EXTH-51. GENETICALLY STABLE POLIOVIRUS VECTOR PLATFORM FOR DIPG IMMUNOTHERAPY
Abstract Options for the immunotherapy of diffuse intrinsic pontine glioma (DIPG), due to its anatomical location and inherent therapy resistance, are limited. The histone 3.3(K27M) mutation in ~80% of such tumors offers a unique opportunity for immunotherapy intervention, as it defines a high affin...
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Published in | Neuro-oncology (Charlottesville, Va.) Vol. 21; no. Supplement_6; p. vi93 |
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Main Authors | , , , , , |
Format | Journal Article |
Language | English |
Published |
US
Oxford University Press
11.11.2019
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Subjects | |
Online Access | Get full text |
ISSN | 1522-8517 1523-5866 |
DOI | 10.1093/neuonc/noz175.382 |
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Abstract | Abstract
Options for the immunotherapy of diffuse intrinsic pontine glioma (DIPG), due to its anatomical location and inherent therapy resistance, are limited. The histone 3.3(K27M) mutation in ~80% of such tumors offers a unique opportunity for immunotherapy intervention, as it defines a high affinity, HLA-A2-restricted tumor neoantigen that spontaneously elicits CD8+ T cell responses in DIPG patients. Immunizing against the H3.3(K27M) signature in the clinic has been challenging, as conventional approaches (i.e. peptide-conjugates administered with adjuvants) lack the costimulatory signals known to drive CD8+ effector T cell responses. Therefore, we built on a viral vector approach for engaging innate immune responses to virus infection specifically in antigen presenting cells. Viruses naturally engage innate immunity, induce antigen presentation, and mediate CD8 T cell priming against foreign antigens. Polioviruses can provide a context optimal for generating antigen-specific CD8 T cells, as they have natural tropism for dendritic cells, preeminent inducers of CD8 T cell immunity; elicit Th1-promoting inflammation; and lack interference with innate or adaptive immunity. However, notorious genetic instability and underlying neuropathogenicity has hampered poliovirus-based vector applications. We devised a strategy based on the polio:rhinovirus chimera PVSRIPO, devoid of viral neuropathogenicity after intracerebral inoculation in human subjects, for stable expression of exogenous antigens. PVSRIPO vectors infect, activate, and induce epitope presentation in DCs in vitro; recruit and activate DCs with Th1-dominant cytokine profiles at the injection site in vivo. They efficiently prime tumor antigen-specific CD8 T cells in vivo, induce CD8 T cell migration to the tumor site, delay tumor growth and enhance survival in syngeneic rodent tumor models. We are preparing a prototype PVSRIPO-derived vector delivering the H3.3(K27M) signature for clinical investigation. |
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AbstractList | Options for the immunotherapy of diffuse intrinsic pontine glioma (DIPG), due to its anatomical location and inherent therapy resistance, are limited. The histone 3.3(K27M) mutation in ~80% of such tumors offers a unique opportunity for immunotherapy intervention, as it defines a high affinity, HLA-A2-restricted tumor neoantigen that spontaneously elicits CD8+ T cell responses in DIPG patients. Immunizing against the H3.3(K27M) signature in the clinic has been challenging, as conventional approaches (i.e. peptide-conjugates administered with adjuvants) lack the costimulatory signals known to drive CD8+ effector T cell responses. Therefore, we built on a viral vector approach for engaging innate immune responses to virus infection specifically in antigen presenting cells. Viruses naturally engage innate immunity, induce antigen presentation, and mediate CD8 T cell priming against foreign antigens. Polioviruses can provide a context optimal for generating antigen-specific CD8 T cells, as they have natural tropism for dendritic cells, preeminent inducers of CD8 T cell immunity; elicit Th1-promoting inflammation; and lack interference with innate or adaptive immunity. However, notorious genetic instability and underlying neuropathogenicity has hampered poliovirus-based vector applications. We devised a strategy based on the polio:rhinovirus chimera PVSRIPO, devoid of viral neuropathogenicity after intracerebral inoculation in human subjects, for stable expression of exogenous antigens. PVSRIPO vectors infect, activate, and induce epitope presentation in DCs in vitro; recruit and activate DCs with Th1-dominant cytokine profiles at the injection site in vivo. They efficiently prime tumor antigen-specific CD8 T cells in vivo, induce CD8 T cell migration to the tumor site, delay tumor growth and enhance survival in syngeneic rodent tumor models. We are preparing a prototype PVSRIPO-derived vector delivering the H3.3(K27M) signature for clinical investigation. Abstract Options for the immunotherapy of diffuse intrinsic pontine glioma (DIPG), due to its anatomical location and inherent therapy resistance, are limited. The histone 3.3(K27M) mutation in ~80% of such tumors offers a unique opportunity for immunotherapy intervention, as it defines a high affinity, HLA-A2-restricted tumor neoantigen that spontaneously elicits CD8+ T cell responses in DIPG patients. Immunizing against the H3.3(K27M) signature in the clinic has been challenging, as conventional approaches (i.e. peptide-conjugates administered with adjuvants) lack the costimulatory signals known to drive CD8+ effector T cell responses. Therefore, we built on a viral vector approach for engaging innate immune responses to virus infection specifically in antigen presenting cells. Viruses naturally engage innate immunity, induce antigen presentation, and mediate CD8 T cell priming against foreign antigens. Polioviruses can provide a context optimal for generating antigen-specific CD8 T cells, as they have natural tropism for dendritic cells, preeminent inducers of CD8 T cell immunity; elicit Th1-promoting inflammation; and lack interference with innate or adaptive immunity. However, notorious genetic instability and underlying neuropathogenicity has hampered poliovirus-based vector applications. We devised a strategy based on the polio:rhinovirus chimera PVSRIPO, devoid of viral neuropathogenicity after intracerebral inoculation in human subjects, for stable expression of exogenous antigens. PVSRIPO vectors infect, activate, and induce epitope presentation in DCs in vitro; recruit and activate DCs with Th1-dominant cytokine profiles at the injection site in vivo. They efficiently prime tumor antigen-specific CD8 T cells in vivo, induce CD8 T cell migration to the tumor site, delay tumor growth and enhance survival in syngeneic rodent tumor models. We are preparing a prototype PVSRIPO-derived vector delivering the H3.3(K27M) signature for clinical investigation. |
Author | Gromeier, Matthias Brown, Michael Bigner, Darell Ashley, David Mosaheb, Mubeen Dobrikova, Elena |
AuthorAffiliation | Duke University Medical Center , Durham, NC, USA |
AuthorAffiliation_xml | – name: Duke University Medical Center , Durham, NC, USA |
Author_xml | – sequence: 1 givenname: Matthias surname: Gromeier fullname: Gromeier, Matthias organization: Duke University Medical Center, Durham, NC, USA – sequence: 2 givenname: Mubeen surname: Mosaheb fullname: Mosaheb, Mubeen organization: Duke University Medical Center, Durham, NC, USA – sequence: 3 givenname: Elena surname: Dobrikova fullname: Dobrikova, Elena organization: Duke University Medical Center, Durham, NC, USA – sequence: 4 givenname: Michael surname: Brown fullname: Brown, Michael organization: Duke University Medical Center, Durham, NC, USA – sequence: 5 givenname: Darell surname: Bigner fullname: Bigner, Darell organization: Duke University Medical Center, Durham, NC, USA – sequence: 6 givenname: David surname: Ashley fullname: Ashley, David organization: Duke University Medical Center, Durham, NC, USA |
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Copyright | The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com 2019 |
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Snippet | Abstract
Options for the immunotherapy of diffuse intrinsic pontine glioma (DIPG), due to its anatomical location and inherent therapy resistance, are limited.... Options for the immunotherapy of diffuse intrinsic pontine glioma (DIPG), due to its anatomical location and inherent therapy resistance, are limited. The... |
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SubjectTerms | Experimental Therapeutics |
Title | EXTH-51. GENETICALLY STABLE POLIOVIRUS VECTOR PLATFORM FOR DIPG IMMUNOTHERAPY |
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