5 ms·

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

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] [0] https://en.wikipedia.org/wiki/Talimogene_laherparepvec https://en.wikipedia.org/wiki/Talimogene_laherparepvec [1] https://pubmed.ncbi.nlm.nih.gov/35118191/ https://pubmed.ncbi.nlm.nih.gov/35118191/ [2] https://www.nejm.org/doi/full/10.1056/NEJMoa1910549 https://www.nejm.org/doi/full/10.1056/NEJMoa1910549 [3] https://www.nature.com/articles/s41417-021-00350-4 https://www.nature.com/articles/s41417-021-00350-4

sizzle 4y ago
Here is the original article with similar title: https://news.yahoo.com/first-human-patient-injected-revolutionary-140900099.html https://news.yahoo.com/first-human-patient-injected-revoluti... It obscured the link to the actual clinical trial. Also front page of Reddit: https://www.reddit.com/r/worldnews/comments/uvplpj/first_human_patient_injected_with_revolutionary/ 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/i9n7nbg/ https://www.reddit.com/r/worldnews/comments/uvplpj/comment/i... Thank you for the work you do.
- ddingus 4y ago
  Seconded, and to sizzle for the interesting links. I find this kind of thing fascinating, and there is so much to it!
dghughes 4y ago
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. Found an article about it: https://www.nature.com/articles/d41586-020-03226-z https://www.nature.com/articles/d41586-020-03226-z
mayregretit 4y ago
Scatter-skimming your post drew my eyes to an alarming collection of phrases: misleading human safety dose escalation oncolytic virus in humans T-VEC inoperable engineering the virus to infect immune-mediated killing allows for targeted tumor activity cell death graphical poor prognosis anti-PD-1 pembrolizumab cancer. Like I stumbled across a Resident Evil script. Happily the post is coherent when perused.
upwardbound 4y ago
What do you mean by "cold" tumors and "hot" tumors? Is cold or hot better for the survival of the person? Thank you.
- tempestn 4y ago
  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.
  - MichaelBurge 4y ago
    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?
    - largbae 4y ago
      Let's agree as a species not to try and find out.
      - MichaelBurge 4y ago
        If the answer is "Yes, there's a protein on the cell membrane or a hormone that acts as the signal", then we already know the answer. Can you explain where the uncertainty is coming from?
        smaudet 4y ago
        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? "Oh I didn't think about that". -_-
refurb 4y ago
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.
DeathArrow 4y ago
Can you say it in plain English? Not all of us understand the jargon and the medical, technical and scientific aspects.
- arrosenberg 4y ago
  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).
- dmos62 4y ago
  You might have more luck if you ask for an explanation about a specific thing he said, not the whole of what he said. He said a lot of things.
chromatin 4y ago
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.
- sizzle 4y ago
  Here is the original non-expert article with similar title: https://news.yahoo.com/first-human-patient-injected-revolutionary-140900099.html https://news.yahoo.com/first-human-patient-injected-revoluti... It obscured the link to the actual clinical trial. Also front page of Reddit: https://www.reddit.com/r/worldnews/comments/uvplpj/first_human_patient_injected_with_revolutionary/ 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/i9n7nbg/ https://www.reddit.com/r/worldnews/comments/uvplpj/comment/i...
dontbenebby 4y ago
>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.)
- boppo1 4y ago
  You shouldn't be able to get away with it in psychology
  - dontbenebby 4y ago
    > 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. [1] https://en.wikipedia.org/wiki/Institutional_review_board#United_States_mandate_for_IRBs https://en.wikipedia.org/wiki/Institutional_review_board#Uni... [2]https://www.congress.gov/members/find-your-member https://www.congress.gov/members/find-your-member
    - boppo1 4y ago
      This is helpful, thanks!
      - dontbenebby 4y ago
        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 ;-) [1] https://web.archive.org/web/20150921200100/https://theintercept.com/2015/05/28/nsa-officials-privately-criticize-collect-it-all-surveillance/ https://web.archive.org/web/20150921200100/https://theinterc... [2] https://web.archive.org/web/20150723204817mp_/https://www.documentcloud.org/documents/2088983-too-many-choices.html https://web.archive.org/web/20150723204817mp_/https://www.do...
imtavi 4y ago
Always nice to see other folks on HN in this space. I'd love to connect; my email is in my profile.

sizzle 4y ago

Here is the original article with similar title: https://news.yahoo.com/first-human-patient-injected-revolutionary-140900099.html https://news.yahoo.com/first-human-patient-injected-revoluti... It obscured the link to the actual clinical trial. Also front page of Reddit: https://www.reddit.com/r/worldnews/comments/uvplpj/first_human_patient_injected_with_revolutionary/ 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/i9n7nbg/ https://www.reddit.com/r/worldnews/comments/uvplpj/comment/i... Thank you for the work you do.

ddingus 4y ago
Seconded, and to sizzle for the interesting links. I find this kind of thing fascinating, and there is so much to it!

dghughes 4y ago

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. Found an article about it: https://www.nature.com/articles/d41586-020-03226-z https://www.nature.com/articles/d41586-020-03226-z

mayregretit 4y ago

Scatter-skimming your post drew my eyes to an alarming collection of phrases: misleading human safety dose escalation oncolytic virus in humans T-VEC inoperable engineering the virus to infect immune-mediated killing allows for targeted tumor activity cell death graphical poor prognosis anti-PD-1 pembrolizumab cancer. Like I stumbled across a Resident Evil script. Happily the post is coherent when perused.

upwardbound 4y ago

What do you mean by "cold" tumors and "hot" tumors? Is cold or hot better for the survival of the person? Thank you.

tempestn 4y ago
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.
- MichaelBurge 4y ago
  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?
  - largbae 4y ago
    Let's agree as a species not to try and find out.
    - MichaelBurge 4y ago
      If the answer is "Yes, there's a protein on the cell membrane or a hormone that acts as the signal", then we already know the answer. Can you explain where the uncertainty is coming from?
      - smaudet 4y ago
        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? "Oh I didn't think about that". -_-

refurb 4y ago

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.

DeathArrow 4y ago

Can you say it in plain English? Not all of us understand the jargon and the medical, technical and scientific aspects.

arrosenberg 4y ago
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).
dmos62 4y ago
You might have more luck if you ask for an explanation about a specific thing he said, not the whole of what he said. He said a lot of things.

chromatin 4y ago

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.

sizzle 4y ago
Here is the original non-expert article with similar title: https://news.yahoo.com/first-human-patient-injected-revolutionary-140900099.html https://news.yahoo.com/first-human-patient-injected-revoluti... It obscured the link to the actual clinical trial. Also front page of Reddit: https://www.reddit.com/r/worldnews/comments/uvplpj/first_human_patient_injected_with_revolutionary/ 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/i9n7nbg/ https://www.reddit.com/r/worldnews/comments/uvplpj/comment/i...

dontbenebby 4y ago

>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.)

boppo1 4y ago
You shouldn't be able to get away with it in psychology
- dontbenebby 4y ago
  > 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. [1] https://en.wikipedia.org/wiki/Institutional_review_board#United_States_mandate_for_IRBs https://en.wikipedia.org/wiki/Institutional_review_board#Uni... [2]https://www.congress.gov/members/find-your-member https://www.congress.gov/members/find-your-member
  - boppo1 4y ago
    This is helpful, thanks!
    - dontbenebby 4y ago
      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 ;-) [1] https://web.archive.org/web/20150921200100/https://theintercept.com/2015/05/28/nsa-officials-privately-criticize-collect-it-all-surveillance/ https://web.archive.org/web/20150921200100/https://theinterc... [2] https://web.archive.org/web/20150723204817mp_/https://www.documentcloud.org/documents/2088983-too-many-choices.html https://web.archive.org/web/20150723204817mp_/https://www.do...

imtavi 4y ago

Always nice to see other folks on HN in this space. I'd love to connect; my email is in my profile.