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  1. Article: Fibroblasts Impair Migration and Antitumor Activity of NK-92 Lymphocytes in a Melanoma-on-Chip Model.

    Iaia, Ilenia / Brancato, Virginia / Caballero, David / Reis, Rui L / Aglietta, Massimo / Sangiolo, Dario / Kundu, Subhas C

    Bioengineering (Basel, Switzerland)

    2022  Volume 10, Issue 1

    Abstract: Adoptive cell therapy in solid tumors, such as melanoma, is impaired, but little is known about the role that the fibroblasts present in the tumor microenvironment could exert. However, the mechanism at play is not well understood, partly due to the lack ...

    Abstract Adoptive cell therapy in solid tumors, such as melanoma, is impaired, but little is known about the role that the fibroblasts present in the tumor microenvironment could exert. However, the mechanism at play is not well understood, partly due to the lack of relevant pre-clinical models. Three-dimensional culture and microfluidic chips are used to recapitulate the dynamic interactions among different types of cells in the tumor microenvironment in controlled and physiological settings. In this brief report, we propose a reductionist melanoma-on-a-chip model for evaluating the essential role of fibroblasts in the antitumor activity of lymphocytes. To this end, 3D melanoma spheroids were monocultured and co-cultured with human dermal fibroblasts and the NK-92 cell migration towards the tumor compartment was tested in a commercially available microfluidic device. Utilizing confocal microscopy, we observed the different recruitment of NK-92 cells in the presence and absence of fibroblasts. Our results show that fibroblasts' presence inhibits immune effector recruiting by exploiting a 3D pre-clinical tumor model.
    Language English
    Publishing date 2022-12-30
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2746191-9
    ISSN 2306-5354
    ISSN 2306-5354
    DOI 10.3390/bioengineering10010052
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Characterization of Viral Genome Encapsidated in Adeno-associated Recombinant Vectors Produced in Yeast Saccharomyces cerevisiae

    Galli, Alvaro / Iaia, Ilenia / Milella, Maria Serena / Cipriani, Filippo / Della Latta, Veronica / Giacca, Mauro / Zentilin, Lorena / Cervelli, Tiziana

    Molecular biotechnology. 2021 Feb., v. 63, no. 2

    2021  

    Abstract: Adeno-associated virus (AAV) is a small, non-enveloped virus used as vector in gene therapy, mainly produced in human cells and in baculovirus systems. Intense studies on these platforms led to the production of vectors with titers between 10³ and 10⁵ ... ...

    Abstract Adeno-associated virus (AAV) is a small, non-enveloped virus used as vector in gene therapy, mainly produced in human cells and in baculovirus systems. Intense studies on these platforms led to the production of vectors with titers between 10³ and 10⁵ viral genomes (vg) per cells. In spite of this, vector yields need to be improved to satisfy the high product demands of clinical trials and future commercialization. Our studies and those of other groups have explored the possibility to exploit the yeast Saccharomyces cerevisiae to produce rAAV. We previously demonstrated that yeast supports AAV genome replication and capsid assembly. The purpose of this study was to evaluate the quality of the encapsidated AAV DNA. Here, we report the construction of a yeast strain expressing Rep68/40 from an integrated copy of the Rep gene under the control of the yeast constitutive ADH promoter and Capsid proteins from the Cap gene under the control of an inducible GAL promoter. Our results indicate that a portion of AAV particles generated by this system contains encapsidated AAV DNA. However, the majority of encapsidated DNA consists of fragmented regions of the transgene cassette, with ITRs being the most represented sequences. Altogether, these data indicate that, in yeast, encapsidation occurs with low efficiency and that rAAVs resemble pseudo-vectors that are present in clinical-grade rAAV preparations.
    Keywords DNA ; Dependoparvovirus ; Saccharomyces cerevisiae ; biotechnology ; capsid ; commercialization ; gene therapy ; humans ; transgenes ; viral genome ; viruses ; yeasts
    Language English
    Dates of publication 2021-02
    Size p. 156-165.
    Publishing place Springer US
    Document type Article
    Note NAL-AP-2-clean
    ZDB-ID 1193057-3
    ISSN 1559-0305 ; 1073-6085
    ISSN (online) 1559-0305
    ISSN 1073-6085
    DOI 10.1007/s12033-020-00294-4
    Database NAL-Catalogue (AGRICOLA)

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    In stock of ZB MED Bonn / Germany

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  3. Article ; Online: Characterization of Viral Genome Encapsidated in Adeno-associated Recombinant Vectors Produced in Yeast Saccharomyces cerevisiae.

    Galli, Alvaro / Iaia, Ilenia / Milella, Maria Serena / Cipriani, Filippo / Della Latta, Veronica / Giacca, Mauro / Zentilin, Lorena / Cervelli, Tiziana

    Molecular biotechnology

    2021  Volume 63, Issue 2, Page(s) 156–165

    Abstract: Adeno-associated virus (AAV) is a small, non-enveloped virus used as vector in gene therapy, mainly produced in human cells and in baculovirus systems. Intense studies on these platforms led to the production of vectors with titers between ... ...

    Abstract Adeno-associated virus (AAV) is a small, non-enveloped virus used as vector in gene therapy, mainly produced in human cells and in baculovirus systems. Intense studies on these platforms led to the production of vectors with titers between 10
    MeSH term(s) DNA, Fungal/genetics ; Dependovirus/genetics ; Genetic Vectors/metabolism ; Genome, Fungal ; Genome, Viral ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae Proteins/metabolism
    Chemical Substances DNA, Fungal ; Saccharomyces cerevisiae Proteins
    Language English
    Publishing date 2021-01-03
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1193057-3
    ISSN 1559-0305 ; 1073-6085
    ISSN (online) 1559-0305
    ISSN 1073-6085
    DOI 10.1007/s12033-020-00294-4
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 4031: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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  4. Article: Recruitment, Infiltration, and Cytotoxicity of HLA-Independent Killer Lymphocytes in Three-Dimensional Melanoma Models.

    Iaia, Ilenia / Gammaitoni, Loretta / Cattaneo, Giulia / Giraudo, Lidia / Donini, Chiara / Fiorino, Erika / Primo, Luca / Carnevale-Schianca, Fabrizio / Aglietta, Massimo / Puliafito, Alberto / Sangiolo, Dario

    Cancers

    2021  Volume 13, Issue 10

    Abstract: Cancer adoptive cell therapy (ACT) with HLA-independent tumor killer lymphocytes is a promising approach, with intrinsic features potentially addressing crucial tumor-escape mechanisms of checkpoint inhibitors. Cytokine-induced Killer (CIK) and Natural ... ...

    Abstract Cancer adoptive cell therapy (ACT) with HLA-independent tumor killer lymphocytes is a promising approach, with intrinsic features potentially addressing crucial tumor-escape mechanisms of checkpoint inhibitors. Cytokine-induced Killer (CIK) and Natural Killer (NK) lymphocytes share similar tumor-killing mechanisms, with preclinical evidence of intense activity against multiple solid tumors and currently testing in clinical studies. To improve the effective clinical translation of such ACT approaches, several fundamental questions still need to be addressed within appropriate preclinical contexts, capable of overcoming limitations imposed by most traditional two-dimensional assays. Here, we developed a novel experimental approach to explore, dissect, and visualize the interactions of CIK and NK lymphocytes with melanoma tumors in vitro in 3D. Primary melanoma cells were assembled into small tumors that were dispersed in a 3D matrix and challenged with patient-derived CIK or the NK-92 cell line. By means of imaging-based methods, we reported, visualized, and quantitatively measured the recruitment of CIK and NK on the 3D targets, their infiltration, and cytotoxic activity. Our results support the effective tumor recruitment and tumor infiltration by CIK and NK. Such features appeared dependent on the specific geometric aspects of the environment but can be explained in terms of directional migration toward the tumor, without invoking major feedback components. Overall, our 3D platform allows us to monitor the processes of tumor recruitment, infiltration, and killing by means of live measurements, revealing important kinetic aspects of ACT with CIK and NK against melanoma.
    Language English
    Publishing date 2021-05-11
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2527080-1
    ISSN 2072-6694
    ISSN 2072-6694
    DOI 10.3390/cancers13102302
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: CSPG4 CAR-redirected Cytokine Induced Killer lymphocytes (CIK) as effective cellular immunotherapy for HLA class I defective melanoma.

    Giraudo, Lidia / Cattaneo, Giulia / Gammaitoni, Loretta / Iaia, Ilenia / Donini, Chiara / Massa, Annamaria / Centomo, Maria Laura / Basiricò, Marco / Vigna, Elisa / Pisacane, Alberto / Picciotto, Franco / Berrino, Enrico / Marchiò, Caterina / Merlini, Alessandra / Paruzzo, Luca / Poletto, Stefano / Caravelli, Daniela / Biolato, Andrea Michela / Bortolot, Valentina /
    Landoni, Elisa / Ventin, Marco / Ferrone, Cristina R / Aglietta, Massimo / Dotti, Gianpietro / Leuci, Valeria / Carnevale-Schianca, Fabrizio / Sangiolo, Dario

    Journal of experimental & clinical cancer research : CR

    2023  Volume 42, Issue 1, Page(s) 310

    Abstract: Background: Even acknowledging the game-changing results achieved in the treatment of metastatic melanoma with the use of immune checkpoint inhibitors (ICI), a large proportion of patients (40-60%) still fail to respond or relapse due to the development ...

    Abstract Background: Even acknowledging the game-changing results achieved in the treatment of metastatic melanoma with the use of immune checkpoint inhibitors (ICI), a large proportion of patients (40-60%) still fail to respond or relapse due to the development of resistance. Alterations in the expression of Human Leukocyte Antigen class I (HLA-I) molecules are considered to play a major role in clinical resistance to ICI. Cellular immunotherapy with HLA-independent CAR-redirected lymphocytes is a promising alternative in this challenging setting and dedicated translational models are needed.
    Methods: In this study, we propose an HLA-independent therapeutic strategy with Cytokine Induced Killer lymphocytes (CIK) genetically engineered with a Chimeric Antigen Receptor (CAR) targeting the tumor antigen CSPG4 as effector mechanism. We investigated the preclinical antitumor activity of CSPG4-CAR.CIK in vitro and in a xenograft murine model focusing on patient-derived melanoma cell lines (Mel) with defective expression of HLA-I molecules.
    Results: We successfully generated CSPG4-CAR.CIK from patients with metastatic melanoma and reported their intense activity in vitro against a panel of CSPG4-expressing patient-derived Mel. The melanoma killing activity was intense, even at very low effector to target ratios, and not influenced by the expression level (high, low, defective) of HLA-I molecules on target cells. Furthermore, CAR.CIK conditioned medium was capable of upregulating the expression of HLA-I molecules on melanoma cells. A comparable immunomodulatory effect was replicated by treatment of Mel cells with exogenous IFN-γ and IFN-α. The antimelanoma activity of CSPG4-CAR.CIK was successfully confirmed in vivo, obtaining a significant tumor growth inhibition of an HLA-defective Mel xenograft in immunodeficient mice.
    Conclusions: In this study we reported the intense preclinical activity of CSPG4-CAR.CIK against melanoma, including those with low or defective HLA-I expression. Our findings support CSPG4 as a valuable CAR target in melanoma and provide translational rationale for clinical studies exploring CAR-CIK cellular immunotherapies within the challenging setting of patients not responsive or relapsing to immune checkpoint inhibitors.
    MeSH term(s) Humans ; Animals ; Mice ; Cytokines ; Receptors, Chimeric Antigen/genetics ; Immune Checkpoint Inhibitors ; Immunotherapy, Adoptive/methods ; Neoplasm Recurrence, Local ; Melanoma/genetics ; Melanoma/therapy ; Immunotherapy ; Lymphocytes/pathology ; Membrane Proteins ; Chondroitin Sulfate Proteoglycans
    Chemical Substances Cytokines ; Receptors, Chimeric Antigen ; Immune Checkpoint Inhibitors ; CSPG4 protein, human ; Membrane Proteins ; Chondroitin Sulfate Proteoglycans
    Language English
    Publishing date 2023-11-22
    Publishing country England
    Document type Journal Article
    ZDB-ID 803138-1
    ISSN 1756-9966 ; 0392-9078
    ISSN (online) 1756-9966
    ISSN 0392-9078
    DOI 10.1186/s13046-023-02884-x
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 2065: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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  6. Article ; Online: CSPG4-Specific CAR.CIK Lymphocytes as a Novel Therapy for the Treatment of Multiple Soft-Tissue Sarcoma Histotypes.

    Leuci, Valeria / Donini, Chiara / Grignani, Giovanni / Rotolo, Ramona / Mesiano, Giulia / Fiorino, Erika / Gammaitoni, Loretta / D'Ambrosio, Lorenzo / Merlini, Alessandra / Landoni, Elisa / Medico, Enzo / Capellero, Sonia / Giraudo, Lidia / Cattaneo, Giulia / Iaia, Ilenia / Pignochino, Ymera / Basiricò, Marco / Vigna, Elisa / Pisacane, Alberto /
    Fagioli, Franca / Ferrone, Soldano / Aglietta, Massimo / Dotti, Gianpietro / Sangiolo, Dario

    Clinical cancer research : an official journal of the American Association for Cancer Research

    2020  Volume 26, Issue 23, Page(s) 6321–6334

    Abstract: Purpose: No effective therapy is available for unresectable soft-tissue sarcomas (STS). This unmet clinical need prompted us to test whether chondroitin sulfate proteoglycan 4 (CSPG4)-specific chimeric antigen receptor (CAR)-redirected cytokine-induced ... ...

    Abstract Purpose: No effective therapy is available for unresectable soft-tissue sarcomas (STS). This unmet clinical need prompted us to test whether chondroitin sulfate proteoglycan 4 (CSPG4)-specific chimeric antigen receptor (CAR)-redirected cytokine-induced killer lymphocytes (CAR.CIK) are effective in eliminating tumor cells derived from multiple STS histotypes
    Experimental design: The experimental platform included patient-derived CAR.CIK and cell lines established from multiple STS histotypes. CAR.CIK were transduced with a retroviral vector encoding second-generation CSPG4-specific CAR (CSPG4-CAR) with 4-1BB costimulation. The functional activity of CSPG4-CAR.CIK was explored
    Results: CSPG4-CAR.CIK were efficiently generated from patients with STS. CSPG4 was highly expressed in multiple STS histotypes by
    Conclusions: This study has shown that CSPG4-CAR.CIK effectively targets multiple STS histotypes
    MeSH term(s) Animals ; Apoptosis ; Cell Proliferation ; Chondroitin Sulfate Proteoglycans/genetics ; Chondroitin Sulfate Proteoglycans/metabolism ; Cytokine-Induced Killer Cells/immunology ; Female ; Humans ; Immunotherapy, Adoptive/methods ; Interleukin-2/metabolism ; Lymphocytes/immunology ; Membrane Proteins/genetics ; Membrane Proteins/metabolism ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Receptors, Chimeric Antigen/immunology ; Sarcoma/immunology ; Sarcoma/metabolism ; Sarcoma/pathology ; Sarcoma/therapy ; Tumor Cells, Cultured ; Xenograft Model Antitumor Assays
    Chemical Substances CSPG4 protein, human ; Chondroitin Sulfate Proteoglycans ; Interleukin-2 ; Membrane Proteins ; Receptors, Chimeric Antigen
    Language English
    Publishing date 2020-09-08
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 1225457-5
    ISSN 1557-3265 ; 1078-0432
    ISSN (online) 1557-3265
    ISSN 1078-0432
    DOI 10.1158/1078-0432.CCR-20-0357
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 4223: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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