90 results on '"Arianna Palladini"'
Search Results
2. Virus-like Particle (VLP) Vaccines for Cancer Immunotherapy
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Francesca Ruzzi, Maria Sofia Semprini, Laura Scalambra, Arianna Palladini, Stefania Angelicola, Chiara Cappello, Olga Maria Pittino, Patrizia Nanni, and Pier-Luigi Lollini
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cancer immunotherapy ,cancer immunoprevention ,cancer vaccines ,virus-like particles (VLPs) ,tumor antigens ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Cancer vaccines are increasingly being studied as a possible strategy to prevent and treat cancers. While several prophylactic vaccines for virus-caused cancers are approved and efficiently used worldwide, the development of therapeutic cancer vaccines needs to be further implemented. Virus-like particles (VLPs) are self-assembled protein structures that mimic native viruses or bacteriophages but lack the replicative material. VLP platforms are designed to display single or multiple antigens with a high-density pattern, which can trigger both cellular and humoral responses. The aim of this review is to provide a comprehensive overview of preventive VLP-based vaccines currently approved worldwide against HBV and HPV infections or under evaluation to prevent virus-caused cancers. Furthermore, preclinical and early clinical data on prophylactic and therapeutic VLP-based cancer vaccines were summarized with a focus on HER-2-positive breast cancer.
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- 2023
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3. Evolution of HER2-positive mammary carcinoma: HER2 loss reveals claudin-low traits in cancer progression
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Veronica Giusti, Francesca Ruzzi, Lorena Landuzzi, Marianna L. Ianzano, Roberta Laranga, Elena Nironi, Laura Scalambra, Giordano Nicoletti, Carla De Giovanni, Martina Olivero, Maddalena Arigoni, Raffaele Calogero, Patrizia Nanni, Arianna Palladini, and Pier-Luigi Lollini
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract HER2-positive breast cancers may lose HER2 expression in recurrences and metastases. In this work, we studied cell lines derived from two transgenic mammary tumors driven by human HER2 that showed different dynamics of HER2 status. MamBo89HER2 stable cell line displayed high and stable HER2 expression, which was maintained upon in vivo passages, whereas MamBo43HER2 labile cell line gave rise to HER2-negative tumors from which MamBo38HER2 loss cell line was derived. Both low-density seeding and in vitro trastuzumab treatment of MamBo43HER2 labile cells induced the loss of HER2 expression. MamBo38HER2 loss cells showed a spindle-like morphology, high stemness and acquired in vivo malignancy. A comprehensive molecular profile confirmed the loss of addiction to HER2 signaling and acquisition of an EMT signature, together with increased angiogenesis and migration ability. We identified PDGFR-B among the newly expressed determinants of MamBo38HER2 loss cell tumorigenic ability. Sunitinib inhibited MamBo38HER2 loss tumor growth in vivo and reduced stemness and IL6 production in vitro. In conclusion, HER2-positive mammary tumors can evolve into tumors that display distinctive traits of claudin-low tumors. Our dynamic model of HER2 status can lead to the identification of new druggable targets, such as PDGFR-B, in order to counteract the resistance to HER2-targeted therapy that is caused by HER2 loss.
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- 2021
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4. Early stability and late random tumor progression of a HER2-positive primary breast cancer patient-derived xenograft
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Lorena Landuzzi, Arianna Palladini, Claudio Ceccarelli, Sofia Asioli, Giordano Nicoletti, Veronica Giusti, Francesca Ruzzi, Marianna L. Ianzano, Laura Scalambra, Roberta Laranga, Tania Balboni, Maddalena Arigoni, Martina Olivero, Raffaele A. Calogero, Carla De Giovanni, Massimiliano Dall’Ora, Enrico Di Oto, Donatella Santini, Maria Pia Foschini, Maria Cristina Cucchi, Simone Zanotti, Mario Taffurelli, Patrizia Nanni, and Pier-Luigi Lollini
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Medicine ,Science - Abstract
Abstract We established patient-derived xenografts (PDX) from human primary breast cancers and studied whether stability or progressive events occurred during long-term in vivo passages (up to 4 years) in severely immunodeficient mice. While most PDX showed stable biomarker expression and growth phenotype, a HER2-positive PDX (PDX-BRB4) originated a subline (out of 6 studied in parallel) that progressively acquired a significantly increased tumor growth rate, resistance to cell senescence of in vitro cultures, increased stem cell marker expression and high lung metastatic ability, along with a strong decrease of BCL2 expression. RNAseq analysis of the progressed subline showed that BCL2 was connected to three main hub genes also down-regulated (CDKN2A, STAT5A and WT1). Gene expression of progressed subline suggested a partial epithelial-to-mesenchymal transition. PDX-BRB4 with its progressed subline is a preclinical model mirroring the clinical paradox of high level-BCL2 as a good prognostic factor in breast cancer. Sequential in vivo passages of PDX-BRB4 chronically treated with trastuzumab developed progressive loss of sensitivity to trastuzumab while HER2 expression and sensitivity to the pan-HER tyrosine kinase inhibitor neratinib were maintained. Long-term PDX studies, even though demanding, can originate new preclinical models, suitable to investigate the mechanisms of breast cancer progression and new therapeutic approaches.
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- 2021
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5. Prevention and Therapy of Metastatic HER-2+ Mammary Carcinoma with a Human Candidate HER-2 Virus-like Particle Vaccine
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Francesca Ruzzi, Arianna Palladini, Stine Clemmensen, Anette Strøbæk, Nicolaas Buijs, Tanja Domeyer, Jerzy Dorosz, Vladislav Soroka, Dagmara Grzadziela, Christina Jo Rasmussen, Ida Busch Nielsen, Max Soegaard, Maria Sofia Semprini, Laura Scalambra, Stefania Angelicola, Lorena Landuzzi, Pier-Luigi Lollini, and Mette Thorn
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breast cancer ,vaccine ,virus-like particles (cVLP) ,HER-2 ,tyrosine kinase receptor ,target therapies ,Biology (General) ,QH301-705.5 - Abstract
Vaccines are a promising therapeutic alternative to monoclonal antibodies against HER-2+ breast cancer. We present the preclinical activity of an ES2B-C001, a VLP-based vaccine being developed for human breast cancer therapy. FVB mice challenged with HER-2+ mammary carcinoma cells QD developed progressive tumors, whereas all mice vaccinated with ES2B-C001+Montanide ISA 51, and 70% of mice vaccinated without adjuvant, remained tumor-free. ES2B-C001 completely inhibited lung metastases in mice challenged intravenously. HER-2 transgenic Delta16 mice developed mammary carcinomas by 4–8 months of age; two administrations of ES2B-C001+Montanide prevented tumor onset for >1 year. Young Delta16 mice challenged intravenously with QD cells developed a mean of 68 lung nodules in 13 weeks, whereas all mice vaccinated with ES2B-C001+Montanide, and 73% of mice vaccinated without adjuvant, remained metastasis-free. ES2B-C001 in adjuvant elicited strong anti-HER-2 antibody responses comprising all Ig isotypes; titers ranging from 1–10 mg/mL persisted for many months. Antibodies inhibited the 3D growth of human HER-2+ trastuzumab-sensitive and -resistant breast cancer cells. Vaccination did not induce cytokine storms; however, it increased the ELISpot frequency of IFN-γ secreting HER-2-specific splenocytes. ES2B-C001 is a promising candidate vaccine for the therapy of tumors expressing HER-2. Preclinical results warrant further development towards human clinical studies.
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- 2022
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6. Genomic Landscape, Clinical Features and Outcomes of Non-Small Cell Lung Cancer Patients Harboring BRAF Alterations of Distinct Functional Classes
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Alessandro Di Federico, Andrea De Giglio, Francesco Gelsomino, Dario De Biase, Francesca Giunchi, Arianna Palladini, Francesca Sperandi, Barbara Melotti, and Andrea Ardizzoni
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non-small cell lung cancer ,BRAF ,immunotherapy ,survival ,genomic ,non-V600 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background: In non-small cell lung cancer (NSCLC), BRAF class 1 alterations are effectively targeted by BRAF inhibitors. Conversely, targeted therapies have very low or absent activity in patients carrying class 2 and 3 alterations. The spectrum of BRAF alterations in NSCLC patients, and their accompanying clinical features, genomic landscape and treatment outcomes have been poorly reported. Patients and methods: We identified BRAF alterations of defined functional class across different tumors through a systematic review. Then, we selected NSCLC patients carrying BRAF alterations, according to the systematic review, in the cBioPortal (cBioPortal cohort) to collect and analyze clinical, biomolecular and survival data. Finally, we identified NSCLC patients carrying BRAF non-V600 mutations enrolled in POPLAR and OAK trials (POPLAR/OAK cohort), extracting clinical and survival data for survival analyses. Results: 100 different BRAF non-V600 alterations were identified through the systematic review. In the cBioPortal cohort (n = 139), patients harboring class 2 and 3 alterations were more frequently smokers and had higher tumor mutational burden compared to those carrying class 1 alterations. The spectrum of most frequently co-altered genes was significantly different between BRAF alterations classes, including SETD2, STK11, POM121L12, MUC16, KEAP1, TERT, TP53 and other genes. In the POPLAR/OAK cohort, patients carrying non-V600 BRAF alterations were characterized by poor prognosis compared to BRAF wild-type patients. Conclusions: Different classes of BRAF alterations confer distinctive clinical features, biomolecular signature and disease behavior to NSCLC patients. Non-V600 alterations are characterized by poor prognosis, but key gene co-alterations involved in cancer cell survival and immune pathways may suggest their potential sensitivity to tailored treatments.
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- 2022
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7. Bone sarcoma patient-derived xenografts are faithful and stable preclinical models for molecular and therapeutic investigations
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Patrizia Nanni, Lorena Landuzzi, Maria Cristina Manara, Alberto Righi, Giordano Nicoletti, Camilla Cristalli, Michela Pasello, Alessandro Parra, Marianna Carrabotta, Manuela Ferracin, Arianna Palladini, Marianna L. Ianzano, Veronica Giusti, Francesca Ruzzi, Mauro Magnani, Davide Maria Donati, Piero Picci, Pier-Luigi Lollini, and Katia Scotlandi
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Medicine ,Science - Abstract
Abstract Standard therapy of osteosarcoma (OS) and Ewing sarcoma (EW) rests on cytotoxic regimes, which are largely unsuccessful in advanced patients. Preclinical models are needed to break this impasse. A panel of patient-derived xenografts (PDX) was established by implantation of fresh, surgically resected osteosarcoma (OS) and Ewing sarcoma (EW) in NSG mice. Engraftment was obtained in 22 of 61 OS (36%) and 7 of 29 EW (24%). The success rate in establishing primary cell cultures from OS was lower than the percentage of PDX engraftment in mice, whereas the reverse was observed for EW; the implementation of both in vivo and in vitro seeding increased the proportion of patients yielding at least one workable model. The establishment of in vitro cultures from PDX was highly efficient in both tumor types, reaching 100% for EW. Morphological and immunohistochemical (SATB2, P-glycoprotein 1, CD99, caveolin 1) studies and gene expression profiling showed a remarkable similarity between patient’s tumor and PDX, which was maintained over several passages in mice, whereas cell cultures displayed a lower correlation with human samples. Genes differentially expressed between OS original tumor and PDX mostly belonged to leuykocyte-specific pathways, as human infiltrate is gradually replaced by murine leukocytes during growth in mice. In EW, which contained scant infiltrates, no gene was differentially expressed between the original tumor and the PDX. A novel therapeutic combination of anti-CD99 diabody C7 and irinotecan was tested against two EW PDX; both drugs inhibited PDX growth, the addition of anti-CD99 was beneficial when chemotherapy alone was less effective. The panel of OS and EW PDX faithfully mirrored morphologic and genetic features of bone sarcomas, representing reliable models to test therapeutic approaches.
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- 2019
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8. Immune targeting of autocrine IGF2 hampers rhabdomyosarcoma growth and metastasis
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Carla De Giovanni, Patrizia Nanni, Lorena Landuzzi, Marianna L. Ianzano, Giordano Nicoletti, Stefania Croci, Arianna Palladini, and Pier-Luigi Lollini
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IGF2 ,Immunoprevention ,Rhabdomyosarcoma ,IGF1R ,DNA vaccines ,Neutralizing antibodies ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Insulin-like Growth Factor Receptor-1 (IGF1R) system sustains the genesis of rhabdomyosarcoma through IGF2 autocrine overexpression. While several IGF1R-targeted strategies have been investigated to interphere with rhabdomyosarcoma growth, no attempt to neutralize IGF2 has been reported. We therefore studied the possibility to hamper rhabdomyosarcoma growth with passive and active immune approaches targeting IGF2. Methods A murine model developing IGF2-overexpressing pelvic rhabdomyosarcoma, along with IGF2-independent salivary carcinoma, was used to investigate the efficacy and specificity of passive anti-IGFs antibody treatment. Active vaccinations with electroporated DNA plasmids encoding murine or human IGF2 were performed to elicit autochthonous anti-IGF2 antibodies. Vaccinated mice received the intravenous injection of rhabdomyosarcoma cells to study the effects of anti-IGF2 antibodies against developing metastases. Results Passive administration of antibodies neutralizing IGFs delayed the onset of IGF2-overexpressing rhabdomyosarcoma but not of IGF2-independent salivary carcinoma. A DNA vaccine against murine IGF2 did not elicit antibodies, even when combined with Treg-depletion, while a DNA vaccine encoding the human IGF2 gene elicited antibodies crossreacting with murine IGF2. Mice with anti-IGF2 antibodies were partially protected against the metastatic growth of IGF2-addicted rhabdomyosarcoma cells. Conclusions Immune targeting of autocrine IGF2 inhibited rhabdomyosarcoma genesis and metastatic growth.
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- 2019
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9. Cancer immunoprevention: from mice to early clinical trials
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Arianna Palladini, Lorena Landuzzi, Pier-Luigi Lollini, and Patrizia Nanni
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Cancer immunoprevention ,Cancer vaccines ,Genetically-modified mouse models ,HER-2 ,Oncoantigens ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Abstract Cancer immunoprevention is based on the fact that a functioning immune system controls tumor onset and development in humans and animals, thus leading to the idea that the enhancement of immune responses in healthy individuals could effectively reduce cancer risk later in life. Successful primary immunoprevention of tumors caused by hepatitis B and papilloma viruses is already implemented at the population level with specific vaccines. The immunoprevention of human tumors unrelated to infectious agents is an outstanding challenge. Proof-of-principle preclinical studies in genetically-modified or in carcinogen-exposed mice clearly demonstrated that vaccines and other immunological treatments induce host immune responses that effectively control tumor onset and progression, eventually resulting in cancer prevention. While a straightforward translation to healthy humans is currently unfeasible, a number of pioneering clinical trials showed that cancer immunoprevention can be effectively implemented in human cohorts affected by specific cancer risks, such as preneoplastic/early neoplastic lesions. Future developments will see the implementation of cancer immunoprevention in a wider range of conditions at risk of tumor development, such as the exposure to known carcinogens and genetic predispositions.
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- 2018
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10. HER Tyrosine Kinase Family and Rhabdomyosarcoma: Role in Onset and Targeted Therapy
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Carla De Giovanni, Lorena Landuzzi, Arianna Palladini, Giordano Nicoletti, Patrizia Nanni, and Pier-Luigi Lollini
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rhabdomyosarcoma ,HER2 ,EGFR ,targeted therapy ,CAR-T ,precision medicine ,Cytology ,QH573-671 - Abstract
Rhabdomyosarcomas (RMS) are tumors of the skeletal muscle lineage. Two main features allow for distinction between subtypes: morphology and presence/absence of a translocation between the PAX3 (or PAX7) and FOXO1 genes. The two main subtypes are fusion-positive alveolar RMS (ARMS) and fusion-negative embryonal RMS (ERMS). This review will focus on the role of receptor tyrosine kinases of the human epidermal growth factor receptor (EGFR) family that is comprised EGFR itself, HER2, HER3 and HER4 in RMS onset and the potential therapeutic targeting of receptor tyrosine kinases. EGFR is highly expressed by ERMS tumors and cell lines, in some cases contributing to tumor growth. If not mutated, HER2 is not directly involved in control of RMS cell growth but can be expressed at significant levels. A minority of ERMS carries a HER2 mutation with driving activity on tumor growth. HER3 is frequently overexpressed by RMS and can play a role in the residual myogenic differentiation ability and in resistance to signaling-directed therapy. HER family members could be exploited for therapeutic approaches in two ways: blocking the HER member (playing a driving role for tumor growth with antibodies or inhibitors) and targeting expressed HER members to vehiculate toxins or immune effectors.
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- 2021
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11. IFN-γ and CD38 in Hyperprogressive Cancer Development
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Stefania Angelicola, Francesca Ruzzi, Lorena Landuzzi, Laura Scalambra, Francesco Gelsomino, Andrea Ardizzoni, Patrizia Nanni, Pier-Luigi Lollini, and Arianna Palladini
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hyperprogression ,hyperprogressive disease ,cancer ,immune checkpoint inhibitors ,immunotherapy ,IFN-γ ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
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.
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- 2021
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12. The Mechanisms of PD-L1 Regulation in Non-Small-Cell Lung Cancer (NSCLC): Which Are the Involved Players?
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Giuseppe Lamberti, Monia Sisi, Elisa Andrini, Arianna Palladini, Francesca Giunchi, Pier-Luigi Lollini, Andrea Ardizzoni, and Francesco Gelsomino
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PD-L1 ,PD-1 ,non-small-cell lung cancer ,immunotherapy ,immune checkpoint inhibitors ,T-cell ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Treatment with inhibition of programmed cell death 1 (PD-1) or its ligand (PD-L1) improves survival in advanced non-small-cell lung cancer (NSCLC). Nevertheless, only a subset of patients benefit from treatment and biomarkers of response to immunotherapy are lacking. Expression of PD-L1 on tumor cells is the primary clinically-available predictive factor of response to immune checkpoint inhibitors, and its relevance in cancer immunotherapy has fostered several studies to better characterize the mechanisms that regulate PD-L1 expression. However, the factors associated with PD-L1 expression are still not well understood. Genomic alterations that activate KRAS, EGFR, and ALK, as well as the loss of PTEN, have been associated with increased PD-L1 expression. In addition, PD-L1 expression is reported to be increased by amplification of CD274, and decreased by STK11 deficiency. Furthermore, PD-L1 expression can be modulated by either tumor extrinsic or intrinsic factors. Among extrinsic factors, the most prominent one is interferon-γ release by immune cells, while there are several tumor intrinsic factors such as activation of the mechanistic target of rapamycin (mTOR), mitogen-activated protein kinase (MAPK) and Myc pathways that can increase PD-L1 expression. A deeper understanding of PD-L1 expression regulation is crucial for improving strategies that exploit inhibition of this immune checkpoint in the clinic, especially in NSCLC where it is central in the therapeutic algorithm. We reviewed current preclinical and clinical data about PD-L1 expression regulation in NSCLC.
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- 2020
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13. OX40 triggering concomitant to IL12-engineered cell vaccine hampers the immunoprevention of HER2/neu-driven mammary carcinogenesis
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Patrizia Nanni, Carla De Giovanni, Alessia Burocchi, Giordano Nicoletti, Lorena Landuzzi, Arianna Palladini, Marianna Lucia Ianzano, Ivano Arioli, Mario P. Colombo, and Pier-Luigi Lollini
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cancer vaccine ,her2/neu ,immunoprevention ,mammary cancer ,ox40 ,Immunologic diseases. Allergy ,RC581-607 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
This study evaluated the effects of combining an OX40 agonistic antibody (aOX40) with a cell vaccine targeting HER2/neu, called “Triplex”. Such HER2/neu cell vaccine included two biological adjuvants (interleukin 12 (IL12) and allogeneic histocompatibility antigens) and was previously found able to prevent autochthonous HER2/neu-driven mammary carcinogenesis. Timing of aOX40 administration, concomitantly or after cell vaccination, gave opposite results. Unexpectedly, vaccine efficacy was hampered by concomitant OX40 triggering. Such decreased immunoprevention was likely due to a reduced induction of anti-HER2/neu antibodies and to a higher level of Treg activation. On the contrary, aOX40 administration after the completion of vaccination slightly but significantly increased immunopreventive vaccine efficacy, and led to increased production of GM-CSF and IL10. In conclusion, OX40 triggering can either impair or ameliorate immunoprevention of HER2/neu-driven mammary carcinogenesis depending on the schedule of aOX40 administration.
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- 2018
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14. Virus-like particle display of HER2 induces potent anti-cancer responses
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Arianna Palladini, Susan Thrane, Christoph M. Janitzek, Jessica Pihl, Stine B. Clemmensen, Willem Adriaan de Jongh, Thomas M. Clausen, Giordano Nicoletti, Lorena Landuzzi, Manuel L. Penichet, Tania Balboni, Marianna L. Ianzano, Veronica Giusti, Thor G. Theander, Morten A. Nielsen, Ali Salanti, Pier-Luigi Lollini, Patrizia Nanni, and Adam F. Sander
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virus-like particle ,her2 ,vaccine ,breast cancer ,nano-particle ,therapeutic vaccination ,Immunologic diseases. Allergy ,RC581-607 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Overexpression of human epidermal growth factor receptor-2 (HER2) occurs in 20–30% of invasive breast cancers. Monoclonal antibody therapy is effective in treating HER2-driven mammary carcinomas, but its utility is limited by high costs, side effects and development of resistance. Active vaccination may represent a safer, more effective and cheaper alternative, although the induction of strong and durable autoantibody responses is hampered by immune-tolerogenic mechanisms. Using a novel virus-like particle (VLP) based vaccine platform we show that directional, high-density display of human HER2 on the surface of VLPs, allows induction of therapeutically potent anti-HER2 autoantibody responses. Prophylactic vaccination reduced spontaneous development of mammary carcinomas by 50%-100% in human HER2 transgenic mice and inhibited the growth of HER2-positive tumors implanted in wild-type mice. The HER2-VLP vaccine shows promise as a new cost-effective modality for prevention and treatment of HER2-positive cancer. The VLP platform may represent an effective tool for development of vaccines against other non-communicable diseases.
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- 2018
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15. Cancer Vaccines Co-Targeting HER2/Neu and IGF1R
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Carla De Giovanni, Lorena Landuzzi, Arianna Palladini, Marianna Lucia Ianzano, Giordano Nicoletti, Francesca Ruzzi, Augusto Amici, Stefania Croci, Patrizia Nanni, and Pier-Luigi Lollini
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cancer vaccines ,HER2/neu ,IGF1R ,muscle neoplasms ,DNA vaccines ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
(1) Background: Human epidermal growth factor receptor 2 (HER2)/neu-driven carcinogenesis is delayed by preventive vaccines able to elicit autochthonous antibodies against HER2/neu. Since cooperation between different receptor tyrosine kinases (RTKs) can occur in human as well as in experimental tumors, we investigated the set-up of DNA and cell vaccines to elicit an antibody response co-targeting two RTKs: HER2/neu and the Insulin-like Growth Factor Receptor-1 (IGF1R). (2) Methods: Plasmid vectors carrying the murine optimized IGF1R sequence or the human IGF1R isoform were used as electroporated DNA vaccines. IGF1R plasmids were transfected in allogeneic HER2/neu-positive IL12-producing murine cancer cells to obtain adjuvanted cell vaccines co-expressing HER2/neu and IGF1R. Vaccination was administered in the preneoplastic stage to mice prone to develop HER2/neu-driven, IGF1R-dependent rhabdomyosarcoma. (3) Results: Electroporated DNA vaccines for murine IGF1R did not elicit anti-mIGF1R antibodies, even when combined with Treg-depletion and/or IL12, while DNA vaccines carrying the human IGF1R elicited antibodies recognizing only the human IGF1R isoform. Cell vaccines co-expressing HER2/neu and murine or human IGF1R succeeded in eliciting antibodies recognizing the murine IGF1R isoform. Cell vaccines co-targeting HER2/neu and murine IGF1R induced the highest level of anti-IGF1R antibodies and nearly significantly delayed the onset of spontaneous rhabdomyosarcomas. (4) Conclusions: Multi-engineered adjuvanted cancer cell vaccines can break the tolerance towards a highly tolerized RTK, such as IGF1R. Cell vaccines co-targeting HER2/neu and IGF1R elicited low levels of specific antibodies that slightly delayed onset of HER2/neu-driven, IGF1R-dependent tumors.
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- 2019
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16. Preclinical therapy of disseminated HER-2⁺ ovarian and breast carcinomas with a HER-2-retargeted oncolytic herpesvirus.
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Patrizia Nanni, Valentina Gatta, Laura Menotti, Carla De Giovanni, Marianna Ianzano, Arianna Palladini, Valentina Grosso, Massimiliano Dall'ora, Stefania Croci, Giordano Nicoletti, Lorena Landuzzi, Manuela Iezzi, Gabriella Campadelli-Fiume, and Pier-Luigi Lollini
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Immunologic diseases. Allergy ,RC581-607 ,Biology (General) ,QH301-705.5 - Abstract
Oncolytic viruses aim to specifically kill tumor cells. A major challenge is the effective targeting of disseminated tumors in vivo. We retargeted herpes simplex virus (HSV) tropism to HER-2 oncoprotein p185, overexpressed in ovary and breast cancers. The HER-2-retargeted R-LM249 exclusively infects and kills tumor cells expressing high levels of human HER-2. Here, we assessed the efficacy of systemically i.p. delivered R-LM249 against disseminated tumors in mouse models that recapitulate tumor spread to the peritoneum in women. The human ovarian carcinoma SK-OV-3 cells implanted intraperitoneally (i.p.) in immunodeficient Rag2⁻/⁻;Il2rg⁻/⁻ mice gave rise to a progressive peritoneal carcinomatosis which mimics the fatal condition in advanced human patients. I.p. administration of R-LM249 strongly inhibited carcinomatosis, resulting in 60% of mice free from peritoneal diffusion, and 95% reduction in the total weight of neoplastic nodules. Intraperitoneal metastases are a common outcome in breast cancer: i.p. administration of R-LM249 strongly inhibited the growth of ovarian metastases of HER-2+ MDA-MB-453 breast cells. Brain metastases were also reduced. Cumulatively, upon i.p. administration the HER-2-redirected oncolytic HSV effectively reduced the growth of ovarian and breast carcinoma disseminated to the peritoneal cavity.
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- 2013
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17. Multiorgan metastasis of human HER-2+ breast cancer in Rag2-/-;Il2rg-/- mice and treatment with PI3K inhibitor.
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Patrizia Nanni, Giordano Nicoletti, Arianna Palladini, Stefania Croci, Annalisa Murgo, Marianna L Ianzano, Valentina Grosso, Valeria Stivani, Agnese Antognoli, Alessia Lamolinara, Lorena Landuzzi, Emmanuelle di Tomaso, Manuela Iezzi, Carla De Giovanni, and Pier-Luigi Lollini
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Medicine ,Science - Abstract
In vivo studies of the metastatic process are severely hampered by the fact that most human tumor cell lines derived from highly metastatic tumors fail to consistently metastasize in immunodeficient mice like nude mice. We describe a model system based on a highly immunodeficient double knockout mouse, Rag2-/-;Il2rg-/-, which lacks T, B and NK cell activity. In this model human metastatic HER-2+ breast cancer cells displayed their full multiorgan metastatic potential, without the need for selections or additional manipulations of the system. Human HER-2+ breast cancer cell lines MDA-MB-453 and BT-474 injected into Rag2-/-;Il2rg-/- mice faithfully reproduced human cancer dissemination, with multiple metastatic sites that included lungs, bones, brain, liver, ovaries, and others. Multiorgan metastatic spread was obtained both from local tumors, growing orthotopically or subcutaneously, and from cells injected intravenously. The problem of brain recurrencies is acutely felt in HER-2+ breast cancer, because monoclonal antibodies against HER-2 penetrate poorly the blood-brain barrier. We studied whether a novel oral small molecule inhibitor of downstream PI3K, selected for its penetration of the blood-brain barrier, could affect multiorgan metastatic spread in Rag2-/-;Il2rg-/- mice. NVP-BKM120 effectively controlled metastatic growth in multiple organs, and resulted in a significant proportion of mice free from brain and bone metastases. Human HER-2+ human breast cancer cells in Rag2-/-;Il2rg-/- mice faithfully reproduced the multiorgan metastatic pattern observed in patients, thus allowing the investigation of metastatic mechanisms and the preclinical study of novel antimetastatic agents.
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- 2012
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18. ADK-VR2, a cell line derived from a treatment-naïve patient with SDC4-ROS1 fusion-positive primarily crizotinib-resistant NSCLC: a novel preclinical model for new drug development of ROS1-rearranged NSCLC
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Francesca Ruzzi, Stefania Angelicola, Lorena Landuzzi, Elena Nironi, Maria Sofia Semprini, Laura Scalambra, Annalisa Altimari, Elisa Gruppioni, Michelangelo Fiorentino, Francesca Giunchi, Manuela Ferracin, Annalisa Astolfi, Valentina Indio, Andrea Ardizzoni, Francesco Gelsomino, Patrizia Nanni, Pier-Luigi Lollini, Arianna Palladini, Ruzzi, Francesca, Angelicola, Stefania, Landuzzi, Lorena, Nironi, Elena, Semprini, Maria Sofia, Scalambra, Laura, Altimari, Annalisa, Gruppioni, Elisa, Fiorentino, Michelangelo, Giunchi, Francesca, Ferracin, Manuela, Astolfi, Annalisa, Indio, Valentina, Ardizzoni, Andrea, Gelsomino, Francesco, Nanni, Patrizia, Lollini, Pier-Luigi, and Palladini, Arianna
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tyrosine kinase inhibitors (TKIs) ,receptor tyrosine kinase (RTK ,Oncology ,ROS1 fusion ,target therapie ,Non-small cell lung cancer (NSCLC) - Abstract
(NSCLCs). Several tyrosine kinase inhibitors (TKIs) have shown high efficacy in patients whose tumors harbour a ROS1 fusion. However, the limited availability of preclinical models of ROS1-positive NSCLC hinders the discovery of new drugs and the understanding of the mechanisms underlying drug resistance and strategies to overcome it. Methods: The ADK-VR2 cell line was derived from the pleural effusion of a treatment-naïve NSCLC patient bearing SDC4-ROS1 gene fusion. The sensitivity of ADK-VR2 and its crizotinib-resistant clone ADK-VR2 AG143 (selected in 3D culture in the presence of crizotinib) to different TKIs was tested in vitro, in both 2D and 3D conditions. Tumorigenic and metastatic ability was assessed in highly immunodeficient mice. In addition, crizotinib efficacy on ADK-VR2 was evaluated in vivo. Results: 2D-growth of ADK-VR2 cells was partially inhibited by crizotinib. On the contrary, the treatment with other TKIs, such as lorlatinib, entrectinib and DS-6051b, did not result in cell growth inhibition. TKIs showed dramatically different efficacy on ADK-VR2 cells, depending on the cell culture conditions. In 3D culture, ADK-VR2 growth was indeed almost totally inhibited by lorlatinib and DS-6051b. The clone ADK VR2 AG143 showed higher resistance to crizotinib treatment in vitro, compared to its parental cell line, in both 2D and 3D cultures. Similarly to ADK-VR2, ADK-VR2 AG143 growth was strongly inhibited by lorlatinib in 3D conditions. Nevertheless, ADK-VR2 AG143 sphere formation was less affected by TKIs treatment, compared to the parental cell line. In vivo experiments highlighted the high tumorigenic and metastatic ability of ADK-VR2 cell line, which, once injected in immunodeficient mice, gave rise to both spontaneous and experimental lung metastases while the crizotinib-resistant clone ADK-VR2 AG143 showed a slower growth in vivo. In addition, ADK-VR2 tumor growth was significantly reduced but not eradicated by crizotinib treatment. Conclusions: The ADK-VR2 cell line is a promising NSCLC preclinical model for the study
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- 2022
19. Supplementary Figure S2 from Activated d16HER2 Homodimers and SRC Kinase Mediate Optimal Efficacy for Trastuzumab
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Serenella M. Pupa, Elda Tagliabue, Patrizia Nanni, Sylvie Menard, Tiziana Triulzi, Pier Luigi Lollini, Arianna Palladini, Claudia Chiodoni, Augusto Amici, Manuela Campiglio, Patrizia Gasparini, Roberta Zappasodi, Alessia Lamolinara, Giulia Marzano, Valentina Ciravolo, Gaia C. Ghedini, Manuela Iezzi, and Lorenzo Castagnoli
- Abstract
Enrichment plots of significantly enriched gene sets for the comparison between active d16HER2 tumors and inactive or negative d16HER2 tumors.
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- 2023
20. Supplementary Table 3 from Activated d16HER2 Homodimers and SRC Kinase Mediate Optimal Efficacy for Trastuzumab
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Serenella M. Pupa, Elda Tagliabue, Patrizia Nanni, Sylvie Menard, Tiziana Triulzi, Pier Luigi Lollini, Arianna Palladini, Claudia Chiodoni, Augusto Amici, Manuela Campiglio, Patrizia Gasparini, Roberta Zappasodi, Alessia Lamolinara, Giulia Marzano, Valentina Ciravolo, Gaia C. Ghedini, Manuela Iezzi, and Lorenzo Castagnoli
- Abstract
73 genes composing the "activated-d16HER2 signature".
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- 2023
21. Supplementary Figure Legend from In silico Modeling and In vivo Efficacy of Cancer-Preventive Vaccinations
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Pier-Luigi Lollini, Santo Motta, Patrizia Nanni, Carla De Giovanni, Lorena Landuzzi, Stefania Croci, Agnese Antognoli, Marianna L. Ianzano, Valeria Stivani, Valentina Grosso, Annalisa Murgo, Francesco Pappalardo, Giordano Nicoletti, and Arianna Palladini
- Abstract
Supplementary Figure Legend from In silico Modeling and In vivo Efficacy of Cancer-Preventive Vaccinations
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- 2023
22. Supplementary Table 2 from Activated d16HER2 Homodimers and SRC Kinase Mediate Optimal Efficacy for Trastuzumab
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Serenella M. Pupa, Elda Tagliabue, Patrizia Nanni, Sylvie Menard, Tiziana Triulzi, Pier Luigi Lollini, Arianna Palladini, Claudia Chiodoni, Augusto Amici, Manuela Campiglio, Patrizia Gasparini, Roberta Zappasodi, Alessia Lamolinara, Giulia Marzano, Valentina Ciravolo, Gaia C. Ghedini, Manuela Iezzi, and Lorenzo Castagnoli
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Frequency of clinico-pathological characteristics in HER2-positive BC patients according to pSrc classification.
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- 2023
23. Supplementary Methods from In silico Modeling and In vivo Efficacy of Cancer-Preventive Vaccinations
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Pier-Luigi Lollini, Santo Motta, Patrizia Nanni, Carla De Giovanni, Lorena Landuzzi, Stefania Croci, Agnese Antognoli, Marianna L. Ianzano, Valeria Stivani, Valentina Grosso, Annalisa Murgo, Francesco Pappalardo, Giordano Nicoletti, and Arianna Palladini
- Abstract
Supplementary Methods from In silico Modeling and In vivo Efficacy of Cancer-Preventive Vaccinations
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- 2023
24. Supplementary Table 4 from Activated d16HER2 Homodimers and SRC Kinase Mediate Optimal Efficacy for Trastuzumab
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Serenella M. Pupa, Elda Tagliabue, Patrizia Nanni, Sylvie Menard, Tiziana Triulzi, Pier Luigi Lollini, Arianna Palladini, Claudia Chiodoni, Augusto Amici, Manuela Campiglio, Patrizia Gasparini, Roberta Zappasodi, Alessia Lamolinara, Giulia Marzano, Valentina Ciravolo, Gaia C. Ghedini, Manuela Iezzi, and Lorenzo Castagnoli
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List of cases of the GSE 55348.
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- 2023
25. Data from In silico Modeling and In vivo Efficacy of Cancer-Preventive Vaccinations
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Pier-Luigi Lollini, Santo Motta, Patrizia Nanni, Carla De Giovanni, Lorena Landuzzi, Stefania Croci, Agnese Antognoli, Marianna L. Ianzano, Valeria Stivani, Valentina Grosso, Annalisa Murgo, Francesco Pappalardo, Giordano Nicoletti, and Arianna Palladini
- Abstract
Cancer vaccine feasibility would benefit from reducing the number and duration of vaccinations without diminishing efficacy. However, the duration of in vivo studies and the huge number of possible variations in vaccination protocols have discouraged their optimization. In this study, we employed an established mouse model of preventive vaccination using HER-2/neu transgenic mice (BALB-neuT) to validate in silico–designed protocols that reduce the number of vaccinations and optimize efficacy. With biological training, the in silico model captured the overall in vivo behavior and highlighted certain critical issues. First, although vaccinations could be reduced in number without sacrificing efficacy, the intensity of early vaccinations was a key determinant of long-term tumor prevention needed for predictive utility in the model. Second, after vaccinations ended, older mice exhibited more rapid tumor onset and sharper decline in antibody levels than young mice, emphasizing immune aging as a key variable in models of vaccine protocols for elderly individuals. Long-term studies confirmed predictions of in silico modeling in which an immune plateau phase, once reached, could be maintained with a reduced number of vaccinations. Furthermore, that rapid priming in young mice is required for long-term antitumor protection, and that the accuracy of mathematical modeling of early immune responses is critical. Finally, that the design and modeling of cancer vaccines and vaccination protocols must take into account the progressive aging of the immune system, by striving to boost immune responses in elderly hosts. Our results show that an integrated in vivo–in silico approach could improve both mathematical and biological models of cancer immunoprevention. Cancer Res; 70(20); 7755–63. ©2010 AACR.
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- 2023
26. Supplementary Tables 1-4 from In silico Modeling and In vivo Efficacy of Cancer-Preventive Vaccinations
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Pier-Luigi Lollini, Santo Motta, Patrizia Nanni, Carla De Giovanni, Lorena Landuzzi, Stefania Croci, Agnese Antognoli, Marianna L. Ianzano, Valeria Stivani, Valentina Grosso, Annalisa Murgo, Francesco Pappalardo, Giordano Nicoletti, and Arianna Palladini
- Abstract
Supplementary Tables 1-4 from In silico Modeling and In vivo Efficacy of Cancer-Preventive Vaccinations
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- 2023
27. Supplementary methods, figure legends and references from Activated d16HER2 Homodimers and SRC Kinase Mediate Optimal Efficacy for Trastuzumab
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Serenella M. Pupa, Elda Tagliabue, Patrizia Nanni, Sylvie Menard, Tiziana Triulzi, Pier Luigi Lollini, Arianna Palladini, Claudia Chiodoni, Augusto Amici, Manuela Campiglio, Patrizia Gasparini, Roberta Zappasodi, Alessia Lamolinara, Giulia Marzano, Valentina Ciravolo, Gaia C. Ghedini, Manuela Iezzi, and Lorenzo Castagnoli
- Abstract
Supplementary methods, figure legends and references
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- 2023
28. Supplementary Table 1 from Activated d16HER2 Homodimers and SRC Kinase Mediate Optimal Efficacy for Trastuzumab
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Serenella M. Pupa, Elda Tagliabue, Patrizia Nanni, Sylvie Menard, Tiziana Triulzi, Pier Luigi Lollini, Arianna Palladini, Claudia Chiodoni, Augusto Amici, Manuela Campiglio, Patrizia Gasparini, Roberta Zappasodi, Alessia Lamolinara, Giulia Marzano, Valentina Ciravolo, Gaia C. Ghedini, Manuela Iezzi, and Lorenzo Castagnoli
- Abstract
HER2-positive BC patient pathobiological and clinical characteristics.
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- 2023
29. Supplementary Figure 1 from In silico Modeling and In vivo Efficacy of Cancer-Preventive Vaccinations
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Pier-Luigi Lollini, Santo Motta, Patrizia Nanni, Carla De Giovanni, Lorena Landuzzi, Stefania Croci, Agnese Antognoli, Marianna L. Ianzano, Valeria Stivani, Valentina Grosso, Annalisa Murgo, Francesco Pappalardo, Giordano Nicoletti, and Arianna Palladini
- Abstract
Supplementary Figure 1 from In silico Modeling and In vivo Efficacy of Cancer-Preventive Vaccinations
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- 2023
30. Inhibitors of CDK family: New Perspective and Rationale for Drug Combination in Preclinical Model of Solid Tumors
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Andrea Cavazzoni and Arianna Palladini
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- 2023
31. Immune checkpoint inhibitors in lung tumors with rare histologies and other thoracic malignancies
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Elisa Andrini, Alessandro Di Federico, Monia Sisi, Matteo Rosellini, Arianna Palladini, Giuseppe Lamberti, Andrea De Giglio, and Francesco Gelsomino
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Lung Neoplasms ,Oncology ,Carcinoma, Non-Small-Cell Lung ,Immunology ,Immunology and Allergy ,Humans ,Prospective Studies ,Immunotherapy ,Thoracic Neoplasms ,Immune Checkpoint Inhibitors - Abstract
In recent years, immunotherapy has significantly changed the treatment of locally advanced/metastatic non-small-cell lung cancer (NSCLC). Conversely, the role of immunotherapy in NSCLC with uncommon histologies remains unclear, while in other rare thoracic malignancies, such as malignant pleural mesothelioma and thymic epithelial tumors, the use of immune checkpoint inhibitors is modifying therapeutic strategies with solid hopes for the future. However, larger prospective studies are urgently needed to define the best treatment strategies and the role of immunotherapy in these orphan tumors. This review provides a comprehensive overview of the emerging role of immunotherapy in the treatment of patients affected by these rare thoracic malignancies.
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- 2022
32. Abstract 687: Preclinical activity of ES2B-C001, a human candidate HER-2 virus-like particle (VLP) vaccine, against mammary carcinoma onset and metastasis
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Francesca Ruzzi, Arianna Palladini, Stine Clemmensen, Annette Strobaek, Nicolaas Buijs, Tanja Domeyer, Jerzy Dorosz, Vladislav Soroka, Dagmara Grzadziela, Christina Jo Rasmussen, Ida Busch Nielsen, Max Soegaard, Maria Sofia Semprini, Laura Scalambra, Stefania Angelicola, Lorena Landuzzi, Pier-Luigi Lollini, and Mette Thorn
- Subjects
Cancer Research ,Oncology - Abstract
ES2B-C001 is a virus-like particle (VLP) vaccine against human HER-2, developed for the therapy of breast cancer. We show here that ES2B-C001 effectively inhibits mammary carcinoma growth and metastasis in a transgenic mouse model expressing activated human HER-2. ES2B-C001 vaccine is a tag/catcher conjugation system: Acinectobacter phage 205 (AP205) capsid VLP, each with 180 tag peptides, are conjugated with catcher-HER-2 extracellular domain. The vaccine was administered alone, thanks to the intrinsic adjuvanticity of the VLP, or with Montanide ISA 51. QD is a HER-2-positive cell line established from a mammary carcinoma of a Delta16 (FVB background) transgenic mouse, bearing the human HER-2 splice variant Delta16. FVB female mice were challenged in the mammary fat pad with 1 million QD cells; vaccinations started 2 weeks after cell challenge and were repeated every 2 weeks. Untreated mice developed progressive tumors within one month, whereas 70% of mice vaccinated without adjuvant and all mice vaccinated with adjuvant were still tumor-free one year after cell challenge. Mice challenged intravenously (i.v.) developed more than 300 lung metastases, whereas all vaccinated mice remained metastasis-free. Delta16 transgenic mice are immunologically tolerant to human HER-2 and develop aggressive mammary carcinomas with a median latency of 5 months. Vaccination of young, tumor-free Delta16 mice completely prevented tumor onset for more than one year. Delta16 mice challenged i.v. with QD cells mice developed a mean of 68 lung nodules, whereas 73% of mice therapeutically vaccinated without adjuvant, and all mice vaccinated with E2SB-C001+ISA 51, were free from metastases. ES2B-C001 induced copious anti-HER-2 antibodies of all IgG subclasses, ranging 1-10 mg/mL in FVB mice and 0.1-1 mg/mL in Delta16 mice; antibody titers remained very high for 6-10 months after the last vaccination. Antibodies inhibited the 3D growth of human HER-2+++ and HER-2++ breast cancer cells, of trastuzumab resistant cells and of gastric carcinoma cells. Vaccination increased interferon-gamma secreting cells in the spleen, as evaluated by ELISPot (21±3 spots/2x105 cells). The results warrant further development of ES2B-C001 for the therapy of HER-2 positive human breast cancer and of other tumors expressing HER-2. Citation Format: Francesca Ruzzi, Arianna Palladini, Stine Clemmensen, Annette Strobaek, Nicolaas Buijs, Tanja Domeyer, Jerzy Dorosz, Vladislav Soroka, Dagmara Grzadziela, Christina Jo Rasmussen, Ida Busch Nielsen, Max Soegaard, Maria Sofia Semprini, Laura Scalambra, Stefania Angelicola, Lorena Landuzzi, Pier-Luigi Lollini, Mette Thorn. Preclinical activity of ES2B-C001, a human candidate HER-2 virus-like particle (VLP) vaccine, against mammary carcinoma onset and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 687.
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- 2023
33. Early stability and late random tumor progression of a HER2-positive primary breast cancer patient-derived xenograft
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Tania Balboni, Claudio Ceccarelli, Maria Pia Foschini, Mario Taffurelli, Veronica Giusti, Maria C. Cucchi, Francesca Ruzzi, Roberta Laranga, Laura Scalambra, Pier Luigi Lollini, Carla De Giovanni, Arianna Palladini, Raffaele Calogero, Simone Zanotti, Marianna L. Ianzano, Enrico Di Oto, Patrizia Nanni, Maddalena Arigoni, Martina Olivero, Giordano Nicoletti, Lorena Landuzzi, Massimiliano Dall'Ora, Donatella Santini, Sofia Asioli, Landuzzi, Lorena, Palladini, Arianna, Ceccarelli, Claudio, Asioli, Sofia, Nicoletti, Giordano, Giusti, Veronica, Ruzzi, Francesca, Ianzano, Marianna L, Scalambra, Laura, Laranga, Roberta, Balboni, Tania, Arigoni, Maddalena, Olivero, Martina, Calogero, Raffaele A, De Giovanni, Carla, Dall'Ora, Massimiliano, Di Oto, Enrico, Santini, Donatella, Foschini, Maria Pia, Cucchi, Maria Cristina, Zanotti, Simone, Taffurelli, Mario, Nanni, Patrizia, and Lollini, Pier-Luigi
- Subjects
Cancer therapy ,Receptor, ErbB-2 ,Mice, SCID ,Stem cell marker ,Tyrosine-kinase inhibitor ,Patient-derived xenografts, HER-2, tumor progression, BCL2 ,Mice ,ErbB-2 ,Breast cancer ,Mice, Inbred NOD ,CDKN2A ,Trastuzumab ,Medicine ,Animals ,Breast Neoplasms ,Cell Line, Tumor ,Disease Models, Animal ,Disease Progression ,Epithelial-Mesenchymal Transition ,Female ,Humans ,Prognosis ,Protein Kinase Inhibitors ,Quinolines ,Xenograft Model Antitumor Assays ,Tumor ,Multidisciplinary ,Cancer stem cells ,Neratinib ,Receptor ,medicine.drug ,medicine.drug_class ,Tumour heterogeneity ,Science ,SCID ,Article ,Cell Line ,In vivo ,Cancer models ,Animal ,business.industry ,medicine.disease ,Tumor progression ,Disease Models ,Cancer research ,Inbred NOD ,business - Abstract
We established patient-derived xenografts (PDX) from human primary breast cancers and studied whether stability or progressive events occurred during long-term in vivo passages (up to 4 years) in severely immunodeficient mice. While most PDX showed stable biomarker expression and growth phenotype, a HER2-positive PDX (PDX-BRB4) originated a subline (out of 6 studied in parallel) that progressively acquired a significantly increased tumor growth rate, resistance to cell senescence of in vitro cultures, increased stem cell marker expression and high lung metastatic ability, along with a strong decrease of BCL2 expression. RNAseq analysis of the progressed subline showed that BCL2 was connected to three main hub genes also down-regulated (CDKN2A, STAT5A and WT1). Gene expression of progressed subline suggested a partial epithelial-to-mesenchymal transition. PDX-BRB4 with its progressed subline is a preclinical model mirroring the clinical paradox of high level-BCL2 as a good prognostic factor in breast cancer. Sequential in vivo passages of PDX-BRB4 chronically treated with trastuzumab developed progressive loss of sensitivity to trastuzumab while HER2 expression and sensitivity to the pan-HER tyrosine kinase inhibitor neratinib were maintained. Long-term PDX studies, even though demanding, can originate new preclinical models, suitable to investigate the mechanisms of breast cancer progression and new therapeutic approaches.
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- 2021
34. EGFR-RAD51 gene fusion NSCLC responsiveness to different generation EGFR-TKIs: two cases and review of the literature
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Alessandro Di Federico, Marco Filetti, Arianna Palladini, Raffaele Giusti, Marta Piras, Andrea De Giglio, Andrea Ardizzoni, and Francesco Gelsomino
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Oncology ,Case Report ,respiratory tract diseases - Abstract
Epidermal growth factor receptor (EGFR) gene fusions represent an extremely rare aberration, occurring in approximately 0.05–0.13% non-small cell lung cancer (NSCLC) patients. RAD51 is the most frequently involved partner gene in EGFR fusions, but other fusion partner genes have been described. To date, a considerable number of next-generation sequencing (NGS) panels still cannot detect these alterations due to the position of the breakpoint site, mainly involving intron 24 of EGFR. Current evidences show that such gene alteration is more likely to occur in lung adenocarcinomas of young, female, non-smoker patients. Also, brain metastases are frequently reported in these patients. Only very few cases in literature described clinical characteristics and outcomes of patients harboring EGFR gene fusions, reporting responses to 1st generation EGFR tyrosine kinase inhibitors (TKIs). Herein, we report the case of two young non-smoker females with metastatic NSCLC harboring EGFR-RAD51 gene fusion, detected by FoundationOne DX1 assay, who responded to EGFR TKIs. The first patient initially received erlotinib, then switched to osimertinib for renal toxicity, while the second was treated with gefitinib. This is, to our knowledge, the first report describing response to the 3rd EGFR TKI osimertinib. Our experience highlights the need of a broader molecular profiling in young or never smoker NSCLC patients without detectable molecular aberration using standard NGS panels. Finally, further studies to assess the real prevalence of EGFR gene fusions and their spectrum of sensitivity to different EGFR TKIs are needed.
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- 2022
35. ImmunoGrid, an integrative environment for large-scale simulation of the immune system for vaccine discovery, design and optimization.
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Francesco Pappalardo 0001, Mark D. Halling-Brown, Nicolas Rapin, Ping Zhang 0008, Davide Alemani, Andrew P. J. Emerson, Paola Paci, Patrice Duroux, Marzio Pennisi, Arianna Palladini, Olivo Miotto, Daniel Churchill, Elda Rossi, Adrian J. Shepherd, David S. Moss, Filippo Castiglione, Massimo Bernaschi, Marie-Paule Lefranc, Søren Brunak, Santo Motta, Pierluigi Lollini, Kaye E. Basford, and Vladimir Brusic
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- 2009
- Full Text
- View/download PDF
36. Evolution of HER2-positive mammary carcinoma: HER2 loss reveals claudin-low traits in cancer progression
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Pier Luigi Lollini, Giordano Nicoletti, Carla De Giovanni, Patrizia Nanni, Francesca Ruzzi, Lorena Landuzzi, Elena Nironi, Marianna L. Ianzano, Laura Scalambra, Raffaele Calogero, Maddalena Arigoni, M. Olivero, Roberta Laranga, Veronica Giusti, Arianna Palladini, Giusti, Veronica, Ruzzi, Francesca, Landuzzi, Lorena, Ianzano, Marianna L, Laranga, Roberta, Nironi, Elena, Scalambra, Laura, Nicoletti, Giordano, De Giovanni, Carla, Olivero, Martina, Arigoni, Maddalena, Calogero, Raffaele, Nanni, Patrizia, Palladini, Arianna, and Lollini, Pier-Luigi
- Subjects
HER-2 lo ,Cancer Research ,Tumour heterogeneity ,Angiogenesis ,Cell ,Biology ,Article ,Breast cancer ,In vivo ,medicine ,skin and connective tissue diseases ,neoplasms ,Molecular Biology ,RC254-282 ,Sunitinib ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Cancer ,medicine.disease ,Claudin-Low ,medicine.anatomical_structure ,Mammary carcinoma ,HER-2 ,Cell culture ,PDGFRB ,Cancer research ,medicine.drug - Abstract
HER2-positive breast cancers may lose HER2 expression in recurrences and metastases. In this work, we studied cell lines derived from two transgenic mammary tumors driven by human HER2 that showed different dynamics of HER2 status. MamBo89HER2stable cell line displayed high and stable HER2 expression, which was maintained upon in vivo passages, whereas MamBo43HER2labile cell line gave rise to HER2-negative tumors from which MamBo38HER2loss cell line was derived. Both low-density seeding and in vitro trastuzumab treatment of MamBo43HER2labile cells induced the loss of HER2 expression. MamBo38HER2loss cells showed a spindle-like morphology, high stemness and acquired in vivo malignancy. A comprehensive molecular profile confirmed the loss of addiction to HER2 signaling and acquisition of an EMT signature, together with increased angiogenesis and migration ability. We identified PDGFR-B among the newly expressed determinants of MamBo38HER2loss cell tumorigenic ability. Sunitinib inhibited MamBo38HER2loss tumor growth in vivo and reduced stemness and IL6 production in vitro. In conclusion, HER2-positive mammary tumors can evolve into tumors that display distinctive traits of claudin-low tumors. Our dynamic model of HER2 status can lead to the identification of new druggable targets, such as PDGFR-B, in order to counteract the resistance to HER2-targeted therapy that is caused by HER2 loss.
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- 2021
37. HER2 isoforms co-expression differently tunes mammary tumor phenotypes affecting onset, vasculature and therapeutic response
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Roberta Laranga, Lorena Landuzzi, Marianna L. Ianzano, Manuela Iezzi, Massimiliano Dall'Ora, Donatella Santini, Patrizia Nanni, Veronica Giusti, Enrico Di Oto, Mario Taffurelli, Giordano Nicoletti, Augusto Amici, Alessia Lamolinara, Serenella M. Pupa, Tania Balboni, Arianna Palladini, Claudio Ceccarelli, Sofia Asioli, Pier Luigi Lollini, Elda Tagliabue, Carla De Giovanni, Palladini, Arianna, Nicoletti, Giordano, Lamolinara, Alessia, Dall'Ora, Massimiliano, Balboni, Tania, Ianzano, Marianna L, Laranga, Roberta, Landuzzi, Lorena, Giusti, Veronica, Ceccarelli, Claudio, Santini, Donatella, Taffurelli, Mario, Di Oto, Enrico, Asioli, Sofia, Amici, Augusto, Pupa, Serenella M, De Giovanni, Carla, Tagliabue, Elda, Iezzi, Manuela, Nanni, Patrizia, and Lollini, Pier-Luigi
- Subjects
0301 basic medicine ,Gene isoform ,Genetically modified mouse ,medicine.medical_specialty ,Pathology ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,breast cancer ,Trastuzumab ,model of host-tumor interactions ,HER2 ,medicine ,animal models of cancer ,model of host-tumor interaction ,skin and connective tissue diseases ,neoplasms ,Mammary tumor ,business.industry ,Cancer ,Anatomical pathology ,medicine.disease ,Phenotype ,Delta16 ,trastuzumab ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,business ,medicine.drug ,Research Paper - Abstract
// Arianna Palladini 1, * , Giordano Nicoletti 2, * , Alessia Lamolinara 3, * , Massimiliano Dall’Ora 1, * , Tania Balboni 1 , Marianna L. Ianzano 1 , Roberta Laranga 1 , Lorena Landuzzi 2 , Veronica Giusti 1 , Claudio Ceccarelli 1, 4 , Donatella Santini 4 , Mario Taffurelli 5 , Enrico Di Oto 6 , Sofia Asioli 6 , Augusto Amici 7 , Serenella M. Pupa 8 , Carla De Giovanni 1 , Elda Tagliabue 8 , Manuela Iezzi 3 , Patrizia Nanni 1 and Pier-Luigi Lollini 1 1 Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy 2 Rizzoli Orthopedic Institute, Laboratory of Experimental Oncology, Bologna, Italy 3 Aging Research Centre, “Gabriele d’Annunzio” University, Chieti, Italy 4 Pathology Unit, Policlinico S.Orsola-Malpighi University Hospital, Bologna, Italy 5 Department of Medical and Surgical Sciences of Bologna, Bologna, Italy 6 Anatomic Pathology, Department of Biomedical and Neuromotor Sciences, Bellaria Hospital, University of Bologna, Bologna, Italy 7 University of Camerino, Camerino, Italy 8 Istituto Nazionale Tumori, Milano, Italy * These authors have contributed equally to this work Correspondence to: Patrizia Nanni, email: patrizia.nanni@unibo.it Keywords: HER2, Delta16, trastuzumab, breast cancer, model of host-tumor interactions Received: December 16, 2016 Accepted: March 22, 2017 Published: April 13, 2017 ABSTRACT Full-length HER2 oncoprotein and splice variant Delta16 are co-expressed in human breast cancer. We studied their interaction in hybrid transgenic mice bearing human full-length HER2 and Delta16 (F1 HER2/Delta16) in comparison to parental HER2 and Delta16 transgenic mice. Mammary carcinomas onset was faster in F1 HER2/Delta16 and Delta16 than in HER2 mice, however tumor growth was slower, and metastatic spread was comparable in all transgenic mice. Full-length HER2 tumors contained few large vessels or vascular lacunae , whereas Delta16 tumors presented a more regular vascularization with numerous endothelium-lined small vessels. Delta16-expressing tumors showed a higher accumulation of i.v. injected doxorubicin than tumors expressing full-length HER2. F1 HER2/Delta16 tumors with high full-length HER2 expression made few large vessels, whereas tumors with low full-length HER2 and high Delta16 contained numerous small vessels and expressed higher levels of VEGF and VEGFR2. Trastuzumab strongly inhibited tumor onset in F1 HER2/Delta16 and Delta16 mice, but not in full-length HER2 mice. Addiction of F1 tumors to Delta16 was also shown by long-term stability of Delta16 levels during serial transplants, in contrast full-length HER2 levels underwent wide fluctuations. In conclusion, full-length HER2 leads to a faster tumor growth and to an irregular vascularization, whereas Delta16 leads to a faster tumor onset, with more regular vessels, which in turn could better transport cytotoxic drugs within the tumor, and to a higher sensitivity to targeted therapeutic agents. F1 HER2/Delta16 mice are a new immunocompetent mouse model, complementary to patient-derived xenografts, for studies of mammary carcinoma onset, prevention and therapy.
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- 2017
38. Cancer Vaccines Co-Targeting HER2/Neu and IGF1R
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Pier Luigi Lollini, Lorena Landuzzi, Carla De Giovanni, Giordano Nicoletti, Marianna L. Ianzano, Patrizia Nanni, Augusto Amici, Arianna Palladini, Francesca Ruzzi, Stefania Croci, De Giovanni, Carla, Landuzzi, Lorena, Palladini, Arianna, Ianzano, Marianna Lucia, Nicoletti, Giordano, Ruzzi, Francesca, Amici, Augusto, Croci, Stefania, Nanni, Patrizia, and Lollini, Pier-Luigi
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DNA vaccine ,0301 basic medicine ,Cancer Research ,Biology ,medicine.disease_cause ,lcsh:RC254-282 ,Article ,HER2/neu ,Receptor tyrosine kinase ,DNA vaccination ,DNA vaccines ,03 medical and health sciences ,0302 clinical medicine ,IGF1R ,medicine ,Insulin-like growth factor 1 receptor ,Transfection ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,body regions ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Cancer cell ,biology.protein ,Cancer research ,muscle neoplasms ,Antibody ,cancer vaccine ,Carcinogenesis ,cancer vaccines - Abstract
(1) Background: Human epidermal growth factor receptor 2 (HER2)/neu-driven carcinogenesis is delayed by preventive vaccines able to elicit autochthonous antibodies against HER2/neu. Since cooperation between different receptor tyrosine kinases (RTKs) can occur in human as well as in experimental tumors, we investigated the set-up of DNA and cell vaccines to elicit an antibody response co-targeting two RTKs: HER2/neu and the Insulin-like Growth Factor Receptor-1 (IGF1R). (2) Methods: Plasmid vectors carrying the murine optimized IGF1R sequence or the human IGF1R isoform were used as electroporated DNA vaccines. IGF1R plasmids were transfected in allogeneic HER2/neu-positive IL12-producing murine cancer cells to obtain adjuvanted cell vaccines co-expressing HER2/neu and IGF1R. Vaccination was administered in the preneoplastic stage to mice prone to develop HER2/neu-driven, IGF1R-dependent rhabdomyosarcoma. (3) Results: Electroporated DNA vaccines for murine IGF1R did not elicit anti-mIGF1R antibodies, even when combined with Treg-depletion and/or IL12, while DNA vaccines carrying the human IGF1R elicited antibodies recognizing only the human IGF1R isoform. Cell vaccines co-expressing HER2/neu and murine or human IGF1R succeeded in eliciting antibodies recognizing the murine IGF1R isoform. Cell vaccines co-targeting HER2/neu and murine IGF1R induced the highest level of anti-IGF1R antibodies and nearly significantly delayed the onset of spontaneous rhabdomyosarcomas. (4) Conclusions: Multi-engineered adjuvanted cancer cell vaccines can break the tolerance towards a highly tolerized RTK, such as IGF1R. Cell vaccines co-targeting HER2/neu and IGF1R elicited low levels of specific antibodies that slightly delayed onset of HER2/neu-driven, IGF1R-dependent tumors.
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- 2019
39. Bone sarcoma patient-derived xenografts are faithful and stable preclinical models for molecular and therapeutic investigations
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Mauro Magnani, Alessandro Parra, Pier Luigi Lollini, Davide Maria Donati, Marianna L. Ianzano, Arianna Palladini, Alberto Righi, Lorena Landuzzi, Piero Picci, Katia Scotlandi, Francesca Ruzzi, Michela Pasello, Maria Cristina Manara, Patrizia Nanni, Giordano Nicoletti, Marianna Carrabotta, Manuela Ferracin, Camilla Cristalli, Veronica Giusti, Nanni, Patrizia, Landuzzi, Lorena, Manara, Maria Cristina, Righi, Alberto, Nicoletti, Giordano, Cristalli, Camilla, Pasello, Michela, Parra, Alessandro, Carrabotta, Marianna, Ferracin, Manuela, Palladini, Arianna, Ianzano, Marianna L, Giusti, Veronica, Ruzzi, Francesca, Magnani, Mauro, Donati, Davide Maria, Picci, Piero, Lollini, Pier-Luigi, and Scotlandi, Katia
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0301 basic medicine ,endocrine system ,Science ,Transplantation, Heterologous ,CD99 ,Osteosarcoma, Ewing Sarcoma, Patient-derived xenograft (PDX), Mouse models of human cancer, Target therapy ,Antineoplastic Agents ,Bone Neoplasms ,Mice, SCID ,Sarcoma, Ewing ,12E7 Antigen ,Biology ,Bone Sarcoma ,Irinotecan ,Article ,Antibodies ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Mice, Inbred NOD ,In vivo ,Bone cancer ,Tumor Cells, Cultured ,medicine ,Animals ,Humans ,Cytotoxic T cell ,Osteosarcoma ,Multidisciplinary ,Sarcoma ,medicine.disease ,Gene Expression Regulation, Neoplastic ,Transplantation ,Disease Models, Animal ,030104 developmental biology ,Cancer research ,Immunohistochemistry ,Medicine ,Tumor Suppressor Protein p53 ,030217 neurology & neurosurgery - Abstract
Standard therapy of osteosarcoma (OS) and Ewing sarcoma (EW) rests on cytotoxic regimes, which are largely unsuccessful in advanced patients. Preclinical models are needed to break this impasse. A panel of patient-derived xenografts (PDX) was established by implantation of fresh, surgically resected osteosarcoma (OS) and Ewing sarcoma (EW) in NSG mice. Engraftment was obtained in 22 of 61 OS (36%) and 7 of 29 EW (24%). The success rate in establishing primary cell cultures from OS was lower than the percentage of PDX engraftment in mice, whereas the reverse was observed for EW; the implementation of both in vivo and in vitro seeding increased the proportion of patients yielding at least one workable model. The establishment of in vitro cultures from PDX was highly efficient in both tumor types, reaching 100% for EW. Morphological and immunohistochemical (SATB2, P-glycoprotein 1, CD99, caveolin 1) studies and gene expression profiling showed a remarkable similarity between patient’s tumor and PDX, which was maintained over several passages in mice, whereas cell cultures displayed a lower correlation with human samples. Genes differentially expressed between OS original tumor and PDX mostly belonged to leuykocyte-specific pathways, as human infiltrate is gradually replaced by murine leukocytes during growth in mice. In EW, which contained scant infiltrates, no gene was differentially expressed between the original tumor and the PDX. A novel therapeutic combination of anti-CD99 diabody C7 and irinotecan was tested against two EW PDX; both drugs inhibited PDX growth, the addition of anti-CD99 was beneficial when chemotherapy alone was less effective. The panel of OS and EW PDX faithfully mirrored morphologic and genetic features of bone sarcomas, representing reliable models to test therapeutic approaches.
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- 2019
40. Immune targeting of autocrine IGF2 hampers rhabdomyosarcoma growth and metastasis
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Marianna L. Ianzano, Pier Luigi Lollini, Patrizia Nanni, Arianna Palladini, Giordano Nicoletti, Stefania Croci, Carla De Giovanni, Lorena Landuzzi, De Giovanni, Carla, Nanni, Patrizia, Landuzzi, Lorena, Ianzano, Marianna L, Nicoletti, Giordano, Croci, Stefania, Palladini, Arianna, and Lollini, Pier-Luigi
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Male ,0301 basic medicine ,Cancer Research ,endocrine system diseases ,medicine.medical_treatment ,Animals, Genetically Modified ,Mice ,Antineoplastic Agents, Immunological ,0302 clinical medicine ,IGF1R ,Rhabdomyosarcoma ,Medicine ,biology ,IGF2 ,Antibodies, Monoclonal ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,female genital diseases and pregnancy complications ,Autocrine Communication ,Treatment Outcome ,Oncology ,030220 oncology & carcinogenesis ,Female ,Antibody ,Immunoprevention ,Research Article ,DNA vaccine ,animal structures ,Immune Targeting ,Neutralizing antibodies ,lcsh:RC254-282 ,DNA vaccination ,DNA vaccines ,Immunomodulation ,03 medical and health sciences ,Immune system ,Insulin-Like Growth Factor II ,Cell Line, Tumor ,Genetics ,Neutralizing antibodie ,Animals ,Humans ,Autocrine signalling ,neoplasms ,Cell Proliferation ,Insulin-like growth factor 1 receptor ,business.industry ,Growth factor ,medicine.disease ,Rats ,body regions ,Disease Models, Animal ,030104 developmental biology ,biology.protein ,Cancer research ,business - Abstract
Background Insulin-like Growth Factor Receptor-1 (IGF1R) system sustains the genesis of rhabdomyosarcoma through IGF2 autocrine overexpression. While several IGF1R-targeted strategies have been investigated to interphere with rhabdomyosarcoma growth, no attempt to neutralize IGF2 has been reported. We therefore studied the possibility to hamper rhabdomyosarcoma growth with passive and active immune approaches targeting IGF2. Methods A murine model developing IGF2-overexpressing pelvic rhabdomyosarcoma, along with IGF2-independent salivary carcinoma, was used to investigate the efficacy and specificity of passive anti-IGFs antibody treatment. Active vaccinations with electroporated DNA plasmids encoding murine or human IGF2 were performed to elicit autochthonous anti-IGF2 antibodies. Vaccinated mice received the intravenous injection of rhabdomyosarcoma cells to study the effects of anti-IGF2 antibodies against developing metastases. Results Passive administration of antibodies neutralizing IGFs delayed the onset of IGF2-overexpressing rhabdomyosarcoma but not of IGF2-independent salivary carcinoma. A DNA vaccine against murine IGF2 did not elicit antibodies, even when combined with Treg-depletion, while a DNA vaccine encoding the human IGF2 gene elicited antibodies crossreacting with murine IGF2. Mice with anti-IGF2 antibodies were partially protected against the metastatic growth of IGF2-addicted rhabdomyosarcoma cells. Conclusions Immune targeting of autocrine IGF2 inhibited rhabdomyosarcoma genesis and metastatic growth.
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- 2019
41. IFN-γ and CD38 in Hyperprogressive Cancer Development
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Arianna Palladini, Pier Luigi Lollini, Laura Scalambra, Francesco Gelsomino, Lorena Landuzzi, Stefania Angelicola, Andrea Ardizzoni, Patrizia Nanni, Francesca Ruzzi, Angelicola, Stefania, Ruzzi, Francesca, Landuzzi, Lorena, Scalambra, Laura, Gelsomino, Francesco, Ardizzoni, Andrea, Nanni, Patrizia, Lollini, Pier-Luigi, and Palladini, Arianna
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0301 basic medicine ,Cancer Research ,medicine.medical_treatment ,immune checkpoint inhibitor ,Review ,macrophage ,CD38 ,hyperprogression ,lcsh:RC254-282 ,immune checkpoint inhibitors ,03 medical and health sciences ,0302 clinical medicine ,medicine ,cancer ,tumor microenvironment ,IFN-γ ,Tumor microenvironment ,business.industry ,Effector ,Cancer ,Inflammasome ,Immunotherapy ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,hyperprogressive disease ,medicine.disease ,Immune checkpoint ,030104 developmental biology ,Cytokine ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,immunotherapy ,business ,medicine.drug - Abstract
Simple Summary Hyperprogressive disease (HPD) is a pattern of paradoxical tumor progression that has been reported in patients treated with immune checkpoint inhibitors (ICIs). Although a large number of studies have investigated HPD and several associated factors have been reported, the mechanisms that drive the acceleration of tumor growth remain unknown. In this review, we discuss the possible role of IFN-γ and CD38 in the development of HPD, and we report the main findings in the scientific literature on the signaling pathways in which these factors take part, and their involvement in response and resistance to ICI therapy. Abstract 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.
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- 2021
42. Modeling the competition between lung metastases and the immune system using agents.
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Marzio Pennisi, Francesco Pappalardo 0001, Arianna Palladini, Giordano Nicoletti, Patrizia Nanni, Pierluigi Lollini, and Santo Motta
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- 2010
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43. Bioprofiling TS/A Murine Mammary Cancer for a Functional Precision Experimental Model
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Arianna Palladini, Giordano Nicoletti, Pier Luigi Lollini, Carla De Giovanni, Lorena Landuzzi, Patrizia Nanni, De Giovanni, Carla, Nicoletti, Giordano, Landuzzi, Lorena, Palladini, Arianna, Lollini, Pier-Luigi, and Nanni, Patrizia
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0301 basic medicine ,Cancer Research ,TS/A ,Genetic enhancement ,medicine.medical_treatment ,Review ,Biology ,03 medical and health sciences ,0302 clinical medicine ,Biological profile ,medicine ,metastases ,Mammary tumor ,Experimental model ,Immunogenicity ,Cancer ,Immunotherapy ,medicine.disease ,preclinical models ,gene therapy ,030104 developmental biology ,murine mammary cancer ,Oncology ,Cell culture ,metastase ,030220 oncology & carcinogenesis ,Cancer research ,immunotherapy - Abstract
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.
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- 2019
44. Cancer immunoprevention: from mice to early clinical trials
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Patrizia Nanni, Lorena Landuzzi, Arianna Palladini, Pier Luigi Lollini, Palladini, Arianna, Landuzzi, Lorena, Lollini, Pier-Luigi, and Nanni, Patrizia
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0301 basic medicine ,lcsh:Immunologic diseases. Allergy ,Cancer immunoprevention ,Immunology ,Antineoplastic Agents ,Review ,Cancer vaccines ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Neoplasms ,Genetic predisposition ,Cancer vaccine ,Animals ,Humans ,Medicine ,Oncoantigens ,Genetically-modified mouse model ,Cancer prevention ,business.industry ,Immunity ,Cancer ,Hepatitis B ,medicine.disease ,Genetically-modified mouse models ,Clinical trial ,030104 developmental biology ,HER-2 ,030220 oncology & carcinogenesis ,Disease Progression ,Papilloma ,business ,lcsh:RC581-607 ,Precancerous Conditions - Abstract
Cancer immunoprevention is based on the fact that a functioning immune system controls tumor onset and development in humans and animals, thus leading to the idea that the enhancement of immune responses in healthy individuals could effectively reduce cancer risk later in life. Successful primary immunoprevention of tumors caused by hepatitis B and papilloma viruses is already implemented at the population level with specific vaccines. The immunoprevention of human tumors unrelated to infectious agents is an outstanding challenge. Proof-of-principle preclinical studies in genetically-modified or in carcinogen-exposed mice clearly demonstrated that vaccines and other immunological treatments induce host immune responses that effectively control tumor onset and progression, eventually resulting in cancer prevention. While a straightforward translation to healthy humans is currently unfeasible, a number of pioneering clinical trials showed that cancer immunoprevention can be effectively implemented in human cohorts affected by specific cancer risks, such as preneoplastic/early neoplastic lesions. Future developments will see the implementation of cancer immunoprevention in a wider range of conditions at risk of tumor development, such as the exposure to known carcinogens and genetic predispositions.
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- 2018
45. Systemic delivery of HER2-retargeted oncolytic-HSV by mesenchymal stromal cells protects from lung and brain metastases
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Valentina Gatta, Pier Luigi Lollini, Dario Ranieri, Francesco Alviano, Patrizia Nanni, Martina Rossi, Arianna Palladini, Massimiliano Dall'Ora, Valentina Grosso, Giordano Nicoletti, Valerio Leoni, Gabriella Campadelli-Fiume, Laura Bonsi, Leoni, Valerio, Gatta, Valentina, Palladini, Arianna, Nicoletti, Giordano, Ranieri, Dario, Dall'Ora, Massimiliano, Grosso, Valentina, Rossi, Martina, Alviano, Francesco, Bonsi, Laura, Nanni, Patrizia, Lollini, Pier-Luigi, and Campadelli-Fiume, Gabriella
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Simplexvirus ,Lung Neoplasms ,food.ingredient ,Receptor, ErbB-2 ,viruses ,Mice, Nude ,Breast Neoplasms ,Biology ,Mesenchymal Stem Cell Transplantation ,medicine.disease_cause ,Virus ,Mice ,03 medical and health sciences ,0302 clinical medicine ,food ,medicine ,Animals ,Humans ,Neoplasm Metastasis ,metastases ,mesenchymal stem cell ,Tropism ,030304 developmental biology ,Oncolytic Virotherapy ,Ovarian Neoplasms ,viral retargeting ,mesenchymal stem cells ,0303 health sciences ,Brain Neoplasms ,Mesenchymal stem cell ,oncolytic herpes simplex viru ,oncolytic herpes simplex virus ,Flow Cytometry ,medicine.disease ,Xenograft Model Antitumor Assays ,Virology ,systemic delivery ,3. Good health ,Oncolytic virus ,Oncolytic Viruses ,Herpes simplex virus ,Oncology ,metastase ,030220 oncology & carcinogenesis ,Cancer cell ,Female ,Ovarian cancer ,Research Paper - Abstract
// Valerio Leoni 1,* , Valentina Gatta 1,* , Arianna Palladini 1 , Giordano Nicoletti 1 , Dario Ranieri 1 , Massimiliano Dall’Ora 1 , Valentina Grosso 1 , Martina Rossi 1 , Francesco Alviano 1 , Laura Bonsi 1 , Patrizia Nanni 1 , Pier-Luigi Lollini 1 and Gabriella Campadelli-Fiume 1 1 Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy * These authors have contributed equally to this work Correspondence to: Gabriella Campadelli-Fiume, email: // Pier-Luigi Lollini, email: // Keywords : oncolytic herpes simplex virus, viral retargeting, mesenchymal stem cells, systemic delivery, metastases Received : July 02, 2015 Accepted : September 04, 2015 Published : September 27, 2015 Abstract Fully retargeted oncolytic herpes simplex viruses (o-HSVs) gain cancer-specificity from redirection of tropism to cancer-specific receptors, and are non-attenuated. To overcome the hurdles of systemic delivery, and enable oncolytic viruses (o-viruses) to reach metastatic sites, carrier cells are being exploited. Mesenchymal stromal cells (MSCs) were never tested as carriers of retargeted o-viruses, given their scarse-null expression of the cancer-specific receptors. We report that MSCs from different sources can be forcedly infected with a HER2-retargeted oncolytic HSV. Progeny virus spread from MSCs to cancer cells in vitro and in vivo . We evaluated the organ distribution and therapeutic efficacy in two murine models of metastatic cancers, following a single i.v. injection of infected MSCs. As expected, the highest concentration of carrier-cells and of viral genomes was in the lungs. Viral genomes persisted throughout the body for at least two days. The growth of ovarian cancer lung metastases in nude mice was strongly inhibited, and the majority of treated mice appeared metastasis-free. The treatment significantly inhibited also breast cancer metastases to the brain in NSG mice, and reduced by more than one-half the metastatic burden in the brain.
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- 2015
46. ImmunoGrid: towards agent-based simulations of the human immune system at a natural scale
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Annalisa Murgo, Andrew Emerson, David S. Moss, Daniel Churchill, Søren Brunak, Pier Luigi Lollini, Davide Alemani, Massimo Bernaschi, Kaye E. Basford, Filippo Castiglione, Francesco Pappalardo, Adrian J. Shepherd, Mark D. Halling-Brown, Patrice Duroux, Santo Motta, Arianna Palladini, Ole Lund, Elda Rossi, Marie-Paule Lefranc, Olivo Miotto, Ping Zhang, Nicolas Rapin, Vladimir Brusic, Marzio Pennisi, Clare Sansom, Laboratoire d'Informatique, de Traitement de l'Information et des Systèmes (LITIS), Université Le Havre Normandie (ULH), Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Bordelais de Recherche en Informatique (LaBRI), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB), M. Halling-Brown. F. Pappalardo, N. Rapin, P. Zhang, D. Alemani, A. Emerson, F. Castiglione, P. Duroux, M. Pennisi, O. Miotto, D. Churchill, E. Rossi, D. Mo, C. Sansom, M. Bernaschi, M.P. Lefranc, S Brunak, O. Lund, S. Motta, P.L. Lollini, A. Murgo, A. Palladini, K. Basford, V. Brusic, and A.J. Shepherd
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Proteome ,Computer science ,General Mathematics ,Systems biology ,General Physics and Astronomy ,computer.software_genre ,Field (computer science) ,03 medical and health sciences ,0302 clinical medicine ,Agent-based simulation ,biological model ,Virtual physiological human ,Humans ,Computer Simulation ,ComputingMilieux_MISCELLANEOUS ,030304 developmental biology ,0303 health sciences ,Internet ,[SDV.GEN]Life Sciences [q-bio]/Genetics ,business.industry ,Management science ,Scale (chemistry) ,General Engineering ,Models, Immunological ,Virtual Physiological Human ,Grid ,[SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM] ,Immunity, Innate ,3. Good health ,Grid computing ,Risk analysis (engineering) ,030220 oncology & carcinogenesis ,Key (cryptography) ,The Internet ,[INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM] ,business ,computer ,Software - Abstract
The ultimate aim of the EU-funded ImmunoGrid project is to develop a natural-scale model of the human immune system—that is, one that reflects both the diversity and the relative proportions of the molecules and cells that comprise it—together with the grid infrastructure necessary to apply this model to specific applications in the field of immunology. These objectives present the ImmunoGrid Consortium with formidable challenges in terms of complexity of the immune system, our partial understanding about how the immune system works, the lack of reliable data and the scale of computational resources required. In this paper, we explain the key challenges and the approaches adopted to overcome them. We also consider wider implications for the present ambitious plans to develop natural-scale, integrated models of the human body that can make contributions to personalized health care, such as the European Virtual Physiological Human initiative. Finally, we ask a key question: How long will it take us to resolve these challenges and when can we expect to have fully functional models that will deliver health-care benefits in the form of personalized care solutions and improved disease prevention?
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- 2016
47. Evaluation of metastatic burden and recovery of human metastatic cells from a mouse model
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Landuzzi, Lorena, Arianna Palladini, Marianna Lucia Ianzano, Laranga, Roberta, D’intino, Giulia, Patrizia Nanni, Pier Luigi Lollini, Landuzzi, Lorena, Palladini, Arianna, Ianzano, Marianna Lucia, Laranga, Roberta, D’Intino, Giulia, Nanni, Patrizia, and Lollini, Pierluigi
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Breast cancer, HER-2, brain metastases - Abstract
Metastatic dissemination is the major cause of death in cancer. Xenotransplantation of tumor tissue into immunodeficient mice is a widespread preclinical technique to study tumor development. However, preclinical studies on the spreading of metastases were so far hampered by the poor dissemination of malignant human tumors in conventional immunodeficient hosts, like the nude mouse. The development of highly immunodeficient knockout mice spurred a new wave of metastatic model systems. It was recently shown that human HER-2-positive breast cancer cells, which do not metastasize in nude mice, when implanted in knockout mice with severe immunodeficiency, give rise to multiorgan metastatic patterns resembling those observed in human patients. The growth of metastatic nodules in a variety of locations, including brain, lungs, liver, kidneys, adrenals, ovaries, and bone marrow, opens up the problem of quantifying metastatic burden and recovering human metastatic cells from mouse organs for cellular and molecular studies in vitro .Here we used the Mouse Cell Depletion Kit (Miltenyi Biotec) to enrich and quantify metastatic human cells, derived from human breast carcinoma, in a model of brain metastases1 in NOD scid gamma (NOD.Cg- Prkdc scid Il2rg tm1Wjl/SzJ, NSG) mice.
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- 2016
48. Mathematical and Computational Models in Tumor Immunology
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Marzio Pennisi, Arianna Palladini, Santo Motta, Filippo Castiglione, Francesco Pappalardo, Pappalardo F, Palladini A, Pennisi M, Castiglione F, and Motta S.
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Differential equations ,Computational model ,Applied Mathematics ,cacer ,Computational biology ,vaccines ,Biology ,Bioinformatics ,Mathematical modeling ,Increased risk ,Immune system ,Modeling and Simulation ,Tumor immunology ,agent based model - Abstract
The immune system is able to protect the host from tumor onset, and immune deficiencies are accompanied by an increased risk of cancer. Immunology is one of the fields in biology where the role of computational and mathematical modeling and analysis were recognized the earliest, beginning from 60s of the last century. We introduce the two most common methods in simulating the competition among the immune system, cancers and tumor immunology strategies: differential equations and rule-based models. Several specific implementations are presented, describing in details how they work and how they advance or contribute the field of tumor immunology.
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- 2012
49. Proteomic and PROTEOMEX profiling of mammary cancer progression in a HER-2/neu oncogene-driven animal model system
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Carla De Giovanni, Rudolf Lichtenfels, Lorena Landuzzi, Kazuo Shin-ya, Annalisa Astolfi, Barbara Seliger, Giordano Nicoletti, Arianna Palladini, Stefania Croci, Pier Luigi Lollini, Patrizia Nanni, Christian V. Recktenwald, Sven P. Dressler, S. Croci, C.V. Recktenwald, R. Lichtenfel, G. Nicoletti, S.P. Dressler, C. De Giovanni, A. Astolfi, A. Palladini, K. Shin-ya, L. Landuzzi, P. Nanni, P.-L. Lollini, and B. Seliger
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Proteomics ,Antibodies, Neoplasm ,Receptor, ErbB-2 ,Immunoblotting ,Clinical Biochemistry ,Mice, Transgenic ,CELL BIOLOGY ,Biology ,Cancer Vaccines ,Biochemistry ,Transcriptome ,Mice ,Western blot ,Annexin ,Cell Line, Tumor ,medicine ,Animals ,Cluster Analysis ,Electrophoresis, Gel, Two-Dimensional ,Endoplasmic Reticulum Chaperone BiP ,AUTOANTIBODY ,Molecular Biology ,Heat-Shock Proteins ,Autoantibodies ,TRANSGENIC MICE ,Mice, Inbred BALB C ,Principal Component Analysis ,medicine.diagnostic_test ,Proteomic Profiling ,Cell growth ,Gene Expression Profiling ,MAMMARY CANCER ,Mammary Neoplasms, Experimental ,Reproducibility of Results ,Cancer ,medicine.disease ,Disease Models, Animal ,Immunoglobulin G ,IMMUNOPREVENTION ,Immunology ,Disease Progression ,Cancer research ,Female ,Breast disease - Abstract
The prevention of mammary carcinoma by immunological strategies targeting the HER-2/neu receptor has proved to be effective in preclinical models. Thus, a well-characterized HER-2/neu oncogene-driven mammary carcinogenesis model was analysed by various profiling strategies following "triplex" vaccination to identify new candidate targets for breast cancer immunoprevention. 2-DE-based proteomic profiling of preneoplastic and tumour lesions versus normal and aged mammary tissue demonstrated that tumour progression was associated with an up-regulation of molecular chaperones including glucose-regulated protein (GRP)78 and of proteins favouring cell motility, which was in line with the corresponding transcriptomic profiling data. Furthermore, PROTEOMEX analyses suggested that naturally induced autoantibody responses occur during early phases of mammary cancer progression. Most of the cancer progression-induced antibodies targeted proteins of normal and preneoplastic mammary glands. However, three proteins were only recognized by sera obtained from vaccinated mice, including 2 isoforms of annexin A6. The distinct expression patterns for annexin A6 and GRP78 during tumour progression were further verified by western blot and/or immunoprecipitation. In addition, an inhibitor-mediated blockade of GRP78 expression in a model cell line caused a reduced cell growth. Thus, the proteome-based approaches applied in the murine BALB-NeuT model might indeed provide candidates for immunoprevention strategies in breast cancer.
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- 2010
50. Abstract 716: A novel virus-like particle vaccine presenting HER-2 extracellular domain elicits strong immune responses against mammary carcinoma
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Adam F. Sander, Jessica Pihl, Lorena Landuzzi, Pier Luigi Lollini, Ali Salanti, Manuel L. Penichet, Morten Nielsen, Susan Thrane, Thor H. Theander, Veronica Giusti, Thomas Mandel Clausen, Christoph M. Janitzek, Patrizia Nanni, Wilhelm A. de Jongh, Giordano Nicoletti, Stine B. Clemmensen, Tania Balboni, Arianna Palladini, and Marianna L. Ianzano
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Mammary carcinoma ,Cancer Research ,Immune system ,Oncology ,Chemistry ,Novel virus ,Extracellular ,Domain (software engineering) ,Cell biology - Abstract
Overexpression of human epidermal growth factor receptor-2 (HER-2) occurs in about 20% of invasive breast cancers. Anti-HER-2 monoclonal antibody therapy is effective, but its utility is limited by high costs, side effects and development of resistance, thus underlining the need of new therapeutic approaches. A novel anti-HER-2 vaccine made of virus-like particles (VLPs) displaying the extracellular domain (ECD) of the human oncogene/antigen HER-2 induced protective immune responses against transgenic mouse mammary carcinomas expressing human HER-2. We have developed a versatile antigen display platform that, unlike existing technologies, effectively facilitates directional covalent attachment of large antigens at high density on the surface of VLPs (J. Nanobiotechnology 14: 30, 2016). The system uses a tag/catcher conjugation system that was developed by splitting the CnaB2 domain from the fibronectin-binding protein FbaB of Streptococcus pyogenes into a highly reactive peptide (SpyTag) and a protein (SpyCatcher) binding partner. Interaction between SpyTag and SpyCatcher results in the spontaneous formation of an isopeptide bond, occurring at high efficiency in a wide variety of protein contexts and buffer conditions. Here, we genetically fused with SpyCatcher the full extracellular domain (subdomains I-IV) of human HER-2, and bound the fusion antigen (SpyCatcher-HER2) to the surface of VLPs (derived from the AP205 phage), each presenting 360 SpyTag peptides. The vaccine, referred to as HER2-VLP, effectively overcame immune tolerance and induced Th1 cytokines and high-titer, high affinity, therapeutically potent anti-HER-2 antibodies which inhibited tumor growth in wild-type FVB mice implanted with transgenic mammary carcinomas expressing human HER-2. Furthermore, vaccination with HER2-VLP prevented spontaneous development of human HER2-positive mammary carcinomas in tolerant transgenic mice. Vaccination with a control preparation of untagged VLP and HER-2 ECD did not induce protective immune responses. Polyclonal IgG antibodies elicited by HER2-VLP vaccination had an affinity for human HER-2 comparable to trastuzumab and inhibited the 3D growth in vitro of both trastuzumab-sensitive and trastuzumab-resistant BT-474 human breast cancer cells. In conclusion, the HER2-VLP vaccine has the potential to become a tool in the fight against HER-2-positive human cancer. The results also provide strong proof-of-concept for the use of the versatile VLP platform to develop a variety of vaccines against other tumor antigens. Supported by grants from the Italian Association for Cancer Research (AIRC), the University of Bologna, the Danish Research Council, the Eurostars program and the European Research Council (ERC). Citation Format: Arianna Palladini, Susan Thrane, Christoph M. Janitzek, Jessica Pihl, Stine B. Clemmensen, Wilhelm A. de Jongh, Thomas M. Clausen, Giordano Nicoletti, Lorena Landuzzi, Manuel L. Penichet, Tania Balboni, Marianna L. Ianzano, Veronica Giusti, Thor H. Theander, Morten A. Nielsen, Ali Salanti, Pier-Luigi Lollini, Patrizia Nanni, Adam F. Sander. A novel virus-like particle vaccine presenting HER-2 extracellular domain elicits strong immune responses against mammary carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 716.
- Published
- 2018
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