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:

Cancer Immunotherapy Through Intratumoral Activation of Recall Responses

Administered By
Neurosurgery
Role
Principal Investigator
Start Date
End Date

Oncolytic Immunotherapy of Glioblastoma with Recombinant Poliovirus

Administered By
Neurosurgery
Role
Principal Investigator
Start Date
End Date

Phase II/III Manufacture of the Oncolytic Poliovirus Chimera, PVSRIPO

Administered By
Neurosurgery
Role
Principal Investigator
Start Date
End Date

Oncolytic poliovirus therapy of malignant glioma

Administered By
Neurosurgery, Neuro-Oncology
Role
Principal Investigator
Start Date
End Date

Transgenic Mouse Model for the Common Cold

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

Publications:

Improved efficacy against malignant brain tumors with EGFRwt/EGFRvIII targeting immunotoxin and checkpoint inhibitor combinations.

BACKGROUND: D2C7-IT is a novel immunotoxin (IT) targeting wild-type epidermal growth factor receptor (EGFRwt) and mutant EGFR variant III (EGFRvIII) proteins in glioblastoma. In addition to inherent tumoricidal activity, immunotoxins induce secondary immune responses through the activation of T cells. However, glioblastoma-induced immune suppression is a major obstacle to an effective and durable immunotoxin-mediated antitumor response. We hypothesized that D2C7-IT-induced immune response could be effectively augmented in combination with αCTLA-4/αPD-1/αPD-L1 therapies in murine models of glioma. METHODS: To study this, we overexpressed the D2C7-IT antigen, murine EGFRvIII (dmEGFRvIII), in established glioma lines, CT-2A and SMA560. The reactivity and therapeutic efficacy of D2C7-IT against CT-2A-dmEGFRvIII and SMA560-dmEGFRvIII cells was determined by flow cytometry and in vitro cytotoxicity assays, respectively. Antitumor efficacy of D2C7-IT was examined in immunocompetent, intracranial murine glioma models and the role of T cells was assessed by CD4+ and CD8+ T cell depletion. In vivo efficacy of D2C7-IT/αCTLA-4/αPD-1 monotherapy or D2C7-IT+αCTLA-4/αPD-1 combination therapy was evaluated in subcutaneous unilateral and bilateral CT-2A-dmEGFRvIII glioma-bearing immunocompetent mice. Further, antitumor efficacy of D2C7-IT+αCTLA-4/αPD-1/αPD-L1/αTim-3/αLag-3/αCD73 combination therapy was evaluated in intracranial CT-2A-dmEGFRvIII and SMA560-dmEGFRvIII glioma-bearing mice. Pairwise differences in survival curves were assessed using the generalized Wilcoxon test. RESULTS: D2C7-IT effectively killed CT-2A-dmEGFRvIII (IC50 = 0.47 ng/mL) and SMA560-dmEGFRvIII (IC50 = 1.05 ng/mL) cells in vitro. Treatment of intracranial CT-2A-dmEGFRvIII and SMA560-dmEGFRvIII tumors with D2C7-IT prolonged survival (P = 0.0188 and P = 0.0057, respectively), which was significantly reduced by the depletion of CD4+ and CD8+ T cells. To augment antitumor immune responses, we combined D2C7-IT with αCTLA-4/αPD-1 in an in vivo subcutaneous CT-2A-dmEGFRvIII model. Tumor-bearing mice exhibited complete tumor regressions (4/10 in D2C7-IT+αCTLA-4 and 5/10 in D2C7-IT+αPD-1 treatment groups), and combination therapy-induced systemic antitumor response was effective against both dmEGFRvIII-positive and dmEGFRvIII-negative CT-2A tumors. In a subcutaneous bilateral CT-2A-dmEGFRvIII model, D2C7-IT+αCTLA-4/αPD-1 combination therapies showed dramatic regression of the treated tumors and measurable regression of untreated tumors. Notably, in CT-2A-dmEGFRvIII and SMA560-dmEGFRvIII intracranial glioma models, D2C7-IT+αPD-1/αPD-L1 combinations improved survival, and in selected cases generated cures and protection against tumor re-challenge. CONCLUSIONS: These data support the development of D2C7-IT and immune checkpoint blockade combinations for patients with malignant glioma.
Authors
Chandramohan, V; Bao, X; Yu, X; Parker, S; McDowall, C; Yu, Y-R; Healy, P; Desjardins, A; Gunn, MD; Gromeier, M; Nair, SK; Pastan, IH; Bigner, DD
MLA Citation
Chandramohan, Vidyalakshmi, et al. “Improved efficacy against malignant brain tumors with EGFRwt/EGFRvIII targeting immunotoxin and checkpoint inhibitor combinations..” J Immunother Cancer, vol. 7, no. 1, May 2019. Pubmed, doi:10.1186/s40425-019-0614-0.
URI
https://scholars.duke.edu/individual/pub1388030
PMID
31142380
Source
pubmed
Published In
Journal for Immunotherapy of Cancer
Volume
7
Published Date
Start Page
142
DOI
10.1186/s40425-019-0614-0

Oncolytic immunotherapy through tumor-specific translation and cytotoxicity of poliovirus.

Achieving tumor-specific, robust, and durable effector cytotoxic immune responses is key to successful immunotherapy. This has been accomplished with adoptive cell transfer of ex vivo-expanded autologous tumor-infiltrating or engineered T cells, or with immune checkpoint inhibitors, enhancing inherent T cell reactivity. A natural ability to recruit effector responses makes tumor-targeting ('oncolytic') viruses attractive as immunotherapy vehicles. However, most viruses actively block inflammatory and immunogenic events; or, host innate immune responses may prevent immune initiating events in the first place. Moreover, the mechanisms of how virus infection can produce effector responses against host (tumor) neo-antigens are unclear. We are pioneering oncolytic immunotherapy based on poliovirus, which has no specific mechanism to interfere with host immune activation, exhibits lytic cytotoxicity in the presence of an antiviral interferon response and pre-existing immunity, and engages a powerful innate immune sensor implicated in recruiting cytotoxic T cell responses. Central to this approach is a unique confluence of factors that drive tumor-specific viral translation and cytotoxicity.
Authors
Brown, MC; Gromeier, M
MLA Citation
Brown, Michael C., and Matthias Gromeier. “Oncolytic immunotherapy through tumor-specific translation and cytotoxicity of poliovirus..” Discov Med, vol. 19, no. 106, May 2015, pp. 359–65.
URI
https://scholars.duke.edu/individual/pub1075599
PMID
26105699
Source
pubmed
Published In
Discov Med
Volume
19
Published Date
Start Page
359
End Page
365

Preparing an oncolytic poliovirus recombinant for clinical application against glioblastoma multiforme.

PVS-RIPO is a genetically recombinant, non-pathogenic poliovirus chimera with a tumor-specific conditional replication phenotype. Consisting of the genome of the live attenuated poliovirus type 1 (Sabin) vaccine with its cognate IRES element replaced with that of human rhinovirus type 2, PVS-RIPO displays an inability to translate its genome in untransformed neuronal cells, but effectively does so in cells originating from primary tumors in the central nervous system or other cancers. Hence, PVS-RIPO unleashes potent cytotoxic effects on infected cancer cells and produces sustained anti-tumoral responses in animal tumor models. PVS-RIPO presents a novel approach to the treatment of patients with glioblastoma multiforme, based on conditions favoring an unconventional viral translation initiation mechanism in cancerous cells. In this review we summarize advances in the understanding of major molecular determinants of PVS-RIPO oncolytic efficacy and safety and discuss their implications for upcoming clinical investigations.
MLA Citation
Goetz, Christian, and Matthias Gromeier. “Preparing an oncolytic poliovirus recombinant for clinical application against glioblastoma multiforme..” Cytokine Growth Factor Rev, vol. 21, no. 2–3, Apr. 2010, pp. 197–203. Pubmed, doi:10.1016/j.cytogfr.2010.02.005.
URI
https://scholars.duke.edu/individual/pub721583
PMID
20299272
Source
pubmed
Published In
Cytokine Growth Factor Rev
Volume
21
Published Date
Start Page
197
End Page
203
DOI
10.1016/j.cytogfr.2010.02.005

Cell-type-specific repression of internal ribosome entry site activity by double-stranded RNA-binding protein 76.

Translation of picornavirus plus-strand RNA genomes occurs via internal ribosomal entry at highly structured 5' untranslated regions. In addition to canonical translation factors, translation rate is likely influenced by supplementary host and viral trans-acting factors. We previously reported that insertion of a heterologous human rhinovirus type 2 internal ribosomal entry site (IRES) into the poliovirus (PV) genome, generating the chimeric virus PV-RIPO, selectively abrogates viral translation and propagation in neurons, which eliminate poliovirus's signature neuropathogenicity. While severely deficient in cells of neuronal lineage, the rhinovirus IRES promotes efficient propagation of PV-RIPO in cancer cells. Tumor-specific IRES function can be therapeutically exploited to direct viral cytotoxicity to cancer cells. Neuron-glioma heterokaryon analysis implicates neuronal trans-dominant inhibition in this effect, suggesting that host trans-acting factors repress IRES function in a cell-type-specific manner. We identified a set of proteins from neuronal cells with affinity for the rhinovirus IRES, including double-stranded RNA-binding protein 76 (DRBP76). DRBP76 associates with the IRES in neuronal but not in malignant glioma cells. Moreover, DRBP76 depletion in neuronal cells enhances rhinovirus IRES-driven translation and virus propagation. Our observations suggest that cell-type-specific association of DRBP76 with the rhinovirus IRES represses PV-RIPO translation and propagation in neuronal cells.
Authors
Merrill, MK; Dobrikova, EY; Gromeier, M
MLA Citation
Merrill, Melinda K., et al. “Cell-type-specific repression of internal ribosome entry site activity by double-stranded RNA-binding protein 76..” J Virol, vol. 80, no. 7, Apr. 2006, pp. 3147–56. Pubmed, doi:10.1128/JVI.80.7.3147-3156.2006.
URI
https://scholars.duke.edu/individual/pub721607
PMID
16537583
Source
pubmed
Published In
Journal of Virology
Volume
80
Published Date
Start Page
3147
End Page
3156
DOI
10.1128/JVI.80.7.3147-3156.2006

Oncolytic Viruses for Cancer Therapy

After being recognized for their antineoplastic properties at the beginning of the last century, viruses are again being considered for use as therapeutic agents against cancer. Certain species of virus have a propensity to replicate within transformed cells, commonly rendered vulnerable because of tumor-specific defects in their defense against viral infection. Other viruses have been modified to tumor-specific growth conditions. Oncolytic viruses carry the promise to efficiently target cancer cells for destruction and spread throughout tumor tissue to reach distant neoplastic loci without causing collateral damage to healthy tissues. In contrast to conventional cancer chemotherapy, viral antineoplastic agents require complex interactions with the host organism to reach their target and to develop oncolytic activity. Recent progress in the elucidation of the molecular mechanisms of viral pathogenesis has opened up new opportunities to manipulate virus-host interactions, generating effective antitumor strategies. On the other hand, significant obstacles towards the application of safe and efficacious viral therapies have become apparent. These frequently relate to the lack of cell culture and animal tumor models that accurately reflect the characteristics of cancerous tissues in patients. Throughout the past century, viral therapeutics against cancer has evolved into a new class of treatment strategies characterized by unique opportunities and challenges. A growing number of oncolytic viruses have entered clinical investigation or are scheduled to do so in the near future. Great efforts are being undertaken to rekindle an old idea and, with the help of new technologies, to realize its promise of new treatment options for cancer.
Authors
MLA Citation
Gromeier, M. “Oncolytic Viruses for Cancer Therapy.” American Journal of Cancer, vol. 2, no. 5, Nov. 2003, pp. 313–23. Scopus, doi:10.2165/00024669-200302050-00002.
URI
https://scholars.duke.edu/individual/pub774780
Source
scopus
Published In
American Journal of Cancer
Volume
2
Published Date
Start Page
313
End Page
323
DOI
10.2165/00024669-200302050-00002