IMMU-12. NOVEL APPROACH FOR THE TREATMENT OF PEDIATRIC HIGH-GRADE GLIOMAS WITH THE COMBINATION OF ONCOLYTIC ADENOVIRUSES AND GENE THERAPY ENCODING A BiTE DIRECTED TO THE EphA2 TUMOR ANTIGEN

Abstract Pediatric high-grade gliomas (pHGG) are amongst the most common malignant neoplasms of childhood, whose outcome remains dismal with conventional treatments. New therapeutic approaches are urgently needed. Immunotherapy based on Oncolytic Adenovirus(OA)is a promising strategy but its efficac...

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Published in:Neuro-oncology (Charlottesville, Va.) Va.), 2019-04, Vol.21 (Supplement_2), p.ii95-ii95
Main Authors: Arnone, Claudia Manuela, Belardinilli, Tamascia, Mastronuzzi, Angela, Polito, Vinicia, Cacchione, Antonella, Carai, Andrea, Camassei, Francesca Diomedi, Scarsella, Marco, Quintarelli, Concetta, Angelis, Biagio De, Locatelli, Franco, Caruana, Ignazio, Del Bufalo, Francesca
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container_issue Supplement_2
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container_title Neuro-oncology (Charlottesville, Va.)
container_volume 21
creator Arnone, Claudia Manuela
Belardinilli, Tamascia
Mastronuzzi, Angela
Polito, Vinicia
Cacchione, Antonella
Carai, Andrea
Camassei, Francesca Diomedi
Scarsella, Marco
Quintarelli, Concetta
Angelis, Biagio De
Locatelli, Franco
Caruana, Ignazio
Del Bufalo, Francesca
description Abstract Pediatric high-grade gliomas (pHGG) are amongst the most common malignant neoplasms of childhood, whose outcome remains dismal with conventional treatments. New therapeutic approaches are urgently needed. Immunotherapy based on Oncolytic Adenovirus(OA)is a promising strategy but its efficacy is suboptimal. We aimed at improving the antitumor efficacy by combining the OA and a gene-therapy with the Bibispecific T-cell Engager (BiTE) directed towards the erythropoietin-producing human hepatocellular carcinoma A2-receptor (EphA2),conveyed by a replication-incompetent adenoviral vector (EAd). We demonstrated, by immunohistochemistry and qPCR, the expression of EphA2 in 100% (16/16) of the pHGGs, its intensity correlating significantly with a worst outcome. We then tested the transgene amplification, after co-infection, on two HGG cell lines (U373, U87) by qPCR and Flow Cytometry (FACS) for the selectable marker ∆CD19, confirming a significantly enhanced production in OA+EAd vs EAd alone (p
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NOVEL APPROACH FOR THE TREATMENT OF PEDIATRIC HIGH-GRADE GLIOMAS WITH THE COMBINATION OF ONCOLYTIC ADENOVIRUSES AND GENE THERAPY ENCODING A BiTE DIRECTED TO THE EphA2 TUMOR ANTIGEN</title><source>PubMed (Medline)</source><source>Oxford Journals Online</source><creator>Arnone, Claudia Manuela ; Belardinilli, Tamascia ; Mastronuzzi, Angela ; Polito, Vinicia ; Cacchione, Antonella ; Carai, Andrea ; Camassei, Francesca Diomedi ; Scarsella, Marco ; Quintarelli, Concetta ; Angelis, Biagio De ; Locatelli, Franco ; Caruana, Ignazio ; Del Bufalo, Francesca</creator><creatorcontrib>Arnone, Claudia Manuela ; Belardinilli, Tamascia ; Mastronuzzi, Angela ; Polito, Vinicia ; Cacchione, Antonella ; Carai, Andrea ; Camassei, Francesca Diomedi ; Scarsella, Marco ; Quintarelli, Concetta ; Angelis, Biagio De ; Locatelli, Franco ; Caruana, Ignazio ; Del Bufalo, Francesca</creatorcontrib><description>Abstract Pediatric high-grade gliomas (pHGG) are amongst the most common malignant neoplasms of childhood, whose outcome remains dismal with conventional treatments. New therapeutic approaches are urgently needed. Immunotherapy based on Oncolytic Adenovirus(OA)is a promising strategy but its efficacy is suboptimal. We aimed at improving the antitumor efficacy by combining the OA and a gene-therapy with the Bibispecific T-cell Engager (BiTE) directed towards the erythropoietin-producing human hepatocellular carcinoma A2-receptor (EphA2),conveyed by a replication-incompetent adenoviral vector (EAd). We demonstrated, by immunohistochemistry and qPCR, the expression of EphA2 in 100% (16/16) of the pHGGs, its intensity correlating significantly with a worst outcome. We then tested the transgene amplification, after co-infection, on two HGG cell lines (U373, U87) by qPCR and Flow Cytometry (FACS) for the selectable marker ∆CD19, confirming a significantly enhanced production in OA+EAd vs EAd alone (p&lt;0.01 and p&lt;0.001, respectively). Notably, the FACS analysis of the infected tumor cells after 5 days of co-culture with T-cells showed a significantly increased apoptosis in the OA+EAd compared to the controls (p&lt;0.001). To obtain the tumor eradication, we then fully activated the T-cells by including an anti-CD28 antibody (αCD28), revealing a further apoptosis enhancement. We then characterized the T-cell populations by FACS analysis showing a significant increase of activation and non-exhaustion markers and the addition of the αCD28 was able to induce a significantly higher production of interferon-γ in EAd or OA+EAd conditions. Finally, we established an orthotopic HGG mouse model and administered OA/Ead/OA+EAd and T cells intracranially. Preliminary data show that the treatment is well tolerated and that the EphA2-BiTE improves tumor control compared to the control groups. In conclusion, the combinatorial approach is able to amplify the production of the BiTE and to determine an effective tumor control in the presence of T-cells and αCD28, representing a promising innovative treatment.</description><identifier>ISSN: 1522-8517</identifier><identifier>EISSN: 1523-5866</identifier><identifier>DOI: 10.1093/neuonc/noz036.133</identifier><language>eng</language><publisher>US: Oxford University Press</publisher><subject>Immunology/Immunotherapy</subject><ispartof>Neuro-oncology (Charlottesville, Va.), 2019-04, Vol.21 (Supplement_2), p.ii95-ii95</ispartof><rights>The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. 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NOVEL APPROACH FOR THE TREATMENT OF PEDIATRIC HIGH-GRADE GLIOMAS WITH THE COMBINATION OF ONCOLYTIC ADENOVIRUSES AND GENE THERAPY ENCODING A BiTE DIRECTED TO THE EphA2 TUMOR ANTIGEN</title><title>Neuro-oncology (Charlottesville, Va.)</title><description>Abstract Pediatric high-grade gliomas (pHGG) are amongst the most common malignant neoplasms of childhood, whose outcome remains dismal with conventional treatments. New therapeutic approaches are urgently needed. Immunotherapy based on Oncolytic Adenovirus(OA)is a promising strategy but its efficacy is suboptimal. We aimed at improving the antitumor efficacy by combining the OA and a gene-therapy with the Bibispecific T-cell Engager (BiTE) directed towards the erythropoietin-producing human hepatocellular carcinoma A2-receptor (EphA2),conveyed by a replication-incompetent adenoviral vector (EAd). We demonstrated, by immunohistochemistry and qPCR, the expression of EphA2 in 100% (16/16) of the pHGGs, its intensity correlating significantly with a worst outcome. We then tested the transgene amplification, after co-infection, on two HGG cell lines (U373, U87) by qPCR and Flow Cytometry (FACS) for the selectable marker ∆CD19, confirming a significantly enhanced production in OA+EAd vs EAd alone (p&lt;0.01 and p&lt;0.001, respectively). Notably, the FACS analysis of the infected tumor cells after 5 days of co-culture with T-cells showed a significantly increased apoptosis in the OA+EAd compared to the controls (p&lt;0.001). To obtain the tumor eradication, we then fully activated the T-cells by including an anti-CD28 antibody (αCD28), revealing a further apoptosis enhancement. We then characterized the T-cell populations by FACS analysis showing a significant increase of activation and non-exhaustion markers and the addition of the αCD28 was able to induce a significantly higher production of interferon-γ in EAd or OA+EAd conditions. Finally, we established an orthotopic HGG mouse model and administered OA/Ead/OA+EAd and T cells intracranially. Preliminary data show that the treatment is well tolerated and that the EphA2-BiTE improves tumor control compared to the control groups. 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NOVEL APPROACH FOR THE TREATMENT OF PEDIATRIC HIGH-GRADE GLIOMAS WITH THE COMBINATION OF ONCOLYTIC ADENOVIRUSES AND GENE THERAPY ENCODING A BiTE DIRECTED TO THE EphA2 TUMOR ANTIGEN</atitle><jtitle>Neuro-oncology (Charlottesville, Va.)</jtitle><date>2019-04-23</date><risdate>2019</risdate><volume>21</volume><issue>Supplement_2</issue><spage>ii95</spage><epage>ii95</epage><pages>ii95-ii95</pages><issn>1522-8517</issn><eissn>1523-5866</eissn><abstract>Abstract Pediatric high-grade gliomas (pHGG) are amongst the most common malignant neoplasms of childhood, whose outcome remains dismal with conventional treatments. New therapeutic approaches are urgently needed. Immunotherapy based on Oncolytic Adenovirus(OA)is a promising strategy but its efficacy is suboptimal. We aimed at improving the antitumor efficacy by combining the OA and a gene-therapy with the Bibispecific T-cell Engager (BiTE) directed towards the erythropoietin-producing human hepatocellular carcinoma A2-receptor (EphA2),conveyed by a replication-incompetent adenoviral vector (EAd). We demonstrated, by immunohistochemistry and qPCR, the expression of EphA2 in 100% (16/16) of the pHGGs, its intensity correlating significantly with a worst outcome. We then tested the transgene amplification, after co-infection, on two HGG cell lines (U373, U87) by qPCR and Flow Cytometry (FACS) for the selectable marker ∆CD19, confirming a significantly enhanced production in OA+EAd vs EAd alone (p&lt;0.01 and p&lt;0.001, respectively). Notably, the FACS analysis of the infected tumor cells after 5 days of co-culture with T-cells showed a significantly increased apoptosis in the OA+EAd compared to the controls (p&lt;0.001). To obtain the tumor eradication, we then fully activated the T-cells by including an anti-CD28 antibody (αCD28), revealing a further apoptosis enhancement. We then characterized the T-cell populations by FACS analysis showing a significant increase of activation and non-exhaustion markers and the addition of the αCD28 was able to induce a significantly higher production of interferon-γ in EAd or OA+EAd conditions. Finally, we established an orthotopic HGG mouse model and administered OA/Ead/OA+EAd and T cells intracranially. Preliminary data show that the treatment is well tolerated and that the EphA2-BiTE improves tumor control compared to the control groups. 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title IMMU-12. NOVEL APPROACH FOR THE TREATMENT OF PEDIATRIC HIGH-GRADE GLIOMAS WITH THE COMBINATION OF ONCOLYTIC ADENOVIRUSES AND GENE THERAPY ENCODING A BiTE DIRECTED TO THE EphA2 TUMOR ANTIGEN
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