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.

scholarly journals Tumor-Infiltrating Lymphocytes and Breast Cancer: Are Immune Checkpoint Inhibitors Ready for Prime Time in Breast Cancer?

2016 ◽  
Vol 33 (4) ◽  
pp. 237-246 ◽  
Author(s):  
Ana Cvetanović ◽  
Slađana Filipović ◽  
Nikola Živković ◽  
Miloš Kostić ◽  
Svetislav Vrbić ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Tumor Biology ◽  
Predictive Biomarkers ◽  
Tumor Infiltrating Lymphocytes ◽  
Breast Tumors ◽  
Prime Time ◽  
Infiltrating Lymphocytes

SummaryIn recent years, results obtained from different studies with large cohorts have revealed a bond between the presence of extensive lymphocytic infiltration and favourable prognostic associations in the early-stage of breast cancer (BC) and high response rates to neoadjuvant chemotherapy. Examiners used tumors from large cohorts of patients who took part in randomized neoadjuvant and adjuvant clinical trials. The importance of tumor infiltrating lymphocytes (TILs) appears to be subtype-specific and varies depending on the histological characteristics of the tumor. TILs have proven to be a good prognostic marker, but only in highly proliferative breast tumors such as triple negative breast tumors (TNBC) or HER 2 positive BC.In the era when standard, well-known, prognostic and predictive biomarkers are ever changing and the use of molecular profiling analyses are increasing, we are looking for techniques to improve our understanding of tumor biology and improve patient outcome. The relevance of TILs cannot be ignored but needs to be properly evaluated in larger prospective studies which must encompass the parameters set out in previous studies. The use of TILs as prognostic biomarkers in early breast cancer may represent a new dawn, and use of immunotherapy, especially immune checkpoint inhibitors, probably is the future for the breast cancer but it is not yet ready for prime time.

Immune Checkpoint Inhibitors in Brain Metastases: From Biology to Treatment

2016 ◽  
pp. e116-e122 ◽  
Author(s):  
Anna S. Berghoff ◽  
Vyshak A. Venur ◽  
Matthias Preusser ◽  
Manmeet S. Ahluwalia
Keyword(s):  
Immune Response ◽  
Brain Metastases ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Scientific Evidence ◽  
Tumor Infiltrating Lymphocytes ◽  
Treatment Target ◽  
Infiltrating Lymphocytes ◽  
Extracranial Metastases

Cancer immunotherapy has been a subject of intense research over the last several years, leading to new approaches for modulation of the immune system to treat malignancies. Immune checkpoint inhibitors (anti–CLTA-4 antibodies and anti–PD-1/PD-L1 antibodies) potentiate the host’s own antitumor immune response. These immune checkpoint inhibitors have shown impressive clinical efficacy in advanced melanoma, metastatic kidney cancer, and metastatic non–small cell lung cancer (NSCLC)—all malignancies that frequently cause brain metastases. The immune response in the brain is highly regulated, challenging the treatment of brain metastases with immune-modulatory therapies. The immune microenvironment in brain metastases is active with a high density of tumor-infiltrating lymphocytes in certain patients and, therefore, may serve as a potential treatment target. However, clinical data of the efficacy of immune checkpoint inhibitors in brain metastases compared with extracranial metastases are limited, as most clinical trials with these new agents excluded patients with active brain metastases. In this article, we review the current scientific evidence of brain metastases biology with specific emphasis on inflammatory tumor microenvironment and the evolving state of clinical application of immune checkpoint inhibitors for patients with brain metastases.

scholarly journals Integrating Immunotherapy with Chemotherapy: A New Approach to Drug Repurposing

2021 ◽  
Author(s):  
Hina Qayoom ◽  
Umar Mehraj ◽  
Shariqa Aisha ◽  
Shazia Sofi ◽  
Manzoor Ahmad Mir
Keyword(s):  
Breast Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Therapeutic Potential ◽  
Checkpoint Inhibitors ◽  
Breast Cancer Subtype ◽  
Drug Repurposing ◽  
Tumor Infiltrating Lymphocytes ◽  
Her2 Receptor ◽  
Infiltrating Lymphocytes

Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype lacking the three hormonal receptors namely estrogen receptor, progesterone receptor and HER2 receptor, and the only treatment option available for TNBC is chemotherapy. Chemotherapy lacks specificity since it acts on normal healthy cells as well resulting into secondary diseases in TNBC patients. In addition chemotherapy poses recurrence and relapse issues due to the development of chemoresistance among TNBC patients. Immunotherapy remarkably immune checkpoint inhibitors show a great therapeutic potential in TNBC. As TNBC contain an increased TILs (tumor infiltrating lymphocytes) infiltration making it more suitable as a therapeutic target anti-tumor immune strategy. Moreover, evidences have indicated that chemotherapy upregulates the anti-tumor immune response in TNBC. As a result, a combination of immunotherapy with chemotherapy may increase the overall relapse and recurrence free survival of TNBC patients. Therefore, in this chapter we will focus on how the immunotherapy works in TNBC, their effects and consequences. We will further be discussing the clinical studies and the importance of immune checkpoint inhibitors (ICIs) in combination with various therapeutic agents and target. Further, we will explore the processes involved.

scholarly journals Current status of PD-1/PD-L1 blockade immunotherapy in breast cancer

2020 ◽  
Author(s):  
Emi Noguchi ◽  
Tadahiko Shien ◽  
Hiroji Iwata
Keyword(s):  
Breast Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Tumor Infiltrating Lymphocytes ◽  
The United States ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Current Status ◽  
Infiltrating Lymphocytes

Abstract Over the past 10 years, immunotherapy with immune checkpoint inhibitors has revolutionized the management of various cancers. However, immunotherapy in breast cancer has not been successful. Breast cancer has long been recognized as an immunologically ‘cold’ tumor, although a higher frequency of tumor-infiltrating lymphocytes present in certain subtypes and an association between tumor-infiltrating lymphocytes and favorable prognosis have been reported. In March 2019, the combination of atezolizumab and nanoparticle albumin-bound paclitaxel was granted accelerated approval in the United States for the treatment of programmed death-ligand 1-positive advanced or metastatic triple-negative breast cancer. This finally opened the door for immune checkpoint blockade therapy for breast cancer. Several clinical trials have been conducted using different combinations of immune checkpoint inhibitors and chemotherapy or targeted agents in various treatment settings for metastatic breast cancer and early-stage breast cancer. In this review, we summarize recent advances in immune checkpoint blockade therapy and predictive biomarkers in breast cancer.

Can immunologically hot lung cancer be distinguished from cold tumor by peripheral blood?

2020 ◽  
Vol 38 (5_suppl) ◽  
pp. 48-48
Author(s):  
Satoshi Muto ◽  
Hayato Mine ◽  
Hironori Takagi ◽  
Masayuki Watanabe ◽  
Yuki Ozaki ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Lymphocytes ◽  
Immune Checkpoint ◽  
Peripheral Blood ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Tumor Infiltrating Lymphocytes ◽  
Antigen Specificity ◽  
Significant Difference ◽  
Infiltrating Lymphocytes

48 Background: Depending on the number of tumor infiltrating lymphocytes, immunological cold to hot conditions vary. There are several clinical trials of administering immune checkpoint inhibitors as perioperative adjuvant therapy. Immune checkpoint inhibitors are generally effective in immunologically hot conditions. However, biopsy specimens are not enough to determine the amount of tumor infiltrating lymphocytes. Therefore, we focused on effector T lymphocytes in peripheral blood, and tried to understand the tumor microenvironment by looking at peripheral blood. Methods: Twenty-four patients with lung cancer who underwent surgery at Fukushima Medical University Hospital from December 2018 to June 2019 were able to separate and collect tumor infiltrating lymphocytes by magnetic cell sorting. Flow cytometry was used to analyze infiltrating lymphocytes and preoperative peripheral blood lymphocytes. Those not expressing CD62L, a marker of Naïve T lymphocytes, were designated as effector T lymphocytes. Results: In the group with a high proportion of cytotoxic T lymphocytes in tumor infiltrating lymphocytes, the proportion of CD62L-negative effector CD4 T lymphocytes in peripheral blood was high (p < 0.05). The percentage of lymphocytes in peripheral blood was also high (p < 0.05). Furthermore, tumor infiltrating lymphocytes had a high proportion of effector CD4 T lymphocytes (p < 0.05). There was a similar trend in the proportion of CD8 T lymphocytes, but there was no statistically significant difference. Conclusions: These results showed that immunologically hot cases could be identified by measuring effector CD4 T lymphocytes in peripheral blood. In the future, we will continue to verify the results and examine antigen specificity of these T lymphocytes.

scholarly journals Expression of Immune Checkpoint Regulators IDO, VISTA, LAG3, and TIM3 in Resected Pancreatic Ductal Adenocarcinoma

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2689
Author(s):  
Felix Popp ◽  
Ingracia Capino ◽  
Joana Bartels ◽  
Alexander Damanakis ◽  
Jiahui Li ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Immune Checkpoint ◽  
Patient Survival ◽  
Checkpoint Inhibitors ◽  
Tumor Infiltrating Lymphocytes ◽  
Ductal Adenocarcinoma ◽  
Lymph Node Status ◽  
Clinicopathologic Parameters ◽  
Survival Differences ◽  
Infiltrating Lymphocytes

Pancreatic cancer features elaborate mechanisms of immune evasion. The potential of new immune molecules was explored to restore the antitumor immune response. If these immune molecules are associated with poor survival, specific drugs could take effect. Here, we analyze the expression of VISTA, LAG3, IDO, and TIM3 on tumor-infiltrating lymphocytes (TILs) and its impact on patient survival. We analyzed 153 pancreatic cancer patients from the prospectively managed database of the multicentered PANCALYZE study. Immunohistochemistry on a tissue microarray assessed VISTA, LAG3, IDO, and TIM3 expression of TILs from the patients undergoing primary resection. Complementarily, we analyzed publicly available transcriptomic data (n = 903). Successful completion of chemotherapy, and lymph node status were independent predictors of survival in the multivariate analysis of the clinicopathologic parameters. Fifteen tumors were exclusively VISTA-positive, thirteen tumors expressed VISTA together with TIM3, and ten tumors expressed VISTA together with IDO. Patients featuring tumors with high numbers of IDO-positive TILs had better patient survival (p = 0.037). VISTA, LAG3, and TIM3 expression did not correlate with survival. The analysis of publicly available data did not show survival differences. Tumors rarely co-express more than two immune molecules at the same time, and VISTA is most frequently co-expressed. Although IDO generally inhibits T-cell proliferation, a high expression of IDO was associated with improved survival. We expect immune checkpoint inhibitors against VISTA, LAG3, and TIM3 to be inefficient in a clinical application.

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