Using Polio as a Cure for Cancer?

Researchers at Duke University Treat Brain Cancer with Polio

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The quest to defeat cancer speaks to humanity's fundamental desires. It represents a cardinal human landmark kind of like traveling to the moon or finding a solution to world hunger. 

I'm sure that many of us think that, if researchers were ever able to find a cure for cancer, this world-changing discovery would be decades or centuries away. After all, cancer is a dangerous, diverse and complicated disease--a disease that we still have much more to learn about.

However, researchers at Duke University Medical Center have made an amazing discovery: In some people with recurrent glioblastoma multiforme, a type of brain cancer, infection with poliovirus sets off an immune response that kills the tumor.

What is glioblastoma multiforme?

Glioblastoma multiforme (GBM) is a fast-growing cancer which derives from glial cells in the cerebral portion of the brain (temporal and frontal regions). Glial cells usually support the function of normal brain cells, but when their growth goes haywire, as is the case with Grade IV GBM, the cancer kills most people within about 15 months. GBM tumors can double in size every 2 weeks. 

GBM affects about 2 to 3 people per 100,000 and accounts for 52 percent of primary brain tumors (GBM rarely metastasizes or spreads).  Between 2005 and 2009, the median age for death from this brain cancer was 64.

Unfortunately, in people with GBM, the success of current therapeutic options including surgery, chemotherapy and radiotherapy is measured in mere months of additional survival, and many of these additional months proffer poor quality of life.

 

Symptoms of GBM are related to swelling and shifting of brain structures (mass effect) caused by the tumor and associated edema or swelling. The tumor, which can be the size of a golf ball, presses on other structures of the brain causing:

  • headaches
  • loss of appetite
  • blurred vision
  • seizures
  • vomiting
  • difficulty with speech
  • difficulty with cognition

Brief history of the oncolytic virus

No matter how radical it may sound, the practice of using viruses to treat people with cancer is nothing new and was first suggested in the early twentieth century. In these early years of cancer treatment (way before OSHA), we had no good way to treat cancer, so physicians and cancer sufferers were willing to try anything including exposure to infectious tissue or body fluids. For example, in 1949, people with Hodgkin's disease, a cancer of the lymph nodes, were infected with hepatitis virus. 

As can probably be expected, infecting people with indiscriminate viruses did little to improve the lives of those with cancer (although on occasion it killed parts of tumors or caused very short term remission of disease). 

Starting in the 1950s, we got to know a lot about viruses; we now understand them better than any other living organism. We also know how to reproduce and genetically manipulate viruses in laboratory settings. Thus, we can enable viruses to become oncolytic viruses or carriers of treatment which set off the body's immune system.

Most importantly, these oncolytic viruses need to kill tumor cells only and not attack normal human cells.

Immunotherapy: when our bodies kill the polio-tumors

Tumor cells are deadly because they evade our body's immune system. Cancer immunotherapy is a field of medicine that examines how to unmask the cancer as foreign, and thus harness the body's own immune system to defeat the cancer. The use of oncolytic virus PVS-RIPO in people with GBM represents one of the most significant and encouraging advances to date in the field of cancer immunotherapy.

Once the virus is delivered to the the tumor, the magic happens.  According to a review article authored by the Duke researchers and published in Cancer in November 2014, this process involves:

  • direct viral cytotoxicity
  • innate antiviral activation
  • stromal proinflammatory stimulation
  • recruitment of adaptive immune effector responses.

Essentially, after PVS-RIPO (oncolytic poliovirus) propagates in the GBM (brain) tumor, our bodies recognize the "polio-tumor" as toxic.  This recognition sets off an alarm for the immune system to go to war with polio-tumor.  The hallmark of this war is inflammation, a natural immune response.

Results from PVS-RIPO Phase I Trial

At Duke's Preston Robert Tisch Brain Tumor Center, researchers have spent years of bench work developing and testing PVS-RIPO.  Specifically, these researchers have taken live, attenuated poliovirus and switched out a virulent sliver of ribosome that causes polio for a harmless bit of cold-causing rhinovirus.  Then, in a recent PVS-RIPO Phase 1 clinical trial, these researchers surgically infused (a procedure formally called intratumoral convection enhanced delivery and done via catheter) this oncolytic poliovirus into the primary brain tumors of adults with GBM. 

The tumors that received injection of poliovirus were 1- to 5-centimeter, supratentorial GBM tumors at least 1 centimeter from the brain ventricles.  In addition to having moderately sized tumors, PVS-RIPO Phase I clinical research participants had GBM that recurred after previous treatment (surgery, chemotherapy and radiotherapy), were no longer receiving such treatment, and had good organ function and daily functioning (KPS greater than or equal to 70).  Finally, participants must also have been vaccinated for polio.  In sum, oncolytic virus PVS-RIPO is currently being tested as a last-line treatment in functioning adults with recurrent brain tumors that are limited in size.

To be sure, it's taken more than a decade of basic medical science research (done on petri dishes and in animals) as well as millions of dollars for researchers to identify that PVS-RIPO could effectively treat GBM. Specifically, PVS-RIPO has a tropism or affinity for nectin-like molecule 5 (Necl5), a cell-adhesion molecule expressed in GBM stem cells and not in normal somatic cells.  Furthermore, Necl5 is also expressed in various other tumors like colorectal carcinoma, lung adenocarcinoma, breast cancers, and melanoma, which hints that PVS-RIPO may be effective in the treatment of other cancers, too.

Once the oncolytic poliovirus takes hold, GBM tumors of participants in the study are monitored using serial 3-D MRI.  Initially, MRI images show inflammation of the tumor, a sign that the body's immune system is going to war with polio-tumor.  This inflammation and associated edema (swelling) exacerbate symptoms of GBM like problems with speech, cognition and sensory deficits.  Other adverse effects of treatment include diarrhea.

In many of the patients who are still alive after treatment with PVS-RIPO, something amazing happens a few months after treatment. The tumors start shrinking, and in the first 2 patients treated way back in 2012, the tumors have disappeared!

Here are some specific findings from the PVS-RIPO Phase I clinical trial:

  • Of the 22 people who have been administered oncolytic poliovirus PVS-RIPO, 11 are still alive. 
  • One person hemorrhaged during removal of the catheter carrying PVS-RIPO.
  • The first 2 patients administered PVS-RIPO in 2012 are still alive!  By 2015, the original publication date of this article, they have lived 3 years and counting.
  • Researchers now believe that a medium dosage of PVS-RIPO is best.
  • Several people have died after receiving higher doses of PVS-RIPO.
  • The median survival of patients with GBM who receive oncolytic poliovirus is 6 months.  (Median is a mid-point indicator.) 

We must remember that for any other disease, a 50 percent mortality rate probably seems abysmal.  However, in people with GBM, one of the worst types of cancers out there, the fact that half the people are still alive after treatment with PVS-RIPO is absolutely astounding.  And survival of 3 or more years after experimental treatment, as is the case with 2 research participants, is unheard of.

Although the results that we are seeing from the Duke clinical trial are, to say the least, highly encouraging,  we must remember that these results represent a really small sample size.  We need higher-powered results to make sure that these initial findings were no fluke or represented only a fragment of the population at large. 

In all truth, the Duke researchers are still only on the first leg of their journey, having just determined an effective dose.  Plenty of questions remain which is why further studies are in the works, and these studies will undoubtedly shed some light on who can benefit from PVS-RIPO therapy.  Specifically, we know only that poliovirus has worked on adults with GBM, but children get GBM, too, and could benefit from such therapy.  Moreover, we don't know what happens when the PVS-RIPO oncolytic virus is administered earlier during a person's clinical course of GBM.

In medicine, the term "cure" is loaded with connotation.  However, to the 2 patients who received oncolytic poliovirus in 2012 and now have no visible trace of brain cancer (are in sustained remission), it sure seems like PVS-RIPO is a cure.  Even more amazing than the cure of deadly brain cancer, however, is the prospect that PVS-RIPO could be used to treat (cure) other types of cancer like colorectal carcinoma, lung adenocarcinoma, breast cancers, and melanoma. 

Only time and more GBM survivors will tell whether PVS-RIPO can truly cure GBM.  It's anticipated that PVS-RIPO as treatment of GBM could soon receive FDA breakthrough therapy designation which will give the greater public access to this oncolytic poliovirus treatment.  Once more people receive treatment and remain in remission, cure will be apt description for the actions of PVS-RIPO.  

Note to reader: It was my full intention to interview the cancer researchers at Duke University conducting the PVS-RIPO Phase I clinical trial. I absolutely concede that this article is solely based on my own interpretation of limited research and coverage of this topic. In order to provide the readers a robust, coherent and accurate assessment of PVS-RIPO's effect on GBM, I need expert input. Unfortunately, in the wake of all the media attention secondary to 60 Minutes reporting on the Duke cancer researchers' findings, I was unable to secure an interview before timely publication of this piece. Consequently, I gathered all the information and did my own assessment of the topic. Should I ever be granted an interview with a representative of Duke's cancer research team, I plan to publish an addendum to this article which details my findings.

Selected Sources

Review article titled "Oncolytic Polio Virotherapy of Cancer" by MC Brown and co-authors from Cancer in 2014.  Accessed on 4/14/2016.

Abstract titled "ONCOLYTIC POLIO/RHINOVIRUS RECOMBINANT (PVSRIPO) IN RECURRENT GLIOBLASTOMA (GBM): FIRST PHASE I CLINICAL TRIAL EVALUATING THE INTRATUMORAL
ADMINISTRATION" by A. Desjardins and co-authors published in Neuro-Oncology in 2014.  Accessed on 4/14/2015.

Article titled "Preparing an oncolytic poliovirus recombinant for clinical application against glioblastoma multiforme" by C Goetz and M Gromeier published in Cytokine and Growth Factor Reviews in 2010.  Accessed on 4/14/2015.

Article titled "History of Oncolytic Viruses: Genesis to Genetic Engineering" by E Kelly and S Russell from Molecular Therapy published in 2007.

60 Minutes special Killing Cancer which aired on March 29, 2015. Scott Pelley (correspondent), Michael Radutzky (producer) and Denise Schrier Cetta (producer)

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