Oncolytic Immunotherapy Laboratory

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Regarding recent FDA breakthrough status for poliotherapy, please visit Duke Health.

 

BASIC RESEARCH CURRENTLY UNDERWAY

We are studying PVSRIPO, a recombinant poliovirus that is a fusion of the human rhinovirus 2 (HRV2, a basic cold-causing virus) and the live attenuated vaccine strain of poliovirus

  • PVSRIPO is growth attenuated in normal tissue but is capable of replicating in cancer cells
    • The empirical rationale for targeting cancer with oncolytic polioviruses is based on a) ectopic expression of the poliovirus receptor Necl5/CD155 in almost all cancers; b) tumor-specific cell killing by PVS-RIPO due to constitutively active MAPK signals to protein synthesis machinery
  • PVSRIPO is in general clinical trials as a treatment of recurrent glioblastoma multiforme (GBM), an extremely aggressive form of brain cancer. Investigator-initiated Investigational New Drug application (IND no. 14,735); clinicaltrials.gov trial no. NCT01491893.
  • PVSRIPO as an immunotherapeutic agent

What we know so far:

  • treatment of tumors with PVSRIPO has led to long-term survival of some patients
  • we believe the agent is causing tumor-specific adaptive immunity based on T-cell mediated cytotoxicity
  • we believe this adaptive immune response is a key component in treatment efficacy

How PVSRIPO triggers this anti-tumor response is the focus of our investigation.

PROJECTS IN LAB

1. PVSRIPO is capable of infecting innate immune cells (macrophages and dendritic cells) without killing the cells. This promotes activation of both types of cells -- in vitro studies have shown activation of dendritic cells leads to tumor-antigen specific activation of cytotoxic T-cells [currently under peer review]

2. Testing of PVSRIPO in other high-impact tumor types, including prostate, pancreatic and inflammatory breast cancers (not yet published)

3. PVSRIPO as a tumor vaccine adjuvant (not yet published)

4. The interplay of viral mediated innate immune activation and the downstream antitumor adaptive immune responses (not yet published)

5. Translation initiation in cancer cells and how it effects viral propagation of the oncolytic agent, PVSRIPO (published)

 

Fig 1: Major signal transduction pathways converging on protein synthesis machinery

Key biological properties of malignancy, e.g. unhinged cell cycle control, metabolic/hypoxic stress resistance, improper apoptotic/survival regulation, involve translation control. These properties of malignancy also seem to determine PVSRIPOs replication capacity in cancer cells and attenuation in normal cells.

Areas under investigation include:
• Mitogen-activated protein kinase (MAPK) signals to the translation initiation helicase complex and their role in translation initiation control
• MAPK signal convergence on Mnk and its role in oncogenesis
• Translation control of mitosis
• The translation control response to stress/pro-inflammatory cytokine signals
• The functional effects of signal transduction to the central scaffold and ribosome adaptor of the translation apparatus, the eukaryotic initiation factor 4G

 

Lab Director

Matthias Gromeier, MD
Professor of Neurosurgery
Duke University Medical Center
Box 3020
Durham, NC 27710

Phone: 919-668-6205
Fax: 919-681-4991
E-mail: gromeierlab@duke.edu

Current Lab Members

  • Mikhail Dobrikov, PhD
  • Elena Dobrikova, PhD
  • Michael Brown, PhD
  • Jeffrey Bryant, PhD candidate
  • Ross Walton, PhD candidate
  • John Kastan, graduate student
  • Mubeen Mosaheb, graduate student

Collaborating Duke Labs:

Darell Bigner, PhD

Smita Nair, MD

Representative Publications

  • Brown MC, Gromeier M (2015) Cytotoxic and immunogenic mechanisms of recombinant oncolytic poliovirus. Curr Opin Virol. 13:81-5. PMID: 26083317
  • Brown MC, Dobrikov MI, Gromeier M (2014) Mitogen-activated protein kinase-interacting kinase regulates mTOR/AKT signaling and controls the serine/arginine-rich protein kinase-responsive type 1 internal ribosome entry site-mediated translation and viral oncolysis. J Virol. 88(22):13149-60. PMID: 25187540
  • Dobrikov MI, Shveygert M, Brown MC, Gromeier M (2014) Mitotic phosphorylation of eukaryotic initiation factor 4G1 (eIF4G1) at Ser1232 by Cdk1:cyclin B inhibits eIF4A helicase complex binding with RNA. Mol Cell Biol. 34(3):439-51. PMID: 24248602
  • Lawson SK, Dobrikova EY, Shveygert M, Gromeier M (2013) p38α mitogen-activated protein kinase depletion and repression of signal transduction to translation machinery by miR-124 and -128 in neurons. Mol Cell Biol. 33(1):127-35. PMID: 23109423
  • Dobrikova EY, Goetz C, Walters RW, Lawson SK, Peggins JO, Muszynski K, Ruppel S, Poole K, Giardina SL, Vela EM, Estep JE, Gromeier M (2012) Attenuation of neurovirulence, biodistribution, and shedding of a poliovirus:rhinovirus chimera after intrathalamic inoculation in Macaca fascicularis. J Virol. 86(5):2750-9. PMID: 22171271
  • Goetz C, Dobrikova E, Shveygert M, Dobrikov M, Gromeier M (2011) Oncolytic poliovirus against malignant glioma. Future Virol. 6(9):1045-1058. PMID: 21984883
  • Goetz C, Everson RG, Zhang LC, Gromeier M (2010) MAPK signal-integrating kinase controls cap-independent translation and cell type-specific cytotoxicity of an oncolytic poliovirus. Mol Ther. 18(11):1937-46. PMID: 20648000
  • Goetz C, Gromeier M (2010) Preparing an oncolytic poliovirus recombinant for clinical application against glioblastoma multiforme. Cytokine Growth Factor Rev. 21(2-3):197-203. doi: 10.1016/j.cytogfr.2010.02.005. PMID: 20299272
  • Merrill MK, Gromeier M (2006) The double-stranded RNA binding protein 76:NF45 heterodimer inhibits translation initiation at the rhinovirus type 2 internal ribosome entry site. J Virol. 80(14):6936-42. PMID: 16809299
  • Gromeier M, Lachmann S, Rosenfeld MR, Gutin PH, Wimmer E (2000) Intergeneric poliovirus recombinants for the treatment of malignant glioma. Proc Natl Acad Sci U S A 97(12):6803-8. PMID: 10841575