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.
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.)
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.
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.
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.
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.
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.
Readit News
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
It obscured the link to the actual clinical trial.
Also front page of Reddit: https://www.reddit.com/r/worldnews/comments/uvplpj/first_hum...
AMA with creator of vaccinia oncolytic viruses here: https://www.reddit.com/r/worldnews/comments/uvplpj/comment/i...
Thank you for the work you do.
Found an article about it: https://www.nature.com/articles/d41586-020-03226-z
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.)
It obscured the link to the actual clinical trial.
Also front page of Reddit: https://www.reddit.com/r/worldnews/comments/uvplpj/first_hum...
AMA with creator of vaccinia oncolytic viruses here: https://www.reddit.com/r/worldnews/comments/uvplpj/comment/i...
The theranostic aspect to me is the most interesting part.
It obscured the link to the actual clinical trial.
Also front page of Reddit: https://www.reddit.com/r/worldnews/comments/uvplpj/first_hum...
AMA with creator of vaccinia oncolytic viruses here: https://www.reddit.com/r/worldnews/comments/uvplpj/comment/i...
It obscured the link to the actual clinical trial.
Also front page of Reddit: https://www.reddit.com/r/worldnews/comments/uvplpj/first_hum...
AMA with creator of vaccinia oncolytic viruses here: https://www.reddit.com/r/worldnews/comments/uvplpj/comment/i...
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.
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.
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.
Do we have effective measures to stop this virus in the event that this occurs? If so, what are they?
Edit: I don't know a lot about virology. Please don't downvote an honest question.
For some reason, the article isn't opening for me, so I don't know anything about this virus.
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.
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.
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.
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.
[1] https://journals.lww.com/journalacs/Abstract/2020/04000/Nove...
[2] https://en.wikipedia.org/wiki/Orthopoxvirus
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.
Let us know if they respond!
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4243974/
Haven't heard about it since.
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