Matthias Gromeier

Overview:

Neuro-Oncology
Protein Synthesis Regulation
Signal Transduction
Growth & Proliferation Control in Cancer
Oncolytic Viruses
Viral Neuropathogenesis
Immunization Vectors

Positions:

Professor of Neurosurgery

Neurosurgery, Neuro-Oncology
School of Medicine

Professor in Molecular Genetics and Microbiology

Molecular Genetics and Microbiology
School of Medicine

Professor in Medicine

Medicine, Infectious Diseases
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 1992

University of Hamburg (Germany)

Postdoctoral fellow, Molecular Genetics & Microbiology

State University of New York at Stony Brook

Postdoctoral Associate, Molecular Genetics & Microbiology

State University of New York at Stony Brook

Grants:

Recombinant Attenuated Poliovirus Immunization Vectors Targeting H3.3(K27M) in DIPG

Administered By
Neurosurgery, Neuro-Oncology Clinical Research
Role
Co Investigator
Start Date
End Date

Oncolytic PVSRIPO Expressing Tumor Antigens as a Cancer Vaccine

Administered By
Neurosurgery
Role
Principal Investigator
Start Date
End Date

Oncolytic Poliovirus Immunotherapy of Malignant Glioma

Administered By
Pathology
Role
Co Investigator
Start Date
End Date

Oncolytic Virotherapy of Meningeal Cancer

Administered By
Neurosurgery, Neuro-Oncology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Establishing a Rationale for PVSRIPO Immunotherapy in Newly Diagnosed GBM

Administered By
Neurosurgery
Role
Principal Investigator
Start Date
End Date

Publications:

Genetically stable poliovirus vectors activate dendritic cells and prime antitumor CD8 T cell immunity.

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. Here 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; they 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 murine tumor models.
Authors
Mosaheb, MM; Dobrikova, EY; Brown, MC; Yang, Y; Cable, J; Okada, H; Nair, SK; Bigner, DD; Ashley, DM; Gromeier, M
MLA Citation
Mosaheb, Mubeen M., et al. “Genetically stable poliovirus vectors activate dendritic cells and prime antitumor CD8 T cell immunity.Nat Commun, vol. 11, no. 1, Jan. 2020, p. 524. Pubmed, doi:10.1038/s41467-019-13939-z.
URI
https://scholars.duke.edu/individual/pub1428870
PMID
31988324
Source
pubmed
Published In
Nature Communications
Volume
11
Published Date
Start Page
524
DOI
10.1038/s41467-019-13939-z

Cytotoxic and immunogenic mechanisms of recombinant oncolytic poliovirus.

An oncolytic virus (OV) based on poliovirus (PV), the highly attenuated polio/rhinovirus recombinant PVSRIPO, may deliver targeted inflammatory cancer cell killing; a principle that is showing promise in clinical trials for recurrent glioblastoma (GBM). The two decisive factors in PVSRIPO anti-tumor efficacy are selective cytotoxicity and its in situ immunogenic imprint. While our work is focused on what constitutes PVSRIPO cancer cytotoxicity, we are also studying how this engenders host immune responses that are vital to tumor regression. We hypothesize that PVSRIPO cytotoxicity and immunogenicity are inextricably linked in essential, complimentary roles that define the anti-neoplastic response. Herein we delineate mechanisms we unraveled to decipher the basis for PVSRIPO cytotoxicity and its immunotherapeutic potential.
Authors
Brown, MC; Gromeier, M
MLA Citation
Brown, Michael C., and Matthias Gromeier. “Cytotoxic and immunogenic mechanisms of recombinant oncolytic poliovirus.Curr Opin Virol, vol. 13, Aug. 2015, pp. 81–85. Pubmed, doi:10.1016/j.coviro.2015.05.007.
URI
https://scholars.duke.edu/individual/pub1074528
PMID
26083317
Source
pubmed
Published In
Curr Opin Virol
Volume
13
Published Date
Start Page
81
End Page
85
DOI
10.1016/j.coviro.2015.05.007

Tissue type-specific expression of the dsRNA-binding protein 76 and genome-wide elucidation of its target mRNAs.

BACKGROUND: RNA-binding proteins accompany all steps in the life of mRNAs and provide dynamic gene regulatory functions for rapid adjustment to changing extra- or intracellular conditions. The association of RNA-binding proteins with their targets is regulated through changing subcellular distribution, post-translational modification or association with other proteins. METHODOLOGY: We demonstrate that the dsRNA binding protein 76 (DRBP76), synonymous with nuclear factor 90, displays inherently distinct tissue type-specific subcellular distribution in the normal human central nervous system and in malignant brain tumors of glial origin. Altered subcellular localization and isoform distribution in malignant glioma indicate that tumor-specific changes in DRBP76-related gene products and their regulatory functions may contribute to the formation and/or maintenance of these tumors. To identify endogenous mRNA targets of DRBP76, we performed RNA-immunoprecipitation and genome-wide microarray analyses in HEK293 cells, and identified specific classes of transcripts encoding critical functions in cellular metabolism. SIGNIFICANCE: Our data suggest that physiologic DRBP76 expression, isoform distribution and subcellular localization are profoundly altered upon malignant transformation. Thus, the functional role of DRBP76 in co- or post-transcriptional gene regulation may contribute to the neoplastic phenotype.
Authors
Neplioueva, V; Dobrikova, EY; Mukherjee, N; Keene, JD; Gromeier, M
MLA Citation
Neplioueva, Valentina, et al. “Tissue type-specific expression of the dsRNA-binding protein 76 and genome-wide elucidation of its target mRNAs.Plos One, vol. 5, no. 7, July 2010, p. e11710. Pubmed, doi:10.1371/journal.pone.0011710.
URI
https://scholars.duke.edu/individual/pub721590
PMID
20668518
Source
pubmed
Published In
Plos One
Volume
5
Published Date
Start Page
e11710
DOI
10.1371/journal.pone.0011710

Competitive translation efficiency at the picornavirus type 1 internal ribosome entry site facilitated by viral cis and trans factors.

Enteroviruses (EVs) overcome their host cells by usurping the translation machinery to benefit viral gene expression. This is accomplished through alternative translation initiation in a cap-independent manner at the viral internal ribosomal entry site (IRES). We have investigated the role of cis- and trans-acting viral factors in EV IRES translation in living cells. We observed that considerable portions of the viral genome, including the 5'-proximal open reading frame and the 3' untranslated region, contribute to stimulation of IRES-mediated translation. With the IRES in proper context, translation via internal initiation in uninfected cells is as efficient as at capped messages with short, unstructured 5' untranslated regions. IRES function is enhanced in cells infected with the EV coxsackievirus B3, but the related poliovirus has no significant stimulatory activity. This differential is due to the inherent properties of their 2A protease and is not coupled to 2A-mediated proteolytic degradation of the eukaryotic initiation factor 4G. Our results suggest that the efficiency of alternative translation initiation at EV IRESs depends on a properly configured template rather than on targeted alterations of the host cell translation machinery.
Authors
Dobrikova, EY; Grisham, RN; Kaiser, C; Lin, J; Gromeier, M
MLA Citation
Dobrikova, Elena Y., et al. “Competitive translation efficiency at the picornavirus type 1 internal ribosome entry site facilitated by viral cis and trans factors.J Virol, vol. 80, no. 7, Apr. 2006, pp. 3310–21. Pubmed, doi:10.1128/JVI.80.7.3310-3321.2006.
URI
https://scholars.duke.edu/individual/pub721585
PMID
16537598
Source
pubmed
Published In
Journal of Virology
Volume
80
Published Date
Start Page
3310
End Page
3321
DOI
10.1128/JVI.80.7.3310-3321.2006

Activity of a type 1 picornavirus internal ribosomal entry site is determined by sequences within the 3' nontranslated region.

We have proposed a cancer treatment modality based on poliovirus chimeras replicating under the translational control of an internal ribosomal entry site (IRES) derived from human rhinovirus type 2. Insertion of the heterologous IRES causes a neuron-specific propagation deficit and eliminates neurovirulence inherent in poliovirus without affecting viral growth in cells derived from malignant gliomas. We now report the elucidation of a molecular mechanism responsible for the cell type-specific defect mediated by the rhinovirus IRES. Rhinovirus IRES function in neuronal cell types depends on specific structural elements within the 3' non-translated region of the viral genome. Our observations suggest long-range interactions between the IRES and the 3' terminus that control IRES-mediated gene expression and virus propagation.
Authors
Dobrikova, E; Florez, P; Bradrick, S; Gromeier, M
MLA Citation
Dobrikova, Elena, et al. “Activity of a type 1 picornavirus internal ribosomal entry site is determined by sequences within the 3' nontranslated region.Proc Natl Acad Sci U S A, vol. 100, no. 25, Dec. 2003, pp. 15125–30. Pubmed, doi:10.1073/pnas.2436464100.
URI
https://scholars.duke.edu/individual/pub721604
PMID
14645707
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of the United States of America
Volume
100
Published Date
Start Page
15125
End Page
15130
DOI
10.1073/pnas.2436464100