Infiltrating Lymphocytes – TILs). Συνέπεια αυτού είναι και οι θεραπείες που βασίζονται στην καταστολή των σημείων ελέγχου του ανοσοποιητικού συστήματος (Immune Checkpoint Inhibitors). Είναι γνωστό ότι φάρμακα με αντιμυκητιακές ιδιότητες συμβάλλουν στην ενίσχυση του ανοσοποιητικού συστήματος. Ένα χαρακτηριστικό παράδειγμα είναι η κυκλοπιροξολαμίνη (Ciclopirox Olamine, CPX), που χορηγείται σε άτομα που ταλαιπωρούνται από μυκητιάσεις. Σύμφωνα με την παρούσα διατριβή η συγκεκριμένη θεραπεία μπορεί να μειώσει δραστικά την ταχύτητα εξέλιξης των καρκινικών όγκων, αλλά παράλληλα ενισχύει τη δράση των κυτταροστατικών που χορηγούνται στον ασθενή. Επίσης, η τινζαπαρίνη (Ηπαρίνη Χαμηλού Μοριακού Βάρους) χρησιμοποιείται για την πρόληψη και την αντιμετώπιση της φλεβικής θρομβοεμβολής, αλλά από τα αποτελέσματα της παρούσης διατριβής φαίνεται ότι μπορεί να διαδραματίζει ρόλο στην αντιμετώπιση του όγκου. Οι μηχανισμοί στους οποίους οφείλονται τα σημαντικά in vivο αποτελέσματα, είναι η αύξηση της IFN-γ, η αύξηση των CD8+ κυττάρων, η μείωση των Tregs κυττάρων, η μείωση της έκφρασης του VEGFR-2 και η αύξηση της απόπτωσης στα καρκινικά κύτταρα. Στην παρούσα διατριβή, προτείνεται πως η συνδυαστική θεραπεία με τη συμμετοχή της ανοσοθεραπείας, έχει προφανώς υψηλότερη αντινεοπλασματική επίδραση στη μείωση της ανάπτυξης του όγκου, υποδηλώνοντας μια συνεργική δράση. Αυτή η συνεργική στρατηγική μπορεί να ανοίξει νέους δρόμους για τη θεραπεία ασθενών με καρκίνο του παγκρέατος.

Insurance data of patients receiving sequential immune checkpoint inhibitors: A single center experience.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e18835-e18835
Author(s):  
Muhammad Awidi ◽  
Rojer Ranjit ◽  
Brendan James Connell ◽  
Brigitte Gil ◽  
Natalie Dalbo ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Disease Progression ◽  
Cell Lung Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Insurance Status ◽  
Tumor Cell Death ◽  
Oncology Patients ◽  
Commercial Insurance

e18835 Background: Immune checkpoint inhibitors (ICI) up regulate T cell activity promoting tumor cell death and revolutionized modern oncology. The use and number of indications for ICI is growing at an unprecedented speed. Combination and sequential ICI therapies have been shown to be beneficial in certain types of cancer. There is no significant data to support non-FDA approved sequential use of ICI when patients develop toxicities or progression which could result in a significant financial burden on the patient and the health care system. We conducted a retrospective review of cancer patients receiving ICI at our institution and evaluated the insurance status of these patients who received sequential ICI. Methods: We retrospectively reviewed Oncology patients’ charts who received ICI between January 1, 2014 to December 18, 2018. We identified patients receiving sequential ICI, to be defined as patients who received a second ICI, following an initial ICI therapy. Insurance status was evaluated for patients receiving sequential therapy. Commercial insurance was defined as either private or non-Medicare/Medicaid. Results: Out of total 437 patients receiving ICI, 15 patients received sequential ICI. 11 patients were transitioned to a secondary ICI following disease progression (73%), three had immune related adverse events and one was switched per standard of care. Nine patients (60%) had commercial insurance and six patients (40%) had medicare/medicaid. Of those, one had urothelial carcinoma and was switched to pembrolizumab from atezolizumab due to disease progression. One patient had melanoma and received nivolumab following ipilimumab when data from the CHECKMATE 238 were published. Three patients with melanoma were transitioned from ipilimumab to nivolumab, two had disease progression and one had autoimmune dermatitis. Two patients had lung adenocarcinoma and were switched from nivolumab to pembrolizumab due to disease progression. One patient had small cell lung cancer and received pembrolizumab following nivolumab due to disease progression. One patient had squamous cell lung cancer and was switched to pembrolizumab from nivolumab following disease progression. Conclusions: With the rapid growth and advancement of ICI indications, there is limited data available on the benefits of sequential ICI to our patients in the clinical setting. We report a small percentage of oncology patients receiving sequential treatment with or without FDA approval and explore their insurance status. Majority of our patients who transitioned to a second ICI due to progression had commercial insurance. Larger prospective studies are needed to evaluate sequential ICI efficacy and tolerability and cost effectiveness.

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