Matthias Gromeier

Overview:

I am a classically trained virologist with a focus on molecular mechanisms of RNA virus pathogenesis. My career is dedicated to unraveling RNA virus:host relations and devising methods of exploiting them for cancer immunotherapy and vaccine design. My background is in translation regulation and mRNA metabolism, viral RNA sensing and innate immunity, and cancer immunology and immunotherapy. Basic mechanistic research in my laboratory is supporting an ambitious clinical translational research program with active multi-center clinical trials in several cancer indications. 

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, Stony Brook

Postdoctoral Associate, Molecular Genetics & Microbiology

State University of New York, Stony Brook

Grants:

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

Administered By
Neurosurgery, Neuro-Oncology Clinical Research
Awarded By
Michael Mosier Defeat DIPG Foundation
Role
Co Investigator
Start Date
End Date

Establishing a Rationale for PVSRIPO Immunotherapy in Newly Diagnosed GBM

Administered By
Neurosurgery
Awarded By
National Brain Tumor Society
Role
Principal Investigator
Start Date
End Date

Combining PVSRIPO Immunotherapy with Lomustine for the Treatment of Recurrent GBM

Administered By
Neurosurgery
Awarded By
National Brain Tumor Society
Role
Principal Investigator
Start Date
End Date

Cancer Immunotherapy Through Intratumoral Activation of Recall Responses

Administered By
Neurosurgery
Awarded By
National Cancer Center
Role
Principal Investigator
Start Date
End Date

Oncolytic Immunotherapy of Glioblastoma with Recombinant Poliovirus

Administered By
Neurosurgery
Awarded By
Blast Glioblastoma
Role
Principal Investigator
Start Date
End Date

Publications:

LUMINOS-101: Phase 2 study of PVSRIPO with pembrolizumab in recurrent glioblastoma.

Authors
Kelly, AT; Ambady, P; Brown, M; Butowski, N; Cavaliere, R; Curry, W; Desjardins, A; Franklin, L; Friedman, H; Gromeier, M; Jackson, L; Mixson, L; Ong, S; Randazzo, D; Sloan, A; Wen, P; Nichols., G
MLA Citation
Kelly, Andrea True, et al. “LUMINOS-101: Phase 2 study of PVSRIPO with pembrolizumab in recurrent glioblastoma.Cancer Research, vol. 81, no. 13, 2021.
URI
https://scholars.duke.edu/individual/pub1496094
Source
wos-lite
Published In
Cancer Research
Volume
81
Published Date

Enterovirus 2Apro Cleavage of the YTHDF m6A Readers Implicates YTHDF3 as a Mediator of Type I Interferon-Driven JAK/STAT Signaling.

Enteroviruses (EV) deploy two proteases that mediate viral polyprotein cleavage and host cell manipulation. Here, we report that EV 2A proteases cleave all three members of the YTHDF protein family, cytosolic N 6-methyladenosine (m6A) "readers" that regulate target mRNA fate. YTHDF protein cleavage occurs very early during infection, before viral translation is detected or cytopathogenic effects are observed. Preemptive YTHDF protein depletion enhanced viral translation and replication but only in cells with restrained viral translation, signs of inefficient 2A protease activity, and protective innate host immune responses. This effect corresponded with repression of interferon (IFN)-stimulated gene (ISG) induction, while type I/III IFN production was not significantly altered. Moreover, YTHDF3 depletion impaired JAK/STAT signaling in cells treated with type I, but not type II, IFN. YTHDF3 depletion's stimulatory effect on viral dynamics was dampened by JAK/STAT blockade and enhanced by type I IFN pretreatment of cells. We propose that EV 2A proteases cleave YTHDF proteins to antagonize ISG induction in infected cells.IMPORTANCE It is believed that ∼7,000 messenger RNAs (mRNAs) are subject to N 6-methyladenosine modification. The biological significance of this remains mysterious. The YTHDF m6A readers are three related proteins with high affinity for m6A-modified mRNA, yet their biological functions remain obscure. We discovered that polio/enteroviruses elicit very early proteolysis of YTHDF1 to 3 in infected cells. Our research demonstrates that YTHDF3 acts as a positive regulator of antiviral JAK/STAT signaling in response to positive single-strand RNA virus infection, enabling type I interferon (IFN)-mediated gene regulatory programs to unfurl in infected cells. Our observation of viral degradation of the YTHDF proteins demonstrates that they are key response modifiers in the innate antiviral immune response.
Authors
Kastan, JP; Tremblay, MW; Brown, MC; Trimarco, JD; Dobrikova, EY; Dobrikov, MI; Gromeier, M
MLA Citation
Kastan, Jonathan P., et al. “Enterovirus 2Apro Cleavage of the YTHDF m6A Readers Implicates YTHDF3 as a Mediator of Type I Interferon-Driven JAK/STAT Signaling.Mbio, vol. 12, no. 2, Apr. 2021. Pubmed, doi:10.1128/mBio.00116-21.
URI
https://scholars.duke.edu/individual/pub1480548
PMID
33849973
Source
pubmed
Published In
Mbio
Volume
12
Published Date
DOI
10.1128/mBio.00116-21

Phase I trial of intratumoral PVSRIPO in patients with unresectable, treatment-refractory melanoma.

BACKGROUND: While programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) antagonists have improved the prognosis for many patients with melanoma, around 60% fail therapy. PVSRIPO is a non-neurovirulent rhinovirus:poliovirus chimera that facilitates an antitumor immune response following cell entry via the poliovirus receptor CD155, which is expressed on tumor and antigen-presenting cells. Preclinical studies show that oncolytic virus plus anti-PD-1 therapy leads to a greater antitumor response than either agent alone, warranting clinical investigation. METHODS: An open-label phase I trial of intratumoral PVSRIPO in patients with unresectable melanoma (American Joint Committee on Cancer V.7 stage IIIB, IIIC, or IV) was performed. Eligible patients had disease progression on anti-PD-1 and V-raf murine sarcoma viral oncogene homolog B (BRAF)/mitogen activated protein kinase kinase (MEK) inhibitors (if BRAF mutant). The primary objective was to characterize the safety and tolerability of PVSRIPO. Twelve patients in four cohorts received a total of 1, 2 or 3 injections of PVSRIPO monotherapy, with 21 days between injections. RESULTS: PVSRIPO injections were well tolerated with no serious adverse events (SAEs) or dose-limiting toxicities (DLTs) reported. All adverse events (AEs) were grade (G) 1 or G2 (G1 pruritus most common at 58%); all but two PVSRIPO-treatment related AEs were localized to the injected or adjacent lesions (n=1 G1 hot flash, n=1 G1 fatigue). Four out of 12 patients (33%) achieved an objective response per immune-related response criteria (two observations, 4 weeks apart), including 4/6 (67%) who received three injections. In the four patients with in-transit disease, a pathological complete response (pCR) was observed in two (50%) patients. Following study completion, 11/12 patients (92%) reinitiated immune checkpoint inhibitor-based therapy, and 6/12 patients (50%) remained without progression at a median follow-up time of 18 months. CONCLUSION: Intratumoral PVSRIPO was well tolerated. Despite the limited number of PVSRIPO treatments relative to the overall lesion burden (67% patients>5 lesions), intratumoral PVSRIPO showed promising antitumor activity, with pCR in injected as well as non-injected lesions in select patients. TRIAL REGISTRATION NUMBER: NCT03712358.
Authors
Beasley, GM; Nair, SK; Farrow, NE; Landa, K; Selim, MA; Wiggs, CA; Jung, S-H; Bigner, DD; True Kelly, A; Gromeier, M; Salama, AK
MLA Citation
Beasley, Georgia M., et al. “Phase I trial of intratumoral PVSRIPO in patients with unresectable, treatment-refractory melanoma.J Immunother Cancer, vol. 9, no. 4, Apr. 2021. Pubmed, doi:10.1136/jitc-2020-002203.
URI
https://scholars.duke.edu/individual/pub1480357
PMID
33875611
Source
pubmed
Published In
Journal for Immunotherapy of Cancer
Volume
9
Published Date
DOI
10.1136/jitc-2020-002203

Intergeneric poliovirus recombinants for the treatment of malignant glioma

Authors
MLA Citation
GROMEIER, M. “Intergeneric poliovirus recombinants for the treatment of malignant glioma.” Proc Natl Acad Sci Usa, vol. 97, 2000, pp. 6803–08.
URI
https://scholars.duke.edu/individual/pub856923
Source
cinii-english
Published In
Proc Natl Acad Sci Usa
Volume
97
Published Date
Start Page
6803
End Page
6808

POLIOVIRUS RECEPTORS

Authors
WIMMER, E; HARBER, JJ; BIBB, JA; GROMEIER, M; LU, HH; BERNHARDT, G
MLA Citation
WIMMER, E., et al. “POLIOVIRUS RECEPTORS.” Cellular Receptors for Animal Viruses, edited by E. Wimmer, COLD SPRING HARBOR LABORATORY PRESS, 1994, pp. 101–27.
URI
https://scholars.duke.edu/individual/pub882120
Source
wos
Published In
Cellular Receptors for Animal Viruses
Published Date
Start Page
101
End Page
127

Research Areas:

Brain--Tumors
Cancer--Immunotherapy
Immunity, Innate
Peptide Chain Initiation, Translational
Vaccines
Virology