Friday, May 13, 2016

Glioblastoma and polio virus

The Food and Drug Administration has given so-called "breakthrough" status to a treatment that uses the once-feared polio virus to target aggressive forms of brain cancer, in the hope of speeding it to market.

The therapy, developed at Duke University, hopes to use the virus’ debilitating properties to help fight cancer instead of harming its host, CBS News reported Thursday.

The experimental treatment was the brainchild of molecular biologist Matthias Gromeier. By removing a certain genetic sequence and replacing it with material from the common cold virus, the polio would not be able to cause the incapacitating symptoms that once afflicted President Franklin D. Roosevelt and numerous others because it would be unable to reproduce in normal cells.

However, the altered version of polio could still reproduce in cancer cells—therefore making the cancer susceptible to Lipscomb’s and other patients’ immune systems.

“All human cancers ... develop a shield of protective measures that make them invisible to this immune system,” Gromeier told CBS. “By infecting the tumor, we are actually removing this protective shield and enabling the immune system to attack."

While the altered polio virus initiates the fight against the cancer cells, its ability to alert the immune system to the trouble is what often finishes off the virus, the network reported.
A woman once afflicted with an aggressive form of brain cancer who used the treatment saw her virus all but disappear three years after she became the first volunteer in the study.

As a 20-year-old student in 2011, Stephanie Lipscomb was diagnosed as having a glioblastoma, a type of malignant tumor, in her brain, the network reported.

She had been complaining of headaches prior to the diagnosis. Her doctor told her the tumor had grown to the size of a tennis ball and that she only had a few months to live.

Lipscomb then had 98 percent of the cancerous tumor removed. But by 2012, the cancer had returned.

With no other treatment options available, Lupscomb decided to volunteer for Duke’s experiment. For 21 months after Lipscomb began participating, her glioblastoma shrank until it was gone.

In August 2014, three years after her initial diagnosis, an MRI showed no active cancer cells in Lipscomb’s body.


  1. Brown MC, Gromeier M. Cytotoxic and immunogenic mechanisms of recombinant oncolytic poliovirus. Curr Opin Virol. 2015 Aug;13:81-5. doi:10.1016/j.coviro.2015.05.007. Epub 2015 Jun 12. Review.

    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.

  2. Brown MC, Gromeier M. Oncolytic immunotherapy through tumor-specific
    translation and cytotoxicity of poliovirus. Discov Med. 2015 May;19(106):359-65. Review.

    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.

  3. Brown MC, Dobrikova EY, Dobrikov MI, Walton RW, Gemberling SL, Nair SK,
    Desjardins A, Sampson JH, Friedman HS, Friedman AH, Tyler DS, Bigner DD, Gromeier M. Oncolytic polio virotherapy of cancer. Cancer. 2014 Nov 1;120(21):3277-86. doi: 10.1002/cncr.28862. Epub 2014 Jun 17. Review.

    Recently, the century-old idea of targeting cancer with viruses (oncolytic viruses) has come of age, and promise has been documented in early stage and several late-stage clinical trials in a variety of cancers. Although originally prized for their direct tumor cytotoxicity (oncolytic virotherapy), recently, the proinflammatory and immunogenic effects of viral tumor infection (oncolytic immunotherapy) have come into focus. Indeed, a capacity for eliciting broad, sustained antineoplastic effects stemming from combined direct viral cytotoxicity, innate antiviral activation, stromal proinflammatory stimulation, and recruitment of adaptive immune effector responses is the greatest asset of oncolytic viruses. However, it also is the source for enormous mechanistic complexity that must be considered for successful clinical translation. Because of fundamentally different relationships with their hosts (malignant or not), diverse replication strategies, and distinct modes of tumor cytotoxicity/killing, oncolytic viruses should not be referred to collectively. These agents must be evaluated based on their individual merits. In this review, the authors highlight key mechanistic principles of cancer treatment with the polio:rhinovirus chimera PVSRIPO and their implications for oncolytic immunotherapy in the clinic.

  4. Goetz C, Dobrikova E, Shveygert M, Dobrikov M, Gromeier M. Oncolytic
    poliovirus against malignant glioma. Future Virol. 2011 Sep;6(9):1045-1058.

    In cancerous cells, physiologically tight regulation of protein synthesis is lost, contributing to uncontrolled growth and proliferation. We describe a novel experimental cancer therapy approach based on genetically recombinant poliovirus that targets an intriguing aberration of translation control in malignancy. This strategy is based on the confluence of several factors enabling specific and efficacious cancer cell targeting. Poliovirus naturally targets the vast majority of ectodermal/neuroectodermal cancers expressing its cellular receptor. Evidence from glioblastoma patients suggests that the poliovirus receptor is ectopically upregulated on tumor cells and may be associated with stem cell-like cancer cell populations and proliferating tumor vasculature. We exploit poliovirus' reliance on an unorthodox mechanism of protein synthesis initiation to selectively drive viral translation, propagation and cytotoxicity in glioblastoma. PVSRIPO, a prototype nonpathogenic poliovirus recombinant, is scheduled to enter clinical investigation against glioblastoma.