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Oncolytic Herpes simplex virus - 1 for the treatment of melanoma

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TitleInfo
Title
Oncolytic Herpes simplex virus - 1 for the treatment of melanoma
Name (type = personal)
NamePart (type = family)
Bommareddy
NamePart (type = given)
Praveen K.
NamePart (type = date)
1987-
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Praveen K. Bommareddy
Role
RoleTerm (authority = RULIB)
author
Name (type = personal)
NamePart (type = family)
Sant'Angelo
NamePart (type = given)
Derek
DisplayForm
Derek Sant'Angelo
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
chair
Name (type = corporate)
NamePart
Rutgers University
Role
RoleTerm (authority = RULIB)
degree grantor
Name (type = corporate)
NamePart
School of Graduate Studies
Role
RoleTerm (authority = RULIB)
school
TypeOfResource
Text
Genre (authority = marcgt)
theses
OriginInfo
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2019
DateOther (qualifier = exact); (type = degree)
2019-05
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2019
Language
LanguageTerm (authority = ISO 639-3:2007); (type = text)
English
Abstract (type = abstract)
Oncolytic viruses (OVs) are native or modified viruses that selectively replicate in and lyse tumor cells. The ability of OVs to selectively lyse tumor cells is attributed to disruption of both oncogenic cell signaling pathways and anti-viral machinery in cancer cells. In melanoma, rapidly dividing cells contain excessive pools of nucleotides that can also be used to enhance replication of attenuated OVs in these cells (1). In addition to the direct lytic effects, OVs are also thought to initiate innate and adaptive immune responses that contribute to both a direct and bystander effect that can promote tumor regression at injected and uninjected sites. The proof-of-concept for OVs in melanoma has recently been confirmed using Talimogene laherparepvec (Imlygic™; T-VEC), a modified form of herpes simplex virus-1 (HSV-1). T-VEC was generated from the JS1 staring of HSV-1 in which the infected cell protein (ICP) 34.5 neurovirulence genes are deleted to limit neurotoxicity and enhance cancer cell specific replication (2). T-VEC also contains a deletion of the herpes ICP47 gene, which otherwise functions to block peptide transport through the transporter associated with antigen processing (TAP) machinery, which the virus uses to avoid immune detection. In the absence of ICP47, tumor-derived and viral peptides should be presented and result in immune recognition. To further enhance anti-tumor immunity, two copies of the human GM-CSF gene have been encoded in T-VEC to promote dendritic cell infiltration and maturation at the tumor site and enhance subsequent tumor-associated antigen presentation to T cells. Therapeutic responses to T-VEC are often limited and targeted therapies such as BRAF and MEK inhibitors often fail due to recurrence of disease in melanoma. To date, combination MAPK inhibition and oncolytic virus therapy has not been clinically tested but this may be an important regimen to consider given the potential for combining agents acting at different parts of the cancer-immunity cycle. Thus, we hypothesized that MAPK inhibition would improve oncolytic virus responses since viral infection could help activate a more robust immune response. Further, we sought to evaluate this concept in melanoma given the frequency of BRAF mutations and the availability of approved MAPK inhibitors and an oncolytic virus for clinical testing. Here, we report a synergistic in vitro and in vivo therapeutic effect for MEK inhibition administered with T-VEC in both human xenograft and immune competent melanoma models. Oncolytic activity was not dependent on BRAF mutation status but was associated with increased viral replication, and the presence of melanoma antigen specific CD8+ T cells and basic leucine zipper transcription factor ATF-like 3 (Batf3+) CD103+ / CD8+ dendritic cells. In addition, we observed that combination treatment resulted in increased PD-1 and PD-L1 expression and found that therapeutic activity could be further expanded when PD-1 blockade was added to the treatment regimen. These data support triple combination therapy with MEK inhibition, oncolytic viruses and PD-1/PD-L1 checkpoint blockade for the treatment of melanoma. A better understanding of how T-VEC can kill melanoma tumor cells might also suggest new targets for combination therapy in melanoma and potentially other tumors permissive to oncolytic virus infection (3). Thus, next we sought to explore the molecular factors involved with T-VEC-mediated lysis melanoma cells and determine which intracellular factors are important for promoting viral replication and promoting anti-tumor immunity. We hypothesized that T-VEC would induce lysis through release of defined Damage-associated molecular patterns (DAMPs) and would promote T cell recruitment to established melanomas through type 1 interferon-related factors, as well as a pro-inflammatory gene signature profile. In addition, we found that specific components of the anti-viral machinery, such as STING, were critical for both T-VEC permissive replication and induction of host anti-tumor immunity. These data support the role of T-VEC in overcoming STING deficiency in melanoma cells and confirms how T-VEC mediates melanoma cell death and triggers innate and adaptive anti-tumor immunity. These data collectively enhance our understanding on how T-VEC can activate anti-tumor immune responses, further help to design rational clinical trials combining oncolytic Herpes simplex viruses and other approved agents in melanoma.
Subject (authority = local)
Topic
Oncolytic virus
Subject (authority = RUETD)
Topic
Microbiology and Molecular Genetics
Subject (authority = LCSH)
Topic
Herpes simplex
Subject (authority = LCSH)
Topic
Melanoma - Treatment
RelatedItem (type = host)
TitleInfo
Title
Rutgers University Electronic Theses and Dissertations
Identifier (type = RULIB)
ETD
Identifier
ETD_9567
PhysicalDescription
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application/pdf
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text/xml
Extent
1 online resource (xiii, 99 pages) : Illustrations
Note (type = degree)
Ph.D.
Note (type = bibliography)
Includes bibliographical references
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TitleInfo
Title
School of Graduate Studies Electronic Theses and Dissertations
Identifier (type = local)
rucore10001600001
Location
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NjNbRU
Identifier (type = doi)
doi:10.7282/t3-xh8f-n123
Genre (authority = ExL-Esploro)
ETD doctoral
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Rights

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The author owns the copyright to this work.
RightsHolder (type = personal)
Name
FamilyName
Bommareddy
GivenName
Praveen
MiddleName
K.
Role
Copyright Holder
RightsEvent
Type
Permission or license
DateTime (encoding = w3cdtf); (qualifier = exact); (point = start)
2019-03-04 12:03:05
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Name
Praveen Bommareddy
Role
Copyright holder
Affiliation
Rutgers University. School of Graduate Studies
AssociatedObject
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License
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Author Agreement License
Detail
I hereby grant to the Rutgers University Libraries and to my school the non-exclusive right to archive, reproduce and distribute my thesis or dissertation, in whole or in part, and/or my abstract, in whole or in part, in and from an electronic format, subject to the release date subsequently stipulated in this submittal form and approved by my school. I represent and stipulate that the thesis or dissertation and its abstract are my original work, that they do not infringe or violate any rights of others, and that I make these grants as the sole owner of the rights to my thesis or dissertation and its abstract. I represent that I have obtained written permissions, when necessary, from the owner(s) of each third party copyrighted matter to be included in my thesis or dissertation and will supply copies of such upon request by my school. I acknowledge that RU ETD and my school will not distribute my thesis or dissertation or its abstract if, in their reasonable judgment, they believe all such rights have not been secured. I acknowledge that I retain ownership rights to the copyright of my work. I also retain the right to use all or part of this thesis or dissertation in future works, such as articles or books.
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Type
Embargo
DateTime (encoding = w3cdtf); (qualifier = exact); (point = start)
2019-05-31
DateTime (encoding = w3cdtf); (qualifier = exact); (point = end)
2021-05-30
Detail
Access to this PDF has been restricted at the author's request. It will be publicly available after May 30th, 2021.
Copyright
Status
Copyright protected
Availability
Status
Open
Reason
Permission or license
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2019-03-04T16:57:22
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