Cancer Vaccines

Recent advances in immuno-oncology have allowed for the design of more specific and efficient cancer vaccine approaches. There has been an improvement in molecular biology techniques, as well as a greater understanding of the mechanisms involved in the activation and regulation of T cells and the interplay between the components of the immune system and the escape mechanisms used by cancer cells and the tumour microenvironment. As a result, many interesting developments in therapeutic cancer vaccines are ongoing, with influence on survival still to be proven. The spectrum of tumour antigens that are recognised by T cells is still largely unchartered and, most importantly, dynamically evolving over time, driven by clonal evolution and treatment-driven selection. Vaccine approaches currently in development and tested in clinical studies are based on tumour antigens specifically identified for each tumour type, on tumour cells or dendritic cells, the latter having the potential to be modified to incorporate immunostimulatory genes. However, interplay between the immune system and the tumour and the inhibitory mechanisms developed by tumour cells to subvert immune responses are crucial issues that will need to be targeted in order for efficient therapeutic vaccines to emerge

Benign Fibrous Histiocytoma of the Buccal Mucosa: Case Report and Literature Review

Benign fibrous histiocytoma is an interesting and challenging entity even in its most usual, cutaneous presentation. Noncutaneous presentation is extremely limited, even more so for the mucosa of the head and neck area. We herein report such a case, describing the clinical characteristics of the lesion, complete diagnostic evaluation, management, and follow-up. Diagnostic histopathological challenges are specifically illustrated. A complete review of the relevant literature is also included

Inverse baseline expression pattern of the NEP/neuropeptides and NFκB/proteasome pathways in androgen-dependent and androgen-independent prostate cancer cells

<p>Abstract</p> <p>Background</p> <p>Castration-resistance in prostate cancer (PC) is a critical event hallmarking a switch to a more aggressive phenotype. Neuroendocrine differentiation and upregulation of NFκB transcriptional activity are two mechanisms that have been independently linked to this process.</p> <p>Methods</p> <p>We investigated these two pathways together using <it>in vitro </it>models of androgen-dependent (AD) and androgen-independent (AI) PC. We measured cellular levels, activity and surface expression of Neutral Endopeptidase (NEP), levels of secreted Endothelin-1 (ET-1), levels, sub-cellular localisation and DNA binding ability of NFκB, and proteasomal activity in human native PC cell lines (LnCaP and PC-3) modelling AD and AI states.</p> <p>Results</p> <p>At baseline, AD cells were found to have high NEP expression and activity and low secreted ET-1. In contrast, they exhibited a low-level activation of the NFκB pathway associated with comparatively low 20S proteasome activity. The AI cells showed the exact mirror image, namely increased proteasomal activity resulting in a canonical pathway-mediated NFκB activation, and minimal NEP activity with increased levels of secreted ET-1.</p> <p>Conclusions</p> <p>Our results seem to support evidence for divergent patterns of expression of the NFκB/proteasome pathway with relation to components of the NEP/neuropeptide axis in PC cells of different level of androgen dependence. NEP and ET-1 are inversely and directly related to an activated state of the NFκB/proteasome pathway, respectively. A combination therapy targeting both pathways may ultimately prove to be of benefit in clinical practice.</p

Expression of Neutral Endopeptidase, Endothelin-1, and Nuclear Factor Kappa B in Prostate Cancer: Interrelations and Associations with Prostate-Specific Antigen Recurrence after Radical Prostatectomy

Objective. To study the impact of the neutral endopeptidase (NEP)/neuropeptides (NPs) axis and nuclear factor kappa B (NFκB) as predictors of prostate-specific antigen (PSA) recurrence after radical prostatectomy (RP). Patients and Methods. 70 patients with early-stage PC were treated with RP and their tumor samples were evaluated for expression of NEP, endothelin-1 (ET-1) and NFκB (p65). Time to PSA recurrence was correlated with the examined parameters and combined with preoperative PSA level, Gleason score, pathological TNM (pT) stage, and surgical margin (SM) assessment. Results and Limitations. Membranous expression of NEP (P < 0.001), cytoplasmic ET-1 (P = 0.002), and cytoplasmic NFκB (P < 0.001) were correlated with time to PSA relapse. NEP was associated with ET-1 (P < 0.001) and NFκB (P < 0.001). ET-1 was also correlated with NFκB (P < 0.001). NEP expression (P = 0.017), pT stage (P = 0.013), and SMs (P = 0.036) were independent predictors of time to PSA recurrence. Conclusions. There seems to be a clinical model of NEP/NPs and NFκB pathways interconnection, with their constituents following inverse patterns of expression in accordance with their biological roles and molecular interrelations

Nutritional index for immune-checkpoint inhibitor in patients with metastatic gastro-esophageal junction/gastric cancer

Background: Nutritional status is strongly associated to prognosis in mGOJ/GC patients. The aim of the present study was to develop an ICI-specific nutritional index (NI).Methods: Ten serum and anthropometric nutritional markers derived from blood tests or CT scans were analyzed at baseline in patients treated with second-line ICI and correlated with overall survival (OS). An ICI-specific NI (the NUTRIICI) was developed with its specificity assessed in an independent group of patients treated with standard second-line chemotherapy.Results: From June 2014 to December 2018, 57 mGOJ/GC patients (14 females, 43 males) with a median(m) age of 61 years (range 29-85) received ICI as second-line therapy (Pembrolizumab n=26, Nivolumab n=1 6, Avelumab n=15). Among the 10 analyzed variables, Onodera's prognostic NI (PNI) &lt;= 33 and waist-to-hip (WHR) &lt;1 were independent predictors of OS and used to build the NUTRIICI. Patients with both favorable factors (i.e., PNI &gt;33 and WHR &gt;= 1, comparator group) had a mOS of 18.0 vs. 6.7 months of patients with one unfavorable factor (either PNI &lt;= 33 or WHR &lt;1, Hazard Ratio, HR 3.06), vs. 1.3 months of patients with both unfavorable factors (HR 17.56), overall P&lt;0.0001. In the independent group of patients treated with standard chemotherapy NUTRIICI was not associated with prognosis (P=0.57).Conclusions: NUTRIICI is the first ICI-specific NI for mOGJ/GC patients receiving second-line ICI. A validation in larger cohorts is strongly encouraged

Redefining cancer of unknown primary: Is precision medicine really shifting the paradigm?

The concept of Cancer of Unknown Primary (CUP) has evolved with the advent of medical oncology. CUP can be difficult to diagnose and represents 2 to 5% of new cancers, therefore not exceptionally rare. Within CUPs can be identified a subset of favourable prognosis tumours, however the vast majority of CUP patients belongs to a poor prognosis group. CUP features significant oncological challenges, such as unravelling biological and transversal issues, and most importantly, improving patient\u27s outcomes. In that regard, CUP patients’ outcomes regrettably showed minimal improvement for decades and CUP remains a cancer group of very poor prognosis. The biology of CUP has two main hypotheses. One is that CUP is a subgroup of a given primary cancer, where the primary is present but cannot be seen due to its small size. The other, the “true” CUP hypothesis, states that CUP share features that make them a specific entity, whatever their tissue of origin. A true biological signature has not yet been described, but chromosomal instability is a hallmark of poor prognosis CUP group. Precision oncology, despite achieving identifying the putative origin of the CUP, so far failed to globally improve outcomes of patients. Targeting molecular pathways based on molecular analysis in CUP management is under investigation. Immunotherapy has not shown ground-breaking results, to date. Accrual is also a crucial issue in CUP trials. Herein we review CUP history, biological features and remaining questions in CUP biology, the two main approaches of molecular oncology in CUP management, in order to draw perspectives in the enormous challenge of improving CUP patient outcomes

Investigation of the relationship between the MME/NPs and NFkB/proteasome pathways in androgen-independent prostate cancer (AIP)

INTRODUCTION Castration-resistance in prostate cancer is a critical event hallmarking a switch to a more aggressive phenotype. Upregulation of NFB activity and neuroendocrine differentiation are two mechanisms known to be involved in prostate cancer progression to castration resistance. We investigated the interrelations of these pathways using in vitro models of androgen-dependent (AD) and androgen-independent (AI) prostate cancer (PC). METHODSWe measured cellular levels, activity and surface expression of neutral endopeptidase (NEP), levels of secreted ET1, levels, sub-cellular localisation and DNA binding ability of NFB, IB levels and proteasomal activity in human native prostate cancer cell lines (LnCaP and PC3) and a transfectant line (WT-5), modelling AD and AI states. RESULTSAt baseline, AD cells were found to have upregulated NEP/NPs pathway with high NEP expression and activity and less secreted ET-1. In contrast, they exhibited a low-level activation of the NFB pathway associated with comparatively low 20S proteasome activity. The AI cells showed the exact mirror image, namely increased proteasomal activity resulting in a canonical pathway-mediated NFB activation, and minimal NEP activity with increased levels of secreted ET-1. Neuropeptides induced nuclear translocation of NFB in AI cells, also evident as increased DNA binding in mobility shift assay (EMSA), reduced total IB levels, and increased 20S proteasomal activity. AD cells showed no appreciable nuclear translocation upon neuropeptide stimulation, with less intense DNA binding signal on EMSA and decreased proteasomal activity. These effects were at least partially prevented by specific neuropeptide receptor inhibitors, as well as NFB, IKK and proteasome inhibitors.CONCLUSIONAnalysis of components of the two pathways at baseline has shown that these pathways exhibit an inverse and mirror image relationship in androgen-dependent (AD) and –independent (AI) states in vitro. Our results also support evidence for a direct mechanistic connection between the neutral endopeptidase/neuropeptides and NFB/proteasome pathways, with a distinct neuropeptide-induced profile in the more aggressive, AI cancer state. A combination therapy targeting both pathways may ultimately prove to be of benefit in clinical practice.Η ανδρογονο-ανεξαρτησία (ή ορθότερα με βάση τον νεότερο όρο η ανθεκτικότητα στον ευνουχισμό) στον καρκίνο του προστάτη (PC) αποτελεί ένα πολύ σημαντικό γεγονός που σηματοδοτεί την πρόοδο της νόσου και την αλλαγή προς έναν επιθετικότερο φαινότυπο. Η νευροενδοκρινική διαφοροποίηση και η αύξηση της μεταγραφικής δραστηριότητας του NF-κΒ είναι δύο μηχανισμοί που έχουν ανεξάρτητα συνδεθεί με αυτή τη διαδικασία. Ερευνήσαμε τις σχέσεις αλληλεπίδρασης αυτών των οδών χρησιμοποιώντας in vitro μοντέλα ανδρογονο-εξαρτώμενου καρκίνου του προστάτη (AD) και μη ανδρογονο-εξαρτώμενου καρκίνου του προστάτη (ΑΙ).Μετρήσαμε τα κυτταρικά επίπεδα, τη δραστηριότητα και την μεμβρανική έκφραση της ουδέτερης ενδοπεπτιδάσης (ΝΕΡ), τα επίπεδα της εκκρινόμενης ΕΤ-1, τα πυρηνικά και κυτταροπλασματικά επίπεδα, την ενδοκυττάρια εντόπιση και το ποσοστό σύνδεσης του DNA του NF-κΒ, καθώς και την πρωτεασωμική δραστηριότητα σε φυσικές και διαμολυσμένες ανθρώπινες κυτταρικές σειρές καρκίνου προστάτη, αντιπροσωπεύοντας πρότυπες καταστάσεις AD και ΑΙ καρκίνου.Σε σταθερή κατάσταση βρήκαμε ότι τα ανδρογονο-εξαρτώμενα κύτταρα είχαν ενεργοποιημένη την οδό NEP/NPs, με υψηλή έκφραση και δραστηριότητα NEP και χαμηλή εκκρινόμενη ΕΤ-1. Αντίθετα, παρουσίασαν χαμηλό επίπεδο ενεργοποίησης της οδού NFκΒ (κυτταροπλασματική εντόπιση, χαμηλά επίπεδα πυρηνικής πρωτεϊνης, χαμηλά ποσοστά σύνδεσης με DNA), με σύγχρονη σχετικά μειωμένη δραστηριότητα του 20S πρωτεοσώματος και αυξημένα κυτταρικά επίπεδα ΙκΒ-. Τα μη ανδρογονο-εξαρτώμενα κύτταρα παρουσίασαν την ακριβώς αντίστροφη εικόνα, δηλαδή αυξημένη δραστηριότητα 20S πρωτεασώματος και ενεργοποίηση του NF-κΒ μέσω της κανονικής οδού, και ελάχιστη δραστηριότητα ΝΕΡ με απότοκο ενισχυμένο νευροπεπτιδικό παρακρινές περιβάλλον.Στην συνέχεια της έρευνας αναλύθηκε η πιθανότητα ύπαρξης μιας δυναμικής σχέσης μεταξύ αυτών των οδών και οι μεταξύ τους αλληλεπιδράσεις. Διέγερση με νευροπεπτίδια προκάλεσε ενεργοποίηση της οδού πρωτεασώματος/NF-κΒ (πυρηνική μετακίνηση NF-Β, άυξηση ποσού πυρηνικής πρωτεϊνης, αυξημένη σύνδεση NF-κΒ/DNA, μειωμένα κυτταρικά επίπεδα ΙκΒα), αυξημένη πρωτεασωμική δραστηριότητα, αλλά μόνο σε συνθήκες έλλειψης NEP. Επιπλέον, η ενεργοποίηση αυτή σαν αποτέλεσμα διέγερσης με νευροπεπτίδια δεν μπορούσε να επιτευχθεί αν προηγούνταν χρήση ειδικών νευροπεπτιδιακών αναστολέων ή αναστολέων της οδού πρωτεασώματος/NF-κΒ. Τέλος, η αύξηση της πρωτεσωμικής δραστηριότητας φαίνεται να είναι πρώιμο αποτελέσμα της νευροπεπτιδιακής διέγερσης, και έπεται η μείωση των κυτταρικών επιπέδων ΙκΒ- και η διέγερση του NF-κΒ.Τα αποτελέσματα μας φαίνεται ότι υποστηρίζουν την ύπαρξη μιας άμεσης μηχανιστικής σχέσης μεταξύ του άξονα ΝΕΡ/νευροπεπτιδίων και της οδού NFκΒ/πρωτεασώματος, με μια σαφή εικόνα εμπλοκής των νευροπεπτιδίων στην εξέλιξη προς την επιθετικότερη κατάσταση του μη-ανδρογονο-εξαρτώμενου καρκίνου προστάτη. ΟΙ σύγχρονες τάσεις στην αντινεοπλασματική θεραπεία υποστηρίζουν τις θεραπείες συνδυασμού για βέλτιστη αποδοτικότητα και εύρος αντικαρκινικής δράσης. Επομένως, η μεταφραστική έρευνα με στόχο την διευκρίνηση των μοριακών μηχανισμών που υπαγορεύουν την μετάβαση σε επιθετικότερους καρκινικούς φαινότυπους στοχεύει στην συνδυαστική κλινική εφαρμογή αγωνιστών/ανταγωνιστών. Τα δεδομένα της παρούσας ερευνητικής εργασίας υποδεικνύουν ότι τα νευροπεπτίδια επηρεάζουν την δραστηριότητα της οδού NFΒ/πρωτεασώματος. Ως εκ τούτου, θεραπεία συνδυασμού που θα στοχεύει και στις δύο οδούς μπορεί τελικά να αποδειχθεί ωφέλιμη στην κλινική πράξη, εμποδίζοντας αποτελεσματικότερα οδούς που έχουν γνωστή εμπλοκή στην επιβίωση, διήθηση και μετάσταση των προστατικών καρκινικών κυττάρων

Exploratory Study of the Effect of IMA950/Poly-ICLC Vaccination on Response to Bevacizumab in Relapsing High-Grade Glioma Patients

Immunotherapy, including therapeutic vaccines, is increasingly being developed for patients with high-grade glioma, and combinations of immunotherapies and synergy with standard of care are being investigated. In this regard, bevacizumab (BEV) has been shown to synergize with immunotherapy in preclinical studies of glioma and in other tumour entities. Here, we conducted a post-hoc exploratory study to evaluate the effect of the IMA950/poly-ICLC peptide vaccine on subsequent BEV administration in high-grade glioma patients. 16 IMA950-vaccinated and 40 non-vaccinated patients were included. At initial diagnosis, patients benefited from surgery and chemoradiation. At first or subsequent recurrence, patients received 10mg/kg of BEV every 2&#8211;3 weeks. Primary endpoints were overall survival (OS) and progression-free survival (PFS) from BEV initiation. IMA950-vaccinated patients did not show improved response to BEV as compared to non-vaccinated patients: there was no difference in median PFS (2.6 vs. 4.2 months for vaccinated and control patients, respectively, p = 0.50) nor in median OS (7.8 vs. 10.0 months for vaccinated and control patients, respectively, p = 0.69). In conclusion, potential synergy of BEV and therapeutic vaccines, when administered sequentially, has yet to be established in the clinical setting of GBM recurrence. Potential synergy of concomitant administration should be tested in future trials