Disclaimer: I’ve spent my career across oncology R&D and commercial roles, but have never worked on oncolytic viruses.
Title is misleading - this is a first in human, safety/dose-escalation study for this particular oncolytic virus. Oncolytic viruses have been in clinical development for quite some time. In response to the predictable “let us know when it works in humans” responses we see following sensationalist clinical research headlines, in 2015 we actually saw an oncolytic virus approved in the US: T-VEC for inoperable melanoma [0]
A few interesting things here from my point of view. First, they’re engineering the virus to infect cancer cells and overexpress PD-L1 to prime for enhanced immune-mediated killing. This could help a “cold” tumor turn “hot” by remodeling the tumor microenvironment. Second, the virus will also overexpress a symporter in the cancer cells which allows for targeted imaging and monitoring of tumor activity and cell death. There’s a nice graphical abstract available for reference [1]
Importantly, they’re assessing this in TNBC as it is associated with a very poor prognosis and has been validated as responsive to anti-PD-1 immunotherapies (eg, Keytruda/pembrolizumab)[2]
For the curious, there’s a preclinical Nature paper from June 2021 describing this in pancreatic cancer cells [3]
Cancer cells have the ability to take advantage of the body's mechanism to prevent the immune system from attacking healthy cells, essentially signalling immune T cells to turn off using what's called immune checkpoint proteins. Essentially a cold tumor is one that has successfully shut off the immune response in this way, whereas a hot tumor is one that hasn't. This can be because of the innate behaviour of the tumor, or due to an intervention to turn it hot—like the one described by the OP, or more traditionally, using immune checkpoint inhibitors.
Is this the same mechanism that the eye and testes use to prevent being attacked by the immune system? I recall the eye has its own "immune system"(tears) since the usual one is deactivated in that region.
Would it be possible to engineer a disease(virus, bacteria) that can't be defeated by the immune system because it has this signal?
Read your question again and then realize you just wondered if it would be possible to engineer a virus to kill all of humanity, with no possible immunity.
See the problem?
This is why people hate (software) engineers, they are oh-so-dumb on the "empathizing with humanity" front... pie-in-the-sky ambitions that are more likely to be shitty solutions replacing ones which worked well enough, to blow up, potentially catastrophically, or cause various humanity-ending apocalypses, than to actually solve the problem in most cases...and what do they have to say for themselves?
The notion is quaint that there exists Knowledge Man Is Not Meant To Know. If it's something humans can find out, it's better that it be right out there in the open so that the danger can be met head on.
I recall reading a news article of a woman Stacy Erholtz who had stage 4 cancer nothing for her worked. She was given a phenomenally massive amount measles vaccine supposedly enough to vaccinate ten million people. Note it was not an engineered version of the virus just the unaltered virus. She recovered and is cancer free which I suppose is why the story was released because it was so amazing.
>Title is misleading - this is a first in human, safety/dose-escalation study for this particular oncolytic virus.
Thanks for this... it's to the point I rarely read articles about medical studies, because I lack the domain knowledge to evaluate them, and if I just look at the study methodology people get angry when I often notice said methods aren't super stringent.
(You can get away with that in psychology, but it's really jarring when I see the same patterns in the physical sciences.)
Oh I can't post on Reddit anymore. People purposefully started sitewide banning me whenever I'd get a decent social media following.
(Have you used Mastadon? I'm considering checking that out)
It was a running joke that I don't look at logs for too long, stemming back to when I did a now deleted blog that listed a way to spoof your location on Facebook and I posted it with zero warning. It was literally just editing Firefo about:config and manually writing out the coordinates, not really even an input sanitization error IMHO.
I got the impression it made some people lose face that I had no security clearance, I was just some random hourly worker who threw my boss' name around too much as I attended a lot of stuff listed as open to the public where people who had TS or TS:SCI questions would show up and ask troll-ish questions.
(That leaks a LOT of information. Don't do that, if you're reading.)
I'll take a look though, thanks for the links, sincerely.
> You shouldn't be able to get away with it in psychology
Then next time you find a study you don't like, contact the IRB[1] that authorized it and contact your representative in Congress[2].
They publish the grant information. Say you'd prefer to receive that money instead, or that it be directed to a more ethical and useful primary investigator.
No problem, but when you speak to your elected representative, please also say that they should have local police adopt a policy that all police officers carry business officers with detailed contact information.
At the meta level if someone "gives me a card" and it's just... the phone number to whoever gatekeeps access to them and an email some assistant monitors, then don't expect the same level of trust, deference, or respect as someone like me who hands out the email tied to their real name, the phone number for the SIM in their phone, and the Signal number tied to the phone number they've held onto since they were 16.
(You might notice some of my more recent posts seemed rushed, or erratic. That is because I was posting like a literal dissident: drafting things, posting, then immiedately changing locations.
A lot of the rhetoric around "community standards" of speech is more about things like, well, yeah, someone might stand up a server with Mein Kampf or something on it, and that's ok because sometimes people want to read that for academic reasons.
Anyways sorry for the wall of text, but when folks spoke to me informally, when I was debating certain roles or... companies... a lot of them spoke of things like "analysis paralysis"[1][2]
I see a lot of people nowadays who seem to take the view that if they prominently display a contact phone number and unique identifier, they can move to more of a model where anti-social behavior is the default, and challenge others to report out to some... entity... to come and deal with the issue.
(Versus making a good faith effort to follow the guidlines, and being willing to accept sincere feedback.)
Anyways sorry to wall of text you, but it's been really interesting seeing how people react to me versus others on the internet, especially when I take a long pause from posting here on the orange website ;-)
I was going to say - T-Vec was being commercialized almost 10 years ago. Using oncolytic viruses isn't new at all. The basic R&D goes back to the 1990's.
Thanks for posting this —- I posted the same objective criticism of the title and was almost instantly downvoted to -1. I expect this was in part because I also implicitly criticized HN voters for voting the original submission, which was pretty information-free, to the front page.
The theranostic aspect to me is the most interesting part.
They infect the cancer cells with a virus. The virus causes the cells to create a protein that has already shown to be a good target (PD-L1). Seeing the high levels of protein, the patients immune system should trigger cell death (apoptosis).
God bless and good luck to the lady who received this treatment. I hope it opens the way to a lot of people getting the same treatment, but first I hope it saves her life.
These engineered viruses are remarkable feats of biotechnology.
I have to wonder if they are great treatments though. The issue is complexity. The virions have to achieve contact with the target cell, penetration, avoidance of host immunity, delivery of whatever their effector function is, and hopefully then killing the cancer cell. They also need to do this for a substantial portion of the billions of cancer cells in the patient (not all cancer cells, bystander killing is part of the way they work), which display considerable heterogeneity. This is a pretty complex chain of events, which is a disadvantage when dealing with an evolvable target like cancer. Other (effective) antibody or small molecule therapies have simpler mechanisms of action. The viruses we know and love have evolved over long periods to infect small populations of homogeneous cells, quite different to the task here. I guess we will see.
If there is niche for the virus in the cancer cells then the virus could in theory and adapt as well. It depends on how the virus was constructed.
In addition to directly killing tumor cells, a small number of dead cells could be processed into antigens by a macrophage nearby and presented to a T-cell.
If in some cases the virus can get in to the tumor cell but can't kill it, it's possible the virus can still be detected and presented on MHC Class I (unless it's suppressed) of the tumor cell by neighboring Natural Killer cells.
That's why it's important to reverse the tolerogenic environment that the tumor creates around itself. The viral infection will hopefully go a long way towards waking up the immune system up.
Real time adapting viruses are not really something that exists, unless I'm mistaken. They would be very hard to build not least because the problem is poorly specified and would introduce an unpredictable element which is undesirable for a medical therapy.
Yeah using viruses to potentiate anti-tumor immunity is an interesting idea. But returning to my main point, this is creating additional complexities. Most successful cancer therapies tend to do one thing well. Reliable synergy between treatments is actually quite rare. Peter Sorger has published some interesting stuff about this point. The reason combination therapies work better is because it is harder for a cancer cell to be resistant to everything, not because the drugs synergise to kill otherwise resistant cells.
MHC Class I mediated killing is done by effector T cells, not NK cells. Cancers of course learn to turn off peptide presentation via MHC, which stops anti-PD-1 drugs from working. Interestingly many real viruses stop the cells they infect from displaying peptides to escape T cell mediated destruction.
There are already studies of treatments which ramp up the immune response without killing off cancer cells much eg intratumoral STING agonists, mRNA compounds which induce manufacture of chemokines. They don't work that well, so I think the cancer killing capacity of the virus is important. Otherwise there are simpler more 'drug-like' ways to attract more effector cells to the tumor.
Sorry, I mis-remembered my immunology. NK cells kill in the absence of MHC Class I, which is something that would be really nice if it could be turned into therapy.
According to Google the virus population on planet earth is 10,000,000,000,000,000,000,000,000,000,000 so there's a lot of mutation going on and we're still here. So random mutation of one more well-intentioned virus that kills cancer probably isn't a threat.
That's a population number. COVID alone accounts for 10^11 virus particles in a single human during peak infection, or about 10^19 in total. That is getting close to the 10^31 total.
But to be precise about all viruses; A over-the-thumb estimate is 10^24 viruses of the total population of the earth's biosphere are actively living in the collective biomass of the human species at every moment. That is merely the population of viruses currently alive in all humans, ranging from the ones going hunt on bacteria in our gut to the ones living in our blood and flesh.
If we estimate the weight of a virion particle to be 1 femtogram (which is roughly the dry mass of a covid particle), that yields you 10^6 kilograms of biomatter. About the weight of a Saturn V rocket.
So not a couple dozen out of the number OP posted. It's a significiant number.
And you have to keep in mind that OP's number does not only include the human virion particles but all virion particles in nature, including megaviruses, virions, virophages, bacteriophages etc. Most of those are not compatible with how human bodies work, probably 99.999% of viruses in nature will not survive in a human body, they're specialised to hunt other things.
By introducing a few nanograms of virus material to a human, you're contributing effectively 0% to the natural virus levels in just a single human, in the grand view of things it does not matter. And the moment these viruses escape, they're subject to evolutionary pressure, meaning they will evolve to not kill their hosts very quickly or perish before they get a chance.
And even, to become a threat, the virus may need to mutate several times just to become even a little contagious. Most viruses are not really contagious (as in respiratory contagious viruses).
I also don't know much about virology, but one thing I have heard is that some types of viruses (eg. RNA) are more prone to mutation, whereas some others (eg. DNA) essentially include something like the biological equivalent of a checksum, slowing mutations.
For some reason, the article isn't opening for me, so I don't know anything about this virus.
Our immune system handles most viruses. If it doesn't we can just develop a vaccine.
Keep in mind that evolution has spend the entirety of time the human species has existed trying to evolve a virus that is effective against human targets. Our immune system is very capable of handling larger infections in 99.99% of cases a virus takes hold in our bodies. And for the remainder we have modern science like vaccines and anti-virals.
> What keeps the virus from mutating and being dangerous?
Entropy, mostly. We're taking wild type viruses and burdening them with, from their genes' perspective, useless overhead. One would expect them to, on average, tend back towards the wild type. There is always the risk that we stumble them onto a path they wouldn't have found naturally, bump them out of a local optimum, but that's currently hypothetical.
That's probably why they tend to start these trials with people who are already in medically dire straits.
If someone is currently pretty much guaranteed to die -- which is what the eligibility criteria sound like to me, someone correct me if I'm wrong here -- then there's less concern compared to accidentally killing someone who was doing fine before. And those initial trials will let you check for things like virus mutations.
They did the same thing with the pig heart transplant recently, did the operation on a guy who desperately needed a new heart but was ineligible for a regular transplant.
We have however developed effective treatment for the infected at this point as well as have a very effective vaccine. If whatever escapes turns out to be worse, I think our response will be much better. Plus remember that we eradicated smallpox entirely.
oh crap, didn't even consider this as a possible 'side effect' I hope someone on HN who has the right scientific background can explain why this is highly unlikely or an impossible outcome..
It's been a while since I read the book, but it makes sense to me people failed to identify with the doctor as the bad guy at the end of the movie.
In the book, we're shown what amounts to a small love story between him and a vampire, and the living-vampires brutalizing the dead-vampires, and finally the doctor.
There's a ton of build up to the reversal that the alt ending does not seem to have.
I would presume because flu vaccines etc. require infecting a human with a virus in some form or another, there was plenty of time to ensure engineered viruses do not transmit.
Is that an accurate comparison? I don't know much about biology so I'm open to be corrected, but I thought that flu vaccines are attenuated or dead versions of the virus, which aren't strong enough to transmit, and RNA vaccines don't include the full virus at all.
I stand corrected (but FWIW I don't think there's a strong reason for worry unless one is a specialist in this field and has concrete grounds for concern).
2) People report being sick from inactivated vaccines so those carcasses you mention evidently still trigger symptoms, and according to Wikipedia "most" viral vectors are designed to be incapable of replication so presumably some could transmit. Additionally, at least with Sputnik botched inactivation had been reported (by Brazil, https://www.dw.com/en/brazil-was-there-sloppiness-with-the-s...). Frankly if I get symptoms and am contagious then I will consider myself infected for all intents and purposes.
In the end, though, we can engineer non-transmittable viruses if warranted, and with proper care we successfully do so. I don't know the approach taken with the cancer-fighting virus in question but I bet proper care had been taken.
It's an Orthopoxvirus [1] [2] and is easy to target and kill. We've already eliminated one of the viruses in the family: Smallpox-causing Variola.
Also notable, it's a doubly stranded DNA virus, so it will mutate less frequently than other virus families, such as ssDNA and RNA viruses.
Patients will undoubtably be monitored closely. That said, we do need to be extremely careful. Wherever it may have originated, Covid should have hopefully instilled caution and respect for safety protocols.
> CF33, and its genetically modified variants
(CF33-hNIS-ΔF14.5L and CF33-hNIS-antiPDL1). The creation of CF33 and its sequenced
genome has been previously described (11). Briefly, recombination among 9 different
species/strains of orthopoxviruses [Cowpox (Brighton), raccoonpox (Herman), rabbitpox
(Utrecht), vaccinia virus (Western Reserve), International Health Department, Elstree, and
VACV strains Ankara (AS)] resulted in a chimeric orthopoxvirus, CF33, which did not
previously exist in nature. This virus has been found to be highly specific for infection,
replication within, and killing of breast cancer and pancreatic cancer (11, 12).
It is an interesting risk assessment worrying about engineered viruses, when we are literally surrounded by them and any of them could mutate and become dangerous. I have always assumed that an engineered virus specifically engineered to not transcend its limits would be less likely to become a problem than all the other viruses whose ability to mutate around our immune systems is required for them to survive more than a few years. Or is there a factor I'm unaware of, such as the the most useful sources to work from are also the most virulent with nasty behavior just one mutation away from being switched on?
> What keeps the virus from mutating and being dangerous?
The large difference between these genetically engineered viruses and ones actively spreading in the wild. They pick and modify them to not spread and get cleared by the immune system and sometimes to include vulnerabilities to treatments.
I don't suppose anything prevents it from doing that, but consider this: Covid19 has infected billions of people. How many times has it mutated? A few hundred, I suppose, with only a few of those mutations having given rise to more infectious variants. That's a few out of billions of cases.
"60 Minutes" ran a piece a couple years ago about a modified polio virus injected into people with inoperable brain tumors. A couple patients were cured, one died as I recall.
On Firefox, this page shows me just skeleton placeholders where the text is supposed to be, and nothing ever loads. Even with content blockers disabled.
Same on my desktop with Chrome, Firefox and Edge as well as on my Android device (Firefox, DuckDuckGo-Browser).
I can see the text shortly while the page is still loading.
Looks interesting. Let us know in 3-5 years when the Phase III trials are done and there's an overall survival benefit beyond the standard of care at that time.
3-5 years and previously completed phase three trials didn’t stop mRNA deployments. So, I have no idea if that is the new standard or not. Let’s hope it was a fluke, and that this on topic is a big deal.
Breast cancer is not contagious and has no chance of becoming a pandemic. The issue with a pandemic is every person infected is several more infectees in the future; geometric death effects instead of linear.
At the risk of starting a flamewar... wasn't the difference actually just the pure volume of severe sickness and death? The clinical trials didn't even attempt to test viral spread, they tested prevention of symptoms.
If suddenly 50% of the world population got breast cancer at once, I'm willing to bet we'd be fine rolling out new technologies faster than the typical standard, despite it being non-contagious.
A major difference is that no two breast cancers are the same. You're probably correct in your second point due to the sheer demand, but developing a treatment for any cancer is not the same as developing a treatment for an infectious disease because there is no one-size-fits-all strategy. A situation like the one you describe with simultaneous onset of breast cancer in a large population would definitely facilitate research and help lead to a better standard of care, though.
mRNA vaccines benefited from the statistical power of having a widespread pandemic. Trials could simply do a double blind test and check how often the treatment subjects got covid vs. control. With thousands of study participants and a fast moving virus statistical power is reached quickly.
For cancers, the disease is slow moving and there are fewer patients seeking experimental treatment. Fewer still are willing to chance that they are part of a control group. The patients who do participate are likely taking multiple other treatments, limiting the statistical power of the trial.
Do you really need a control group for this kind of study? The growth of cancer has been studied for well over a century, with millions of cases; what would a hundred more (to take a random number) tell you? (BTW, this is a real question, not a sarcasm!)
The control group is needed to measure process properties / systematic error.
It does not need to be a placebo group. Previous data at the same hospital does not help because the regular medicine does not run according to study protocols.
You cannot use 10 women to grow a fetus in 1 month. Likewise, you cannot have a good understanding of the long term risks without having s study that runs longterm.
40 weeks is by convention from estimated last menstrual period, which is of course about 2 weeks prior to fertilization - so the actual gestastional period is closer to 38 weeks (that is closer to 9 months than 10 months).
This is a phase I study. The point here is to establish safety. The study believes this treatment could have a benefit for patients, but they aren’t sure if there are unknown risks. This is to establish that there aren’t any unknown risks. The eligible patient population has already advanced on therapy (meaning the current standard of care hasn’t worked).
Getting patients to any sort of long-term response is the goal here. If there are any long term risks, that would be considered a good outcome (because the patient is still alive to have long term effects).
Any further (heritable genetic) risks are mitigated as the patients specifically are excluded if they are planning on having children in the near future.
Luckily we've been studying mRNA vaccines for over 50 years, which gave us a very good understanding of the long-term effects. What we really needed to test for was short-term effects + efficacy. These are easy to determine when 1% of the population is infected at the time of your clinical trial.
I can't stress how much the COVID mRNA deployment wasn't a "#yolo" moment like some folks still continue to insist.
It was a product of years and years of meticulous research and development. This put us at the finish line, and all we had to do was get over it.
We also got the J&J vaccine out in basically the same amount of time - because like the mRNA vaccines, the adenoviral vector vaccine platform had about 50 years of research and development behind it.
To use your analogy, we started with 10 ladies each 8 months pregnant, and we got them over the line in a month.
That doesn't mean the pregnancy took a month - just that we had a head start.
Not to be overly pedantic, but having the idea in the 1970s didn't count for much, because no one could get mRNA into human cells until around 1987. The first attempt at a vaccine was around maybe 1993. I mean, directionally your right but saying "we've been studying mRNA vaccines for over 50 years" isn't really correct.
Vaccines either produce side effects in 3-6 months or they don't.
There's no hidden time bomb in all the people who were vaccinated last year.
The FDA doesn't require long term safety studies for vaccines, and all the coronavirus vaccines have met the requirements. Nothing has been rushed.
We have a good understanding of this because the side effects are entirely dominated by autoimmune conditions, and we understand from the field of rheumatology how those arise.
We don't need to study pregnant women for another 5 years to see if any more babies pop out after the first one. Pregnancy is done in 9 months. Autoimmune side effects from vaccines happen in 3-6.
It is wild how heavily downvoted this is. Everything in this comment is correct (I also note none of the downvotes could be bothered to present any rebuttal to the claims).
It's unfalsifiable. "We don't know of any way this could happen, thus it will not happen" is not a claim that can be rebutted until it is proven wrong. "We don't have any reason to believe thalidomide is unsafe" was another such claim.
"This has never happened before in the recorded history of rheumatology and immunology" is the claim, backed up with pretty well fleshed out mechanistic theories of what happens during vaccination and how the body responds to it.
It also is falsifiable. Find the side effect that falsifies it.
And it has survived the prior testing of 100 years of vaccination.
They actually can, they're not a brand new never before seen kind of magic. They're using mechanisms that viruses and vaccines have used and which we've studied for hundreds of years. We don't actually know nothing about them.
Covid vaccines have already had multiple recalls due to unforeseen heart complications. These complications were, of course, "impossible" before they began occurring.
You cannot, by definition, foresee what unforeseen complications may arise with anything. Especially something as quickly made and widely disseminated as these vaccines. There may not be any "known" way a side effect could occur after 6 months. That does not philosophically mean anything about a risk existing. A lot, and I mean a lot, of medications have no side effects until you take them for years, and then suddenly there are issues. Adderall use is correlated with Parkinsons if you take it for over a decade. Some of these are foreseeable, and some were "no known way it could happen" until it did.
> This complex, specific and intricate process spans a number of months. Ultimately, though, in the absence of further stimulation by new copies of the spike protein, the immune response settles down, and effector cells—those directly and transiently involved in fighting the virus—decrease in frequency. Instead memory cells are established, poised to quickly ramp up production of antibodies, and even to replicate themselves, settling into their biological niches in our bodies until called upon once more if we happen to get infected. (This is what confers immunity to the coronavirus over the long run.) Antibody concentrations, some weeks after immunization, begin to reach their peak concentration in our blood, ultimately plateauing and beginning their slow decline. After this point, the risk of severe immunization-related complications doesn’t increase. Quite the opposite, in fact: it declines to virtually nothing after about three months. The six-month endpoint for these products is thus a rather conservative timeframe. Forget five or ten years: the way your immune system works does not allow for such long-term safety concerns.
HN submission feedback: This is a poor submission.
The linked page is just a bland study information page. This made it to the front page of HN despite being relatively free of actual information.
What's more, the subject line is misleading or wrong. This is not in any way the first human application of antitumor viruses (oncolytic viral therapy which has been going on for a few years), just the first person on this study (presumably -- the link in fact doesn't even indicate FPFD [first patient, first dose] has happened).
Title is misleading - this is a first in human, safety/dose-escalation study for this particular oncolytic virus. Oncolytic viruses have been in clinical development for quite some time. In response to the predictable “let us know when it works in humans” responses we see following sensationalist clinical research headlines, in 2015 we actually saw an oncolytic virus approved in the US: T-VEC for inoperable melanoma [0]
A few interesting things here from my point of view. First, they’re engineering the virus to infect cancer cells and overexpress PD-L1 to prime for enhanced immune-mediated killing. This could help a “cold” tumor turn “hot” by remodeling the tumor microenvironment. Second, the virus will also overexpress a symporter in the cancer cells which allows for targeted imaging and monitoring of tumor activity and cell death. There’s a nice graphical abstract available for reference [1]
Importantly, they’re assessing this in TNBC as it is associated with a very poor prognosis and has been validated as responsive to anti-PD-1 immunotherapies (eg, Keytruda/pembrolizumab)[2]
For the curious, there’s a preclinical Nature paper from June 2021 describing this in pancreatic cancer cells [3]
[0] https://en.wikipedia.org/wiki/Talimogene_laherparepvec
[1] https://pubmed.ncbi.nlm.nih.gov/35118191/
[2] https://www.nejm.org/doi/full/10.1056/NEJMoa1910549
[3] https://www.nature.com/articles/s41417-021-00350-4