Measles is the latest virus to be turned into a weapon against cancer

A false color image of the measles virus.

This week, clinical researchers at the Mayo Clinic announced some promising early results from a clinical trial that turned a killer into a therapy: their work harnessed a modified measles virus to attack a specific type of cancer. A larger clinical trial is still ongoing, but the people running this trial decided to describe two of the patients who received the virus, one of whom ended up in remission.

It’s important to note that a short-term remission in one of the two patients who are described here doesn’t come anywhere close to being a general cure for this type of cancer. Equally important is the fact that attempts to turn viruses into cancer killers go back decades, and a lot of the early trials also looked very promising. But to date, none of the viruses have been turned into treatments.

The idea behind using a virus to target cancer is the same one behind most other cancer treatments: cancer cells, although they look a lot like normal ones, have some key differences. Cancer cells express different proteins on their surface and control their growth differently. So it’s possible to use these differences to design the right virus to specifically target cancer cells or only proliferate when infecting them. This may then lead to the death of the cancer cell, either by the virus itself killing it or because the virus attracts an aggressive immune response.

This idea has been tried a number of times over the past few decades, with many of the viruses causing some significant damage to tumors in preliminary clinical trials. Many further trials are ongoing but, so far at least, none of these viruses have cleared the necessary clinical trials and received FDA approval.

The new work is the result of a fortuitous match between a well characterized virus and a specific type of tumor. One of the measles linages that was used for vaccine development (named the Edmonston lineage) adapted to growing on cells in the lab. As a result, it changed the protein it latches on to in order to enter cells. By chance, that same protein is expressed at high levels on the surface of myeloma cells, a cancer that affects white blood cells normally found in the bone marrow.

To track the spread of the virus in patients, the researchers engineered it to carry the protein your thyroid gland uses to import iodine, an important component of thyroid hormone. With this gene in the virus, any infected cells would also import iodine, allowing them to be marked for imaging with a radioactive isotope of iodine. (This leaves open the possibility of using a different isotope that emits more damaging radioactivity as part of the treatment in the future.)

The researchers have started a small clinical trial to determine the appropriate dose of this virus. While that trial is still in progress, they decided to report on two of the patients who received the highest dose. All of the participants were screened for the presence of antibodies against measles, which could interfere with the treatment. Despite immunization, this wasn’t as much of a problem as it might seem, given that both myeloma and the treatments for it interfere with immune function. One patient’s list of previous treatments was pretty impressive:

Local radiotherapy; high-dose dexamethasone; lenalidomide and dexamethasone; single-agent bortezomib; cyclo- phosphamide, bortezomib, and dexamethasone; ASCT; lenalidomide, bendamustine, and dexamethasone; bortezomib, cyclophosphamide, lenalidomide, and dexamethasone; carfilzomib plus dexamethasone; bortezomib, dexametha- sone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide; and several experimental therapies.

Both of the patients experienced a fever after administration of the virus, but these passed within a few days, after which there was little sign of the virus in the blood of either participant. One of the two patients didn’t respond to the virus; six weeks after treatment, her tumors continued to grow. But the second felt that at least one of her growths began to shrink only 36 hours after the virus was injected. By six weeks, it could no longer be detected by feel, and imaging revealed that it was significantly reduced. At the time the authors wrote the paper, this patient was considered to be in remission.

What can we tell from two patients? Again, pretty much nothing. Larger trials and multiple treatments with the virus (instead of a single dose, as detailed here) are going to be needed to draw any conclusions about this treatment. In fact, we can’t even be certain that this use of the measles virus is safe without the results of the full trial being reported.

The decades-long list of promising results that have not yet ended in a therapy would argue for additional caution when thinking about these results. Nevertheless, it’s clear that researchers are getting increasingly clever in tailoring their viruses for tumors and making sure any infected cells truly end up dead (the iodine pump used here is a neat approach). Hopefully, one of these trials will end up sending something on to the clinic.

Mayo Clinic Proceedings, 2014. DOI: 10.1016/j.mayocp.2014.04.003  (About DOIs).


#cancer, #health, #study, #virus

Mutating Ebola Viruses Not As Scary As Evolving Ones



Scanning electron micrograph of Ebola virus budding from the surface of a Vero cell (African green monkey kidney epithelial cell line. Credit:NIAID

By Rob Brooks
My social media accounts today are cluttered with stories about “mutating” Ebola viruses. The usually excellent ScienceAlert, for example, rather breathlessly informs us “The Ebola virus is mutating faster in humans than in animal hosts.”

But what does that even mean? Should we be terrified of mutant viruses?

The story is based on a paper just published online at the journal Science under the title Genomic surveillance elucidates Ebola virus origin and transmission during the 2014 outbreak. It’s a timely piece of genetic detective work sequencing Ebola virus genomes from 78 patients in Sierra Leone. Viruses accumulate genetic changes through mutation and selection within a host, so the team sequenced multiple viruses from several of the patients making up 99 genomes in total.

They found that mutations – minute changes in the virus genetic code – have accumulated rapidly, both during infections of individuals and during the outbreak of the current epidemic. The accumulation of genetic changes can tell us about the dynamics of an outbreak because when one patient infects another, the virus in the second patient is the descendant of the virus in the first, and contains all mutations that had accumulated in the first, plus any new mutations that occur in the second patient.

The Science paper concludes, from studying these changes, that the current West African outbreak comes from a single zoonotic infection (when a virus crosses from an animal to humans, which is how Ebola outbreaks start). The virus, living in animals like fruit bats, last shared an ancestor with the Middle African strains (which have repeatedly infected people in places like the Democratic Republic of Congo) in approximately 2004.

The virus behind this outbreak made the jump to humans late last year, in Guinea. The key event in the spread to Sierra Leone was the funeral of a faith healer who claimed to be able to cure Ebola patients. When she contracted Ebola and died in late May, a large number of people attended her funeral.

Twelve of the first Ebola cases in Sierra Leone all attended that funeral, and appear to have contracted the virus there. These include two distinct forms of the virus which diverged, in Guinea, in late April.

This paper represents a superb piece of investigative genomics. Because Ebola viruses replicate (make copies of themselves) so rapidly and the epidemic has spread so quickly, there exist many small changes in the virus genome with which to track what has happened.

Are the mutations dangerous?

And those changes have accumulated far faster since the virus made the jump into humans, triggering the current epidemic. Which is the finding behind the headlines that the Ebola virus is mutating rapidly.

Nobody can tell whether mutations happen more rapidly in human infections than in the reservoir host animals where most viruses live. What has happened is that mutations have accumulatedtwice as fast in the course of this infection as they typically do during the long stretches living in other animals.

So when Reuters’ Julie Steenhuysen writes “more than 300 genetic changes in the virus as it has leapt from person to person”, she’s not talking about some mysterious, sinister process that literally happens in the air between one host and the next. Ebola isn’t even an airborne disease; it is transmitted in bodily fluids.

These mutations are simple mistakes in the genetic code, made when the virus is replicating within a host. With millions of replication events during thousands of infections, a huge number of mistakes happen. Steenhuysen quotes study lead author Pardis Sabeti (Harvard University and the Broad Institute) who points out just how mundane this process really is:

We found the virus is doing what viruses do. It’s mutating.

The majority of mutations either render the virus useless at doing its job, or have no effect. Its “job” being to make more copies of the virus and occasionally to infect another host.

So the mutations that do get passed on are usually the very few that succeed at improving the rate of virus replication, or the rate of infection. Exactly how many of the mutations alter the effectiveness of the virus at replicating and being transmitted, and how they do so, remains to be established. And the study’s authors certainly expect this to be an important follow-up:

Since many of the mutations alter protein sequences and other biologically meaningful targets, they should be monitored for impact on diagnostics, vaccines, and therapies critical to outbreak response.

When mutations arise – and they always arise – and effect the way in which an organism (yes, I know some people don’t like calling viruses “living organisms”) makes copies of itself, we have the two main ingredients for natural selection. There can be no clearer or more frightening illustration of natural selection and its inevitable result – biological evolution – in the modern world.

For some, reason, however, the popular press doesn’t like calling evolution – the most important biological process of all – by its proper name. “Mutation” and “development” are neither synonyms, nor euphemisms for evolution.

A new host spurs new adaptation

The reason mutations have accumulated so rapidly during this epidemic is that the virus is in a new host – human beings. While other versions of the virus have jumped across to humans before, the Ebola viruses currently ravaging West Africa have spent all of their history in other animals. They are now adapting to human bodies, tissues and immune systems. The mutations that help the virus work most effectively in the human body and transmit most effectively from sufferer to uninfected victim are the ones we are going to be hearing a whole lot more of in the coming months.

So we have little to fear from mutating viruses. It is the rapidly evolving viruses, fixing the mutations that randomly occur like typos in a Tweet, that we should seriously fear.

#ebola, #health, #mutation, #science, #virus