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

Cancer immunotherapy with recombinant poliovirus induces IFN-dominant activation of dendritic cells and tumor antigen-specific CTLs.

Tumors thrive in an immunosuppressive microenvironment that impedes antitumor innate and adaptive immune responses. Thus, approaches that can overcome immunosuppression and engage antitumor immunity are needed. This study defines the adjuvant and cancer immunotherapy potential of the recombinant poliovirus/rhinovirus chimera PVSRIPO. PVSRIPO is currently in clinical trials against recurrent World Health Organization grade IV malignant glioma, a notoriously treatment-refractory cancer. Cytopathogenic infection of neoplastic cells releases the proteome and exposes pathogen- and damage-associated molecular patterns. At the same time, sublethal infection of antigen-presenting cells, such as dendritic cells and macrophages, yields potent, sustained type I interferon-dominant activation in an immunosuppressed microenvironment and promotes the development of tumor antigen-specific T cell responses in vitro and antitumor immunity in vivo. PVSRIPO's immune adjuvancy stimulates canonical innate anti-pathogen inflammatory responses within the tumor microenvironment that culminate in dendritic cell and T cell infiltration. Our findings provide mechanistic evidence that PVSRIPO functions as a potent intratumor immune adjuvant that generates tumor antigen-specific cytotoxic T lymphocyte responses.
Authors
Brown, MC; Holl, EK; Boczkowski, D; Dobrikova, E; Mosaheb, M; Chandramohan, V; Bigner, DD; Gromeier, M; Nair, SK
MLA Citation
Brown, Michael C., et al. “Cancer immunotherapy with recombinant poliovirus induces IFN-dominant activation of dendritic cells and tumor antigen-specific CTLs.Sci Transl Med, vol. 9, no. 408, Sept. 2017. Pubmed, doi:10.1126/scitranslmed.aan4220.
URI
https://scholars.duke.edu/individual/pub1276144
PMID
28931654
Source
pubmed
Published In
Sci Transl Med
Volume
9
Published Date
DOI
10.1126/scitranslmed.aan4220

Phosphorylation of eukaryotic translation initiation factor 4G1 (eIF4G1) by protein kinase C{alpha} regulates eIF4G1 binding to Mnk1.

Signal transduction through mitogen-activated protein kinases (MAPKs) is implicated in growth and proliferation control through translation regulation and involves posttranslational modification of translation initiation factors. For example, convergent MAPK signals to Mnk1 lead to phosphorylation of eukaryotic translation initiation factor 4E (eIF4E), which has been linked to malignant transformation. However, understanding the compound effects of mitogenic signaling on the translation apparatus and on protein synthesis control remains elusive. This is particularly true for the central scaffold of the translation initiation apparatus and ribosome adaptor eIF4G. To unravel the effects of signal transduction to eIF4G on translation, we used specific activation of protein kinase C (PKC)-Ras-Erk signaling with phorbol esters. Phospho-proteomic and mutational analyses revealed that eIF4G1 is a substrate for PKCα at Ser1186. We show that PKCα activation elicits a cascade of orchestrated phosphorylation events that may modulate eIF4G1 structure and control interaction with the eIF4E kinase, Mnk1.
Authors
Dobrikov, M; Dobrikova, E; Shveygert, M; Gromeier, M
MLA Citation
Dobrikov, Mikhail, et al. “Phosphorylation of eukaryotic translation initiation factor 4G1 (eIF4G1) by protein kinase C{alpha} regulates eIF4G1 binding to Mnk1.Mol Cell Biol, vol. 31, no. 14, July 2011, pp. 2947–59. Pubmed, doi:10.1128/MCB.05589-11.
URI
https://scholars.duke.edu/individual/pub732030
PMID
21576361
Source
pubmed
Published In
Molecular and Cellular Biology
Volume
31
Published Date
Start Page
2947
End Page
2959
DOI
10.1128/MCB.05589-11

Genetic adaptation to untranslated region-mediated enterovirus growth deficits by mutations in the nonstructural proteins 3AB and 3CD.

Both untranslated regions (UTRs) of plus-strand RNA virus genomes jointly control translation and replication of viral genomes. In the case of the Enterovirus genus of the Picornaviridae family, the 5'UTR consists of a cloverleaf-like terminus preceding the internal ribosomal entry site (IRES) and the 3' terminus is composed of a structured 3'UTR and poly(A). The IRES and poly(A) have been implicated in translation control, and all UTR structures, in addition to cis-acting genetic elements mapping to the open reading frame, have been assigned roles in RNA replication. Viral UTRs are recognized by viral and host cell RNA-binding proteins that may co-determine genome stability, translation, plus- and minus-strand RNA replication, and scaffolding of viral replication complexes within host cell substructures. In this report, we describe experiments with coxsackie B viruses with a cell type-specific propagation deficit in Sk-N-Mc neuroblastoma cells conferred by the combination of a heterologous IRES and altered 3'UTR. Serial passage of these constructs in Sk-N-Mc cells yielded genetic adaptation by mutations within the viral nonstructural proteins 3A and 3C. Our data implicate 3A and/or 3C or their precursors 3AB and/or 3CD in a functional complex with the IRES and 3'UTR that drives viral propagation. Adaptation to neuroblastoma cells suggests an involvement of cell type-specific host factors or the host cell cytoplasmic milieu in this phenomenon.
Authors
Florez de Sessions, P; Dobrikova, E; Gromeier, M
MLA Citation
Florez de Sessions, Paola, et al. “Genetic adaptation to untranslated region-mediated enterovirus growth deficits by mutations in the nonstructural proteins 3AB and 3CD.J Virol, vol. 81, no. 16, Aug. 2007, pp. 8396–405. Pubmed, doi:10.1128/JVI.00321-07.
URI
https://scholars.duke.edu/individual/pub721622
PMID
17537861
Source
pubmed
Published In
Journal of Virology
Volume
81
Published Date
Start Page
8396
End Page
8405
DOI
10.1128/JVI.00321-07

Treatment of intracerebral neoplasia and neoplastic meningitis with regional delivery of oncolytic recombinant poliovirus.

PURPOSE: Spread to the central nervous system (CNS) and the leptomeninges is a frequent complication of systemic cancers that is associated with serious morbidity and high mortality. We have evaluated a novel therapeutic approach against CNS complications of breast cancer based on the human neuropathogen poliovirus (PV). EXPERIMENTAL DESIGN: Susceptibility to PV infection and ensuing rapid cell lysis is mediated by the cellular receptor of PV, CD155. We evaluated CD155 expression in several human breast tumor tissue specimens and cultured breast cancer cell lines. In addition, we tested an oncolytic PV recombinant for efficacy in xenotransplantation models of neoplastic meningitis and cerebral metastasis secondary to breast cancer. RESULTS: We observed that breast cancer tissues and cell lines derived thereof express CD155 at levels mediating exquisite sensitivity toward PV-induced oncolysis in the latter. An association with the immunoglobulin superfamily molecule CD155 renders breast cancer a likely target for oncolytic PV recombinants. This assumption was confirmed in xenotransplantation models for neoplastic meningitis or solitary cerebral metastasis, where local virus treatment dramatically improved survival. CONCLUSIONS: Our findings suggest oncolytic PV recombinants as a viable treatment option for CNS complications of breast cancer.
Authors
Ochiai, H; Moore, SA; Archer, GE; Okamura, T; Chewning, TA; Marks, JR; Sampson, JH; Gromeier, M
MLA Citation
Ochiai, Hidenobu, et al. “Treatment of intracerebral neoplasia and neoplastic meningitis with regional delivery of oncolytic recombinant poliovirus.Clin Cancer Res, vol. 10, no. 14, July 2004, pp. 4831–38. Pubmed, doi:10.1158/1078-0432.CCR-03-0694.
URI
https://scholars.duke.edu/individual/pub721619
PMID
15269159
Source
pubmed
Published In
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Volume
10
Published Date
Start Page
4831
End Page
4838
DOI
10.1158/1078-0432.CCR-03-0694