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Cancer Immunology Research
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Abstract A075: Preclinical analysis of combinatorial glioblastoma therapy with the prodrug-mediated gene therapy vector AdV-TK and immune checkpoint inhibition in GBM therapy

Maria Carmela Speranza, Kazue Kasai, Franz Ricklefs, Sarah R. Klein, Carmela Passaro, Hiroshi Nakashima, Johanna Kaufmann, Agnieszka Bronisz, Estuardo Aguilar-Cordova, Brian W. Guzik, Gordon J. Freeman, David A. Reardon, Patrick Wen, E. Antonio Chiocca and Sean E. Lawler
Maria Carmela Speranza
1Harvard Medical School - Brigham and Women's Hospital, Boston, MA;
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Kazue Kasai
1Harvard Medical School - Brigham and Women's Hospital, Boston, MA;
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Franz Ricklefs
1Harvard Medical School - Brigham and Women's Hospital, Boston, MA;
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Sarah R. Klein
2Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
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Carmela Passaro
1Harvard Medical School - Brigham and Women's Hospital, Boston, MA;
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Hiroshi Nakashima
1Harvard Medical School - Brigham and Women's Hospital, Boston, MA;
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Johanna Kaufmann
1Harvard Medical School - Brigham and Women's Hospital, Boston, MA;
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Agnieszka Bronisz
1Harvard Medical School - Brigham and Women's Hospital, Boston, MA;
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Estuardo Aguilar-Cordova
3Advantagene Inc., Auburndale, MA.
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Brian W. Guzik
3Advantagene Inc., Auburndale, MA.
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Gordon J. Freeman
2Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
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David A. Reardon
2Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
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Patrick Wen
2Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
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E. Antonio Chiocca
1Harvard Medical School - Brigham and Women's Hospital, Boston, MA;
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Sean E. Lawler
1Harvard Medical School - Brigham and Women's Hospital, Boston, MA;
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DOI: 10.1158/2326-6066.IMM2016-A075 Published November 2016
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Abstracts: Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; September 25-28, 2016; New York, NY

Abstract

While the brain has traditionally been considered to be an immune-privileged site, evidence supporting the use of immunotherapeutics has been rapidly accumulating. Given that virus-based cancer therapies can be immunostimulatory and immune-checkpoint inhibitors block tumor-induced T-cell exhaustion, the combination of these two approaches offers a potentially synergistic interaction. One of the molecular underpinnings of T-cell exhaustion is the expression of Programmed Death-1 (PD1) on T-cells that recognizes its ligand PD-L1. AdV-tk is an immunostimulatory virus-based approach, known as Gene-Mediated Cytotoxic Immunotherapy (GMCI), that involves the intra-tumoral delivery of a non-replicating adenoviral vector carrying the Herpes virus thymidine kinase gene(TK) followed by administration of an anti-herpetic prodrug(ganciclovir-GCV) and recently showed encouraging results in a Phase II trial in glioblastoma(Wheeler et al.,2016). To provide a rationale for this therapeutic combination we investigated PD-L1 expression during GMCI therapy in human and mouse glioma cells in vitro and found that there was a consistent increase in cell surface PD-L1 levels. Interestingly, this was not associated with an increase of mRNA or protein. We also show that GMCI induces a type-I interferon response, and that the release of IFNβ is at least partially responsible for autocrine/paracrine PD-L1 up-regulation. In vivo studies using an intracranial GL261 model showed high levels of long term survivors in the GMCI/PD1 combination (11/14), compared with GMCI (6/16), anti-PD1 (5/12) and controls (0/11). In addition, tumor infiltrating lymphocytes after GMCI showed an increase in CD8+, CD8+/GranzymeB+, and CD8+/IFNγ+/TNFα+cells suggestive of cytotoxic T-cell activation. However, there was also a significant increase in CD4+, CD4+/FoxP3+, and IL-10 indicating a significant infiltration by Tregs, releasing immunosuppressive cytokines. Additionally, there was a significant increase in PD1+/TIM3+ T-cells, indicative of an immunosuppressive microenvironment. Overall, our data show that GMCI/anti-PD1 combinatorial therapy is effective in a syngeneic tumor model, and strongly support clinical trials of GMCI/checkpoint inhibitor combinations in glioblastoma patients.

Citation Format: Maria Carmela Speranza, Kazue Kasai, Franz Ricklefs, Sarah R. Klein, Carmela Passaro, Hiroshi Nakashima, Johanna Kaufmann, Agnieszka Bronisz, Estuardo Aguilar-Cordova, Brian W. Guzik, Gordon J. Freeman, David A. Reardon, Patrick Wen, E. Antonio Chiocca, Sean E. Lawler. Preclinical analysis of combinatorial glioblastoma therapy with the prodrug-mediated gene therapy vector AdV-TK and immune checkpoint inhibition in GBM therapy [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A075.

  • ©2016 American Association for Cancer Research.
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Cancer Immunology Research: 4 (11 Supplement)
November 2016
Volume 4, Issue 11 Supplement
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Abstract A075: Preclinical analysis of combinatorial glioblastoma therapy with the prodrug-mediated gene therapy vector AdV-TK and immune checkpoint inhibition in GBM therapy
Maria Carmela Speranza, Kazue Kasai, Franz Ricklefs, Sarah R. Klein, Carmela Passaro, Hiroshi Nakashima, Johanna Kaufmann, Agnieszka Bronisz, Estuardo Aguilar-Cordova, Brian W. Guzik, Gordon J. Freeman, David A. Reardon, Patrick Wen, E. Antonio Chiocca and Sean E. Lawler
Cancer Immunol Res November 1 2016 (4) (11 Supplement) A075; DOI: 10.1158/2326-6066.IMM2016-A075

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Abstract A075: Preclinical analysis of combinatorial glioblastoma therapy with the prodrug-mediated gene therapy vector AdV-TK and immune checkpoint inhibition in GBM therapy
Maria Carmela Speranza, Kazue Kasai, Franz Ricklefs, Sarah R. Klein, Carmela Passaro, Hiroshi Nakashima, Johanna Kaufmann, Agnieszka Bronisz, Estuardo Aguilar-Cordova, Brian W. Guzik, Gordon J. Freeman, David A. Reardon, Patrick Wen, E. Antonio Chiocca and Sean E. Lawler
Cancer Immunol Res November 1 2016 (4) (11 Supplement) A075; DOI: 10.1158/2326-6066.IMM2016-A075
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  • Abstract B200: Single-cell RNA-sequencing (ScRNA-seq) reveals broad heterogeneity among CD8 T-cells during chronic viral infection and identifies a critical role for CD4 help in promoting the differentiation of a potent cytotoxic CD8 T-cell subset
  • Abstract B197: Translational control in macrophages during inflammatory response
Show more Other Topics: Poster Presentations - Proffered Abstracts
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