I've been following this field with great interest since my wife was diagnosed with brain cancer.
It seems many types of cancer can evolve resistance to treatment with a single type of immunotherapy. Similar to how HIV quickly evolved resistance to treatment by one ARV (antiretroviral).
But HIV can be kept in check by a cocktail of 3 ARVs simultaneously. And there's some recent research from Mass General where they managed to eradicate brain tumors in mice using 3 different immunotherapies simultaneously: https://advances.massgeneral.org/neuro/journal.aspx?id=1263
> Dr. Curry's group describes "a likely oversimplified, but reasonable" summary of the mechanism of the triple therapy: GVAX expands the number and diversity of activated tumor-specific T cells and increases the number of intratumor CD8+ T cells, while PD-1 inhibition further invigorates the effects of those mobilized cells. Meanwhile, agonist anti-OX40 continues to skew systemic and tumor microenvironments toward Th1 immunity, suppress regulatory T cells and prevent T cell exhaustion.
Hopefully this is a way forward for treating humans too!
Looking through your post history, it seems you wife is doing much better than my dad did with his brain cancer. I assume then that it isn't glioblastoma. That shit is nasty.
Anyway, I hope things continue to remain reasonably in check for her. Cancer is a terrible thing.
Yes, we are relatively lucky that it's a low grade glioma. Sorry to hear about your dad, GBM is a monster.
The oncologist told us life expectancy is around 15 years which, while ~10x better than GBM, is a pretty disappointing thing to hear when you're in your early thirties. But that number comes from looking back at people diagnosed in recent decades, so we're really hoping that new treatments will change the equation going forward.
Re: resistance - it's not that the tumor is resistant to the immunotherapy, it's that the tumor is resistant to the immune system, and the therapy provided doesn't do the right thing to break down the resistance barrier. There are literally dozens of unique ways a tumor can suppress the immune system. So the challenge for each patient is finding which ones the tumor is using .
There are cases of adaptive resistance to immune-based therapies. These are less common, although they do arise. However, it is still the same kind of game - tumors use the same tricks to hide from an immune response ignited by an immunotherapy as they do from an immune response without immunotherapy.
Why the grain of salt? Doesn't the fact that they're actually working on the problem make them more credible, rather than less?
Yes, there's money involved, to be sure. However, on your view, does the fact that I get paid to write software disqualify me from speaking about software with credibility?
If I was the author of a type of software that historically was over-hyped vaporware then it wouldn't disqualify me but it would warrant taking my pronouncements a grain of salt.
Let me nitpick a bit. If for example the official Docker blog posted something on the lines of "Docker is good in these scenarios", or whatever, I'd recognize that there might be a conflict of incentives there, even if they are very well qualified to present Docker. Of course, it doesn't automatically disqualify what they have to say.
It's not about disqualifying anyone or necessarily about money. It's just a matter of noting bias, whether from money or acclaim.
For instance, if an academic works in a particular area of chemistry, they are more predisposed to say their area will have big important contributions to society in the future than a random chemist would.
JFC it’s a literal adaptimmune ad. “At Megaconglomco Inc, we use our patented pan-galactic gargleblaster fragments...”
Here I thought we were going to see something like Steve Forman’s work on CAR-T in glioblastoma, or allo-NK, or diet-based “priming” and the like, but noooooo...
I don't know this company very well but quickly looked at their website after reading that the company authored this article. They recently issued a press release with the headline that 4 of 5 patients treated with their drug had a partial response.
Reading further in the press release shows that 10 total patients were treated, 8 have been assessed, and one of those partial responses was unconfirmed. I haven't looked at the data and don't know the indication well enough to know it 3 or 4 partial responses from 10 patients is good. However i find the company's positioning of the data a bit misleading. For what it's worth, the stock is down a good amount since they announced this data
The wording of that study update combined with the excited yet data-light SA article is a bit concerning. I hope this does not make patients think this potential therapy is more promising than it actually is
I am skeptical that CAR-T therapy will go anywhere with solid tumors. Blood cancers and solid tumors are extremely different - they are basically different diseases. First, blood cancers have very few mutations (< 10); solid tumors may have tens of thousands. This means that blood cancers are a lot less heterogeneous than solid tumors. CAR-T cells are basically like a very specific kind of gun - you can say, "kill anything with protein X". But we've tried targeted therapies in solid tumors; they don't work, because the tumors usually have enough genetic heterogeneity that they can just evolve around the therapy. This is likely to be the case with CAR-T therapy as well.
Solid tumors also have the advantage of not being in the blood (obviously) - this makes them much harder to target with anything, especially circulating cells, which would have to extravasate and infiltrate the tumor itself. Blood is very accessible - you can just inject stuff into it. Heck, we have machines that can take blood out of the body, spin out whatever fractions we want, and put it back in all in one go.
Finally, blood cancers also have no microenvironment; they are circulating in the blood. A solid tumor can recruit and reprogram all sorts of quisling cells to cloak itself. These cells do all kinds of immunosuppressive things that we don't understand.
The main problem with the solid tumor is its complexity and its adaptive potential. CAR-T cells are a magic bullet - but the magic bullet can only kill one thing, not the many-headed thing that is a tumor. To beat the solid tumor I believe we need to fight it with something that has the adaptive potential of the tumor itself - i.e., the adaptive immune system.
For this reason I think we're more likely to see success by recruiting the native immune system. So far we've done this via checkpoint blockade. This also has its limits - unhooking immune checkpoints is like unchaining a mad rottweiler. It might kill the tumor, but it might just as well kill you.
Where I'd like immuno-oncology to go is understanding the mechanisms of immune evasion (i.e., what the tumor is doing to suppress the immune system, which should be mopping up cancerous cells, but isn't) and suppressing those. That way we can recruit the immune system to do its job without also causing it to damage the rest of the body.
But we don't even have an understanding of the immune makeup of the tumor yet, let alone how the tumor is recruiting and reprogramming immune cells to suppress the immune response. If we get there I think we'll see some real progress, but it will take a lot of work. It remains to be seen if we have the patience to do that work before we give up and move on to the next drug fad.
16 comments
[ 3.0 ms ] story [ 66.5 ms ] threadIt seems many types of cancer can evolve resistance to treatment with a single type of immunotherapy. Similar to how HIV quickly evolved resistance to treatment by one ARV (antiretroviral).
But HIV can be kept in check by a cocktail of 3 ARVs simultaneously. And there's some recent research from Mass General where they managed to eradicate brain tumors in mice using 3 different immunotherapies simultaneously: https://advances.massgeneral.org/neuro/journal.aspx?id=1263
> Dr. Curry's group describes "a likely oversimplified, but reasonable" summary of the mechanism of the triple therapy: GVAX expands the number and diversity of activated tumor-specific T cells and increases the number of intratumor CD8+ T cells, while PD-1 inhibition further invigorates the effects of those mobilized cells. Meanwhile, agonist anti-OX40 continues to skew systemic and tumor microenvironments toward Th1 immunity, suppress regulatory T cells and prevent T cell exhaustion.
Hopefully this is a way forward for treating humans too!
Anyway, I hope things continue to remain reasonably in check for her. Cancer is a terrible thing.
The oncologist told us life expectancy is around 15 years which, while ~10x better than GBM, is a pretty disappointing thing to hear when you're in your early thirties. But that number comes from looking back at people diagnosed in recent decades, so we're really hoping that new treatments will change the equation going forward.
This is true.
Interestingly, they're now starting to use Game Theory to beat cancer [1].
[1] http://fortune.com/2018/08/10/beating-cancer-game-theory/
There are cases of adaptive resistance to immune-based therapies. These are less common, although they do arise. However, it is still the same kind of game - tumors use the same tricks to hide from an immune response ignited by an immunotherapy as they do from an immune response without immunotherapy.
> ABOUT THE AUTHOR(S)
> Rafael Amado
> Rafael Amado is president of research and development at Adaptimmune.
Yes, there's money involved, to be sure. However, on your view, does the fact that I get paid to write software disqualify me from speaking about software with credibility?
For instance, if an academic works in a particular area of chemistry, they are more predisposed to say their area will have big important contributions to society in the future than a random chemist would.
Here I thought we were going to see something like Steve Forman’s work on CAR-T in glioblastoma, or allo-NK, or diet-based “priming” and the like, but noooooo...
Not cool at all, SA
Reading further in the press release shows that 10 total patients were treated, 8 have been assessed, and one of those partial responses was unconfirmed. I haven't looked at the data and don't know the indication well enough to know it 3 or 4 partial responses from 10 patients is good. However i find the company's positioning of the data a bit misleading. For what it's worth, the stock is down a good amount since they announced this data
The wording of that study update combined with the excited yet data-light SA article is a bit concerning. I hope this does not make patients think this potential therapy is more promising than it actually is
http://ir.adaptimmune.com/phoenix.zhtml?c=253991&p=irol-news...
Everyone gets a free trip to Florida after 72, and "international observers" collect the data.
Solid tumors also have the advantage of not being in the blood (obviously) - this makes them much harder to target with anything, especially circulating cells, which would have to extravasate and infiltrate the tumor itself. Blood is very accessible - you can just inject stuff into it. Heck, we have machines that can take blood out of the body, spin out whatever fractions we want, and put it back in all in one go.
Finally, blood cancers also have no microenvironment; they are circulating in the blood. A solid tumor can recruit and reprogram all sorts of quisling cells to cloak itself. These cells do all kinds of immunosuppressive things that we don't understand.
The main problem with the solid tumor is its complexity and its adaptive potential. CAR-T cells are a magic bullet - but the magic bullet can only kill one thing, not the many-headed thing that is a tumor. To beat the solid tumor I believe we need to fight it with something that has the adaptive potential of the tumor itself - i.e., the adaptive immune system.
For this reason I think we're more likely to see success by recruiting the native immune system. So far we've done this via checkpoint blockade. This also has its limits - unhooking immune checkpoints is like unchaining a mad rottweiler. It might kill the tumor, but it might just as well kill you.
Where I'd like immuno-oncology to go is understanding the mechanisms of immune evasion (i.e., what the tumor is doing to suppress the immune system, which should be mopping up cancerous cells, but isn't) and suppressing those. That way we can recruit the immune system to do its job without also causing it to damage the rest of the body.
But we don't even have an understanding of the immune makeup of the tumor yet, let alone how the tumor is recruiting and reprogramming immune cells to suppress the immune response. If we get there I think we'll see some real progress, but it will take a lot of work. It remains to be seen if we have the patience to do that work before we give up and move on to the next drug fad.