Case of cancer cured by measles vaccine

[Pythagorean]

Is this is good as it sounds?

Russell said he and his team had engineered the virus to make it more suitable for cancer therapy. And, after just one dose of it, Erholtz’s cancer went into remission. She has been completely cleared of the disease, Russell wrote in Mayo Clinic Proceedings. Though, in this trial, the treatments were successful on only one of the two patients.

http://www.washingtonpost.com/news/...lled-by-measles-virus-in-unprecedented-trial/

 

[DrClaude]

Better to discuss the actual science than a newspaper report:

http://www.mayoclinicproceedings.org/article/S0025-6196(14)00332-2/fulltext

 

[Pythagorean]

Sure, if you're willing to translate.

 

[lisab]

A few questions from a noob:

From what I understand, the virus was altered to attack only cancer cells. Is that correct? Given how many cells there are in the human body, how sure were they that only cancer cells would be affected?

Why measles? Is there something special about that virus?

The dose was enormous. Why didn't the patients have immune reactions?

 

[Curious3141]

Sure, if you're willing to translate.

Since no one else has volunteered to "translate", I'll give it a shot.

A few questions from a noob:

From what I understand, the virus was altered to attack only cancer cells. Is that correct? Given how many cells there are in the human body, how sure were they that only cancer cells would be affected?

They weren't sure. That's the point of a Phase 1 trial, which involves gradually titrating the dose to establish a maximum safe dose. As part of the safety evaluation, they had to put in study procedures that proved that the viruses were mostly focussed on the tumorous regions and were not attacking "innocent bystanders". I'll go briefly into the method used below.

Phase 1 trials are principally about safety and they're mostly conducted with healthy volunteers rather than patients suffering from the syndrome. This study seems to have used the actual target patient group (patients with refractory multiple myeloma (MM)), and the reason for that is not made clear. It could be because of difficulty in securing ethical approval to use viruses on healthy humans with all the attendant risks but without any reasonable expectation of benefit. Of course, I'm speculating about this, but I've previously served on a major interhospital IRB before, and I'd probably have raised an objection if they'd wanted to do this with healthy volunteers.

Whatever the reason may have been, patients were used. Although Phase 1 studies focus on safety, the inclusion of target patients means that it made sense for efficacy to also be monitored. To find convincing evidence of efficacy in a Phase 1 trial is a nice bonus, and it is an encouraging sign, but by no means should it be taken as definitive evidence that the therapy works well enough to be introduced into the market. That will have to await Phase 2, and finally Phase 3 studies.

Why measles? Is there something special about that virus?

To some extent. Measles has been well-established as oncolytic (preferentially lysing or "bursting" cancer cells). But it is not the only such virus - adenovirus is also oncolytic. The particular reasons why they chose measles in this case are not explained, but it may have a lot to do with convenience (having lots of the agent on hand, lots of previous work in animal models, etc).

In particular, the lab-adapted strain of this virus, called MV-Edmonton, has an affinity for a specific cell surface receptor called CD46. This receptor is massively overexpressed in MM cells. As such, they expected the strain of virus they were using to have a particular tropism (fancy word for preference) for the cancer cells over normal cells. It should also be noted that the virus used was passaged on HeLa cells (named for the source patient Henrietta Lacks, you can look up her rather tragic story), which are basically immortalised (meaning they multiply indefinitely) cancer cells, rich in CD46. So it is no surprise that MV-Edmonton had a high affinity for CD46, which it uses to infect cells and also to help it jump from cell to cell by making a gooey mess of cells with blurred boundaries, called "syncytium formation."

They still had to prove it (preferential localisation in tumour tissue) though. So what they did was genetically engineer the viruses they were using to encode a particular iodine transporter (symporter just means it brings in the iodine with another molecule, which is irrelevant). This is called a "reporter gene" because its expression is like a signal flag for the cells infected with the virus. Remember that viruses cannot make proteins on their own - they need to hijack the machinery of the host cells to do so. So infected cells would express proteins encoded by the viral genes, including this engineered iodine symporter reporter gene.

They administered the virus, and then they gave the patients Iodine-123. This is a gamma emitter that doesn't do significant damage to human cells. However, it allows for the areas of increased iodine activity to be photographed by gamma camera. These will correspond to areas of high viral load. The specific technique used in this imaging was SPECT (Single Photon Emission Computed Tomography).

They then correlated those images with the baseline images captured using FDG PET-CT. Now FDG (fludeoxyglucose) is a chemically modified version of glucose (with a fluorine atom stuck on), that is metabolically taken into mammalian cells just like normal glucose. The fluorine is F-18, a radioisotope that emits positrons (I guess you know what those are, this being PF and all. ). The positron emissions are captured by PET-CT, standing for Positron Emission Tomography-Computed Tomography.

Because glucose (and therefore FDG) are gobbled up in huge amounts by metabolically active cells, MM cells (and other aggressively multiplying cancers) would have a much higher uptake rate of FDG than normal cells. This is why cancer cells would light up brightly on the FDG PET-CT scans.

So, by correlating the "pre-therapy" (F-18 FDG-PET CT) with the "post-therapy" (I-123 SPECT) scans, the authors showed heavy localisation of the viruses at the areas with lots of MM cells, but not involving the adjacent healthy areas.

The dose was enormous. Why didn't the patients have immune reactions?

The patients would have had some immune response (although MM patients are often immunocompromised). But specific immune responses usually take some time to mount, whereas these viruses act pretty quickly to kill off the actively multiplying MM cells. The authors had previously determined (using animal models) that it was pre-existing immunity that mattered more in rendering the therapy ineffective. In other words, if you had preformed antibodies against measles, they would quickly bind up the virus particles, so they wouldn't work as well. So the patients chosen for this study had no detectable pre-existing measles immunity. Probably means they had neither suffered a natural measles infection nor been vaccinated with measles prior to the study.

I hope I've answered your questions in an understandable fashion. I think that's enough to now be able to read the article more easily. But I'll just quickly summarise the results and a further avenue for study the authors mentioned.

As mentioned in the lay news, 2 patients were highlighted in the study. Patient 1 (with the forehead (frontal bone) tumour) fared better on the new therapy than patient 2 (with the muscle tumors). The response was measured using various biochemical indicators like the free λ and κ light chains - which are a part of the antibody (immunoglobulin) molecule secreted by MM cells. In addition, clinical response was monitored, and this is the most important, because this is what the patient expects improvement in. In patient 1 at least, the major frontal bone tumour did shrink, but there were signs of a possible reversal 9-months post therapy (as evidenced by increased frontal bone FDG-uptake and a slight increase in the λ light chains). But this was after just one dose, it is possible (but unproven) that repeat doses would be helpful.

An interesting point brought up by the authors was the potential use of therapeutic radioiodine (I-131) in conjunction with this MV therapy. Because of the engineered iodine transporter, the infected MM cells would be exquisitely sensitive to the effects of iodine-131, which is a beta-emitter. (It should be obvious that this iodine isotope is different from the previously mentioned one, which is used diagnostically). However, this is speculative, and therapy with radioisotopes has other potential concerns (uptake into the healthy thyroid gland needs to be pharmacologically blocked, for example, to prevent too much damage to it).

Phew, that's a long post, but I hope it helped to clarify things somewhat.

 

[DrClaude]

Sure, if you're willing to translate.

I'm not the one who can do that . My point was that, per PF rules, only peer-reviewed research is discussed, so I wanted to make the article easily accessible, especially for future reference.

Since no one else has volunteered to "translate", I'll give it a shot.

Wonderful! That was a very clear and interesting presentation.

 

[Curious3141]

Wonderful! That was a very clear and interesting presentation.

Thanks, that's very nice of you to say.

 

[Yanick]

That was a very good synopsis, Curious. I just want to note that both patients became very ill after infusion of the virus. About an hour later they both developed very high temperatures (~40° C) with a very high heart rate and lowered blood pressure as well as headaches. These were treated symptomatically and the patients recovered in the short term. Beyond that I have nothing to add.