Preclinical HER-2 Vaccines: From Rodent to Human HER-2

open3noEffective prevention of human cancer with vaccines against viruses, such as HBV and HPV, raises the question whether also non-virus related tumors could be prevented with immunological means. Studies in HER-2-transgenic mice showed that powerful anti-HER-2 vaccines, could almost completely prevent the onset of mammary carcinoma. Protective immune responses were orchestrated by T cells and their cytokines, and effected by antibodies against HER-2 gene product p185. Analogous findings were reported in a variety of other cancer immunoprevention systems, thus leading to the definition of oncoantigens, optimal target antigens that are causally involved in carcinogenesis and cancer progression. Prophylactic HER-2 vaccines were also effective in preventing metastasis outgrowth, indicating that concepts and approaches developed for cancer immunoprevention could prove fruitful in cancer immunotherapy as well. The availability of cancer-prone mice carrying a human HER-2 transgene is now fostering the design of novel vaccines against human p185. A further bridge toward human cancer was recently provided by novel immunodeficient models, like Rag2-/-;Il2rg-/- mice, which are permissive for metastatic spread of human HER-2C cancer cells and can be engrafted with a functional human immune system, allowing for the first time the study of vaccines against oncoantigens to elicit human immune responses against human cancer cells in vivo.openPier-Luigi Lollini;Carla De Giovanni;Patrizia NanniPier-Luigi Lollini;Carla De Giovanni;Patrizia Nann

Synovial Sarcoma Preclinical Modeling: Integrating Transgenic Mouse Models and Patient-Derived Models for Translational Research

Synovial sarcomas (SyS) are rare malignant tumors predominantly affecting children, adolescents, and young adults. The genetic hallmark of SyS is the t(X;18) translocation encoding the SS18-SSX fusion gene. The fusion protein interacts with both the BAF enhancer and polycomb repressor complexes, and either activates or represses target gene transcription, resulting in genome-wide epigenetic perturbations and altered gene expression. Several experimental in in vivo models, including conditional transgenic mouse models expressing the SS18-SSX fusion protein and spontaneously developing SyS, are available. In addition, patient-derived xenografts have been estab-lished in immunodeficient mice, faithfully reproducing the complex clinical heterogeneity. This review focuses on the main molecular features of SyS and the related preclinical in vivo and in vitro models. We will analyze the different conditional SyS mouse models that, after combination with some of the few other recurrent alterations, such as gains in BCL2, Wnt- -catenin signaling, FGFR family, or loss of PTEN and SMARCB1, have provided additional insight into the mechanisms of synovial sarcomagenesis. The recent advancements in the understanding of SyS biology and improvements in preclinical modeling pave the way to the development of new epigenetic drugs and immunotherapeutic approaches conducive to new treatment options

The Promise of Preventive Cancer Vaccines

Years of unsuccessful attempts at fighting established tumors with vaccines have taught us all that they are only able to truly impact patient survival when used in a preventive setting, as would normally be the case for traditional vaccines against infectious diseases. While true primary cancer prevention is still but a long-term goal, secondary and tertiary prevention are already in the clinic and providing encouraging results. A combination of immunopreventive cancer strategies and recently approved checkpoint inhibitors is a further promise of forthcoming successful cancer disease control, but prevention will require a considerable reduction of currently reported toxicities. These considerations summed with the increased understanding of tumor antigens allow space for an optimistic view of the future

Sviluppo di una micro CT con sorgente Quasi-Monocromatica Multi-Energy per lo studio in vivo della crescita e della metastasi tumorale

Un innovativo micro scanner CT per piccolo animali – basato su di una sorgente che genera una coppia di fasci X Quasi-Monocromatici paralleli con diverse energie selezionabili – è in corso di installazione e caratterizzazione al Dipartimento di Fisica dell’Università di Bologna. Lo scopo della ricerca è quello di effettuare l’imaging radiologico in vivo del tessuto tumorale e/o dei pattern di neo-angiogenesi in una fase diagnostica precoce realizzando la separazione del tessuto patologico da quello sano per mezzo della tecnica multi-energy che consiste nell’utilizzo di due o più fasci di raggi X quasi-monocromatici in sostituzione dell’unico fascio policromatico utilizzato nella radiologia convenzionale. Lo strumento consentirà inoltre lo studio, sui topi, della crescita tumorale e della formazione delle metastasi per differenti tipologie di tumore. Per la diagnosi precoce del tumore è essenziale essere in grado di rivelare i cambiamenti tissutali precancerosi, come la neo-angiogenesi. Si tratta di un meccanismo che si verifica in una fase iniziale dello sviluppo della patologia ed è dovuto alla produzione di molecole che stimolano la creazione di nuovi vasi sanguigni per alimentare la crescita delle cellule cancerose. Come dimostrato in precedenti studi di fattibilità [1], un sistema di imaging basato su due fasci di raggi X quasi-monocromatici di differenti energie fornisce maggiore sensibilità nella rivelazione di basse concentrazioni di mezzo di contrasto iodato rispetto ai tradizionali apparati RX con fascio policromatico. La K-edge dual energy radiology è una tecnologia potenzialmente in grado di rivelare il processo di neo-angiogenesi tumorale in uno stadio precoce quando la strumentazione convenzionale non dispone di sufficiente sensibilità. Inoltre, la possibilità di selezionare le energie dei fasci quasi-monocromatici consente l’applicazione della Multi-Energy Quasi-MonochromaticRadiology: selezionando opportunamente le energie è possibile esaltare le differenze fra i coefficienti di attenuazione lineare del tessuto patologico rispetto a quello sano aumentando il contrasto della patologia. Infatti, la tecnica multi-energy consente di ricostruire il numero atomico efficace e persino la composizione chimica del tessuto irradiato. Tuttavia, per ottenere questo risultato, si dovrebbero conoscere le bande di energia in cui l’assorbimento dei raggi X da parte del tessuto tumorale eventualmente differisce significativamente da quello dei tessuti sani. Per questo motivo è stata iniziata una sistematica caratterizzazione radiologica di molti tipi di tessuti sani e neoplastici, murini e umani allo scopo di costituire un catalogo delle finestre di energia in cui sarà possibile applicare la metodica multi-energy

A novel paradigm for cell and molecule interaction ontology: from the CMM model to IMGT-ONTOLOGY

International audienc

2011: the immune hallmarks of cancer

Ten years after the publication of the position paper “The hallmarks of cancer” (Hanahan and Weinberg Cell 100:57–70, 2000), it has become increasingly clear that mutated cells on their way to giving rise to a tumor have also to learn how to thrive in a chronically inflamed microenvironment, evade immune recognition, and suppress immune reactivity. Genetic and molecular definition of these three immune hallmarks of cancer offers the opportunity to learn how to deploy specific countermeasures to reverse the situation in favor of the immune system and, eventually, the patient. This new information could be channeled to address what seem to be the three major hallmarks for the immune control of cancer progression: effective procedures to activate immune reactivity; characterization of not-disposable oncoantigens; and counteraction of immune suppression

Bioprofiling TS/A Murine Mammary Cancer for a Functional Precision Experimental Model

The TS/A cell line was established in 1983 from a spontaneous mammary tumor arisen in an inbred BALB/c female mouse. Its features (heterogeneity, low immunogenicity and metastatic ability) rendered the TS/A cell line suitable as a preclinical model for studies on tumor-host interactions and for gene therapy approaches. The integrated biological profile of TS/A resulting from the review of the literature could be a path towards the description of a precision experimental model of mammary cancer

An integrated approach of immunogenomics and bioinformatics to identify new Tumor Associated Antigens (TAA) for mammary cancer immunological prevention

BACKGROUND: Neoplastic transformation is a multistep process in which distinct gene products of specific cell regulatory pathways are involved at each stage. Identification of overexpressed genes provides an unprecedented opportunity to address the immune system against antigens typical of defined stages of neoplastic transformation. HER-2/neu/ERBB2 (Her2) oncogene is a prototype of deregulated oncogenic protein kinase membrane receptors. Mice transgenic for rat Her2 (BALB-neuT mice) were studied to evaluate the stage in which vaccines can prevent the onset of Her2 driven mammary carcinomas. As Her2 is not overexpressed in all mammary carcinomas, definition of an additional set of tumor associated antigens (TAAs) expressed at defined stages by most breast carcinomas would allow a broader coverage of vaccination. To address this question, a meta-analysis was performed on two transcription profile studies [1,2] to identify a set of new TAA targets to be used instead of or in conjunction with Her2. RESULTS: The five TAAs identified (Tes, Rcn2, Rnf4, Cradd, Galnt3) are those whose expression is linearly related to the tumor mass increase in BALB-neuT mammary glands. Moreover, they have a low expression in normal tissues and are generally expressed in human breast tumors, though at a lower level than Her2. CONCLUSION: Although the number of putative TAAs identified is limited, this pilot study suggests that meta-analysis of expression profiles produces results that could assist in the designing of pre-clinical immunopreventive vaccines

IFN-γ and CD38 in Hyperprogressive Cancer Development

Immune checkpoint inhibitors (ICIs) improve the survival of patients with multiple types of cancer. However, low response rates and atypical responses limit their success in clinical applications. The paradoxical acceleration of tumor growth after treatment, defined as hyperprogressive disease (HPD), is the most difficult problem facing clinicians and patients alike. The mechanisms that underlie hyperprogression (HP) are still unclear and controversial, although different factors are associated with the phenomenon. In this review, we propose two factors that have not yet been demonstrated to be directly associated with HP, but upon which it is important to focus attention. IFN-γ is a key cytokine in antitumor response and its levels increase during ICI therapy, whereas CD38 is an alternative immune checkpoint that is involved in immunosuppressive responses. As both factors are associated with resistance to ICI therapy, we have discussed their possible involvement in HPD with the conclusion that IFN-γ may contribute to HP onset through the activation of the inflammasome pathway, immunosuppressive enzyme IDO1 and activation-induced cell death (AICD) in effector T cells, while the role of CD38 in HP may be associated with the activation of adenosine receptors, hypoxia pathways and AICD-dependent T-cell depletion