Bladder cancer is a current clinical and social problem. At diagnosis, most patients present with nonmuscle-invasive tumors, characterized by a high recurrence rate, which could progress to ...muscle-invasive disease and metastasis. Bone morphogenetic protein (BMP)-dependent signaling arising from stromal bladder tissue mediates urothelial homeostasis by promoting urothelial cell differentiation. However, the possible role of BMP ligands in bladder cancer is still unclear.
Tumor and normal tissue from 68 patients with urothelial cancer were prospectively collected and analyzed for expression of BMP and macrophage markers. The mechanism of action was assessed
by experiments with bladder cancer cell lines and peripheral blood monocyte-derived macrophages.
We observed
expression is associated and favored type II macrophage differentiation.
experiments showed that both recombinant BMP4 and BMP4-containing conditioned media from bladder cancer cell lines favored monocyte/macrophage polarization toward M2 phenotype macrophages, as shown by the expression and secretion of IL10. Using a series of human bladder cancer patient samples, we also observed increased expression of
in advanced and undifferentiated tumors in close correlation with epithelial-mesenchymal transition (EMT). However, the p-Smad 1,5,8 staining in tumors showing EMT signs was reduced, due to the increased miR-21 expression leading to reduced
expression.
These findings suggest that BMP4 secretion by bladder cancer cells provides the M2 signal necessary for a protumoral immune environment. In addition, the repression of
by miR-21 makes the tumor cells refractory to the prodifferentiating actions mediated by BMP ligands, favoring tumor growth.
.
Bladder Cancer (BC) represents a clinical and social challenge due to its high incidence and recurrence rates, as well as the limited advances in effective disease management. Currently, a ...combination of cytology and cystoscopy is the routinely used methodology for diagnosis, prognosis and disease surveillance. However, both the poor sensitivity of cytology tests as well as the high invasiveness and big variation in tumour stage and grade interpretation using cystoscopy, emphasizes the urgent need for improvements in BC clinical guidance. Liquid biopsy represents a new non-invasive approach that has been extensively studied over the last decade and holds great promise. Even though its clinical use is still compromised, multiple studies have recently focused on the potential application of biomarkers in liquid biopsies for BC, including circulating tumour cells and DNA, RNAs, proteins and peptides, metabolites and extracellular vesicles. In this review, we summarize the present knowledge on the different types of biomarkers, their potential use in liquid biopsy and clinical applications in BC.
Oncolytic viruses possess the ability to infect, replicate and lyse malignantly
transformed tumour cells. This oncolytic activity amplifies the therapeutic advantage
and induces a form of immunogenic ...cell death, characterized by increased CD8
+ T‐cell infiltration into the tumour microenvironment. This
important feature of oncolytic viruses can result in the warming up of immunologically
‘cold’ tumour types, presenting the enticing possibility that oncolytic
virus treatment combined with immunotherapies may enhance efficacy. In this review, we
assess some of the most promising candidates that might be used for oncolytic
virotherapy: immunotherapy combinations. We assess their potential as separate agents or
as agents combined into a single therapy, where the immunotherapy is encoded within the
genome of the oncolytic virus. The development of such advanced agents will require
increasingly sophisticated model systems for their preclinical assessment and
evaluation. In vivo rodent model systems are fraught with limitations in this regard.
Oncolytic viruses replicate selectively within human cells and therefore require human
xenografts in immune‐deficient mice for their evaluation. However, the use of
immune‐deficient rodent models hinders the ability to study immune responses
against any immunomodulatory transgenes engineered within the viral genome and expressed
within the tumour microenvironment. There has therefore been a shift towards the use of
more sophisticated ex vivo patient‐derived model systems based on organoids and
explant co‐cultures with immune cells, which may be more predictive of efficacy
than contrived and artificial animal models. We review the best of those model systems
here.
Oncolytic
virotherapies have immense potential to ‘heat up’ otherwise
immunologically ‘cold’ tumour types. In this review, the capacity of
virotherapies to synergize with or express a range of types of immunotherapies is
explored. Optimizing such combinations in preclinical models is complex, and we
therefore review the most clinically relevant rodent and ex vivo human models available
for such assessment.
BackgroundTROCEPT is a novel tumor-selective oncolytic adenovirus type 5 engineered to remove all natural tissue tropisms. This engineering addresses the main limitation of other viral therapies ...which infect normal tissues and are rapidly removed by the liver, thereby limiting tumour bioavailability. TROCEPT has been further engineered to specifically bind to αvβ6 integrin which is expressed at high frequency in the majority of epithelial cell derived cancers. In addition, the TROCEPT platform can encode transgenes which enables in-tumor production of powerful therapeutic drugs. The lead programme, TROCEPT-01, encodes a fully human, full length immune checkpoint inhibitor (ICI) antibody. TROCEPT-01 is currently undergoing IND-enabling studies and is expected to enter First in Human studies in 2024 in multiple solid tumor indications.MethodsTROCEPT-01’s tumor selectivity was investigated in both in vitro and in vivo studies.ResultsHere we demonstrate in vitro that both viral replication and oncolytic cell death following infection with TROCEPT-01 is selective for tumor cells compared to a panel of normal human primary cells. In addition, following intravenous delivery in in vivo models comprising human αvβ6 integrin-positive tumors engrafted in immune-deficient mice, we demonstrate virus delivery and transgene expression in the tumor.ConclusionsTROCEPT-01’s tumor selective transgene expression and in-tumor production of ICIs enables high local drug concentration in the tumor, potentially reducing systemic toxicity and increasing efficacy. Additionally, several pre-clinical studies have demonstrated that oncolytic viruses can induce anti-viral immunity against infected tumor cells, recruiting cytotoxic T cells and other pro-inflammatory cell types. Thus, TROCEPT delivery of ICIs has the potential to generate a synergistic effect, first attracting and activating T cells, and then enabling tumor-localized production of ICIs to high concentrations to boost anti-tumor T cell responses and increase response rates. TROCEPT has the potential for the delivery of a variety of new and powerful therapeutic drugs to tumors. TROCEPT-01 is currently undergoing IND-enabling studies and is expected to enter First in Human studies in 2024 in multiple solid tumor indications.
BackgroundImmune checkpoint inhibitors (ICIs) have revolutionized immunotherapy, but their efficacy is limited to certain cancers, and response rates are largely dependent on the ability of the ...patients T cells to recognize and activate against tumor antigens. Additionally, systemic delivery can lead to dose limiting toxicity.1TROCEPT is a novel tumor-selective delivery technology, based on type 5 adenovirus, engineered not enter normal human tissues. The removal of normal tissues tropisms addresses the main limitation of other viral therapies, which show limited efficacy due to rapid removal by the liver.2 TROCEPT has been further engineered to specifically bind to a tumor marker expressed on most carcinomas.3 The TROCEPT platform can be loaded with transgenes encoding protein-based drugs for in-tumor delivery (i.e., TROCEPT can deliver the transgene into the cancer cell, turning the cancer cell into a drug factory, which releases the payload into the local tumor environment). TROCEPT-01 enables tumor-localized generation of high concentrations of ICI payloads (figure 1).MethodsSelective cell entry of TROCEPT-01 was assessed in vitro using infectivity assays in target-positive and -negative tumor and healthy cell lines. Further in vitro assays confirmed the production of ICIs in multiple tumor cell lines, and functionality of the in-tumor generated ICI was confirmed using primary T cell activation experiments. Finally, an immune-deficient murine model, engrafted with a human tumor, was used to assess biodistribution of TROCEPT-01, after intravenous delivery, using a bioluminescence in vivo imaging system (IVIS®) and qPCR.ResultsIn vitro testing confirmed TROCEPT-01’s exquisite selectivity for tumor cells and demonstrated functional production of ICIs from treated tumor cells. In vivo experiments demonstrated tumor-localized biodistribution of TROCEPT-01, with a low amount of TROCEPT-01 detected in healthy organs (including the liver) and peripheral blood.ConclusionsTROCEPT’s tumor selective transgene delivery and in-tumor production of ICIs enables high local dosing only in the tumor, addressing systemic toxicity and potentially increasing efficacy. Additionally, several pre-clinical studies have demonstrated that oncolytic viruses can induce anti-viral immunity against infected tumor cells, recruiting cytotoxic T cells and other pro-inflammatory cell types.4 Thus, TROCEPT delivery of ICIs has the potential to generate a synergistic effect, first attracting and activating T cells, and then delivering tumor-localized ICIs at high concentrations to boost the anti-tumor T cell response and increase response rates in several tumor types. TROCEPT has the potential for delivery of new and powerful therapeutic drugs for the in-tumor treatment of cancer.ReferencesWatanabe E, Nishida O, Kakihana Y, Odani M, Okamura T, Harada T, Oda S. Pharmacokinetics, Pharmacodynamics, and Safety of Nivolumab in Patients With Sepsis-Induced Immunosuppression: A Multicenter, Open-Label Phase 1/2 Study. Shock. 2020;53:686–694.DOI: 10.1097/SHK.0000000000001443.Baker A, Aguirre-Hernández C, Halldén G, Parker A. Designer Oncolytic Adenovirus: Coming of Age. Cancers (Basel). 2018;10:201.DOI: 10.3390/cancers10060201.Uusi-Kerttula H, Davies JA, Thompson JM, Wongthida P, Evgin L, Shim KG, Bradshaw A, et al. Ad5 NULL -A20: A Tropism-Modified, αvβ6 integrin-selective oncolytic adenovirus for epithelial ovarian cancer therapies. Clinical Cancer Research. 2018;24:4215–4224.DOI: 10.1158/1078-0432.CCR-18-1089.Kuryk L, Møller A-SW, Jaderberg M. Combination of immunogenic oncolytic adenovirus ONCOS-102 with anti-PD-1 pembrolizumab exhibits synergistic antitumor effect in humanized A2058 melanoma huNOG mouse model. OncoImmunology. 2019;8:e1532763.DOI: 10.1080/2162402X.2018.1532763.Abstract 1349 Figure 1Schematic of the mode of action of TROCEPT-01 encoding an immune checkpoint inhibitorFigure omitted. See PDF
Vaccines derived from chimpanzee adenovirus Y25 (ChAdOx1), human adenovirus type 26 (HAdV-D26), and human adenovirus type 5 (HAdV-C5) are critical in combatting the severe acute respiratory ...coronavirus 2 (SARS-CoV-2) pandemic. As part of the largest vaccination campaign in history, ultrarare side effects not seen in phase 3 trials, including thrombosis with thrombocytopenia syndrome (TTS), a rare condition resembling heparin-induced thrombocytopenia (HIT), have been observed. This study demonstrates that all three adenoviruses deployed as vaccination vectors versus SARS-CoV-2 bind to platelet factor 4 (PF4), a protein implicated in the pathogenesis of HIT. We have determined the structure of the ChAdOx1 viral vector and used it in state-of-the-art computational simulations to demonstrate an electrostatic interaction mechanism with PF4, which was confirmed experimentally by surface plasmon resonance. These data confirm that PF4 is capable of forming stable complexes with clinically relevant adenoviruses, an important step in unraveling the mechanisms underlying TTS.
Destabilization of balanced immune cell numbers and frequencies is a common feature of viral infections. This occurs due to, and further enhances, viral immune evasion and survival. Since the ...discovery of the Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), which manifests in coronavirus disease 2019 (COVID-19), a great number of studies have described the association between this virus and pathologically increased or decreased immune cell counts. In this review, we consider the absolute and relative changes to innate and adaptive immune cell numbers, in COVID-19. In severe disease particularly, neutrophils are increased, which can lead to inflammation and tissue damage. Dysregulation of other granulocytes, basophils and eosinophils represents an unusual COVID-19 phenomenon. Contrastingly, the impact on the different types of monocytes leans more strongly to an altered phenotype, e.g. HLA-DR expression, rather than numerical changes. However, it is the adaptive immune response that bears the most profound impact of SARS-CoV-2 infection. T cell lymphopenia correlates with increased risk of intensive care unit admission and death; therefore, this parameter is particularly important for clinical decision-making. Mild and severe diseases differ in the rate of immune cell counts returning to normal levels post disease. Tracking the recovery trajectories of various immune cell counts may also have implications for long-term COVID-19 monitoring. This review represents a snapshot of our current knowledge, showing that much has been achieved in a short period of time. Alterations in counts of distinct immune cells represent an accessible metric to inform patient care decisions or predict disease outcomes.
COVID-19 is characterized by profound lymphopenia in the peripheral blood, and the remaining T cells display altered phenotypes, characterized by a spectrum of activation and exhaustion. However, ...antigen-specific T cell responses are emerging as a crucial mechanism for both clearance of the virus and as the most likely route to long-lasting immune memory that would protect against re-infection. Therefore, T cell responses are also of considerable interest in vaccine development. Furthermore, persistent alterations in T cell subset composition and function post-infection have important implications for patients' long-term immune function. In this review, we examine T cell phenotypes, including those of innate T cells, in both peripheral blood and lungs, and consider how key markers of activation and exhaustion correlate with, and may be able to predict, disease severity. We focus on SARS-CoV-2-specific T cells to elucidate markers that may indicate formation of antigen-specific T cell memory. We also examine peripheral T cell phenotypes in recovery and the likelihood of long-lasting immune disruption. Finally, we discuss T cell phenotypes in the lung as important drivers of both virus clearance and tissue damage. As our knowledge of the adaptive immune response to COVID-19 rapidly evolves, it has become clear that while some areas of the T cell response have been investigated in some detail, others, such as the T cell response in children remain largely unexplored. Therefore, this review will also highlight areas where T cell phenotypes require urgent characterisation.
Coronavirus disease 2019 has generated a rapidly evolving field of research, with the global scientific community striving for solutions to the current pandemic. Characterizing humoral responses ...towards SARS-CoV-2, as well as closely related strains, will help determine whether antibodies are central to infection control, and aid the design of therapeutics and vaccine candidates. This review outlines the major aspects of SARS-CoV-2-specific antibody research to date, with a focus on the various prophylactic and therapeutic uses of antibodies to alleviate disease in addition to the potential of cross-reactive therapies and the implications of long-term immunity.
COVID-19 was initially characterized as a disease primarily of the lungs, but it is becoming increasingly clear that the SARS-CoV2 virus is able to infect many organs and cause a broad pathological ...response. The primary infection site is likely to be a mucosal surface, mainly the lungs or the intestine, where epithelial cells can be infected with virus. Although it is clear that virus within the lungs can cause severe pathology, driven by an exaggerated immune response, infection within the intestine generally seems to cause minor or no symptoms. In this review, we compare the disease processes between the lungs and gastrointestinal tract, and what might drive these different responses. As the microbiome is a key part of mucosal barrier sites, we also consider the effect that microbial species may play on infection and the subsequent immune responses. Because of difficulties obtaining tissue samples, there are currently few studies focused on the local mucosal response rather than the systemic response, but understanding the local immune response will become increasingly important for understanding the mechanisms of disease in order to develop better treatments.
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