It may be true that we will see such spill overs but I’m not so sure this makes sense from an economic perspective. Autoimmune therapies are one of the few areas more attractive for Pharma than oncology. Consider the case of adalimumab (Humira), largest revenue drug in the world for several years. Anti-aging would be one of the few indications that would be even more lucrative than that! So you would expect spill overs to tend to be in the other direction. Does this just reflect the skew in basic research funding? Assuming all that research in mice is worth anything…
The reason I'm saying this is speculative is because we don't know for sure this is the mechanism behind immune aging and which subpopulations matter. But I think there's a lot of scattered data here and there that's suggestive. To be fair the subset of cells doesn't have to be autoimmune it just has to be a subset of immune cells that's bad and pro inflammatory and we know we wanna get rid of it. I do strongly believe there's are subpopulations of immune cells that are bad.
We could do it with tools we use for autoimmune disease after they had been perfected -- that's my point.
Yeah those are some really interesting studies you pointed to. CAR-T for autoimmune is something I hadn’t noticed. I do think if some of these trials are positive then a large amount of funding could shift from oncology to autoimmune. The economics of CAR-T in oncology aren’t great. The actual survival benefits are a little underwhelming. But in many situations in autoimmune disease this will look much better because you will avoid the costs of life time immunosuppressive therapies.
I was mainly thinking about NICE in England rejecting Yescarta a few years back. And subsequent approvals were only with some very favourable commercial arrangements. But perhaps what I should have said that CAR-T has not produced overwhelming evidence yet. The complete remission numbers are indeed good. But long term survival data are very limited. Often the promise in oncology dries up going from responses and progression to overall survival as you probably know. I just looked at the ZUMA-7 trial for an example. Axi-cel for large B cell lymphoma, reported 60% vs 30% difference in complete response but only 54.6% vs 46.0% difference in overall survival at 4 years. You can see why payers might be reluctant to spend $400,000 per patient for that. But really it is still too early to say definitively that these are underwhelming so I retract that. I guess I was hoping for more good quality RCT results faster.
Do you have any theories on why it is that women are more prone to autoimmune disorders? Given pregnancy, it seems like there should be an evolutionary drive towards being less aggressive when confronted with something on the border of self and foreign, rather than more.
He's been categorizing and analyzing different physiological circuit motifs and using them to make testable predictions that seem really promising, making connections between different disease states including many of the diseases of aging.
He's got two textbooks out, *An Introduction to Systems Biology* (https://a.co/d/8YyZXKs) and *Systems Medicine* (https://a.co/d/1soHeXF), the latter of which is more readable and more obviously related to these sorts of problems.
What does the aging profile look like for people who get autologous stem cell transplants like as part of cancer treatment? Per your hypothesis this should be effective anti-aging therapy as it would wipe out the accumulated subclinical virally induced auto immune response. To be fair it’s confounded by the cancer that would cause the transplant to be necessary in the first place but there should still be some signal like for atherosclerosis risk post transplant or something
It's a good question though I'm not sure what control you'd use here. Like the ppl who have the cancer and don't get the treatment would die and members of the general population without cancer... well they don't have cancer
1. You could do a CAC scan (or epigenetic age measurements etc if you buy that sort of thing) before and after the SCT so patients would be their own controls, 2. Compare CAC/epigenetic age to cancer patients who don’t get stem cell transplants, imperfect control but decent. Needing SCT is more dependent on evolution of resistance to chemo drugs than physiologic state of patient so idk if there would be that many non tumor differences between the groups. Also I’m not sure the evidence for SCT is all that amazing anyway so maybe not much difference in progression between the two groups.
so these cells that are responsible for the progression of the plaque are memory, antigen experienced ones. I think you need to "kill" those ones, not add new stem cells. I mean, it's somewhat complicated because some of the reason why you have accumulation of pro-inflammatory immune cells in plaques is mutations at stem cell level (e.g. those seen in CHIP). So there would be a benefit from that. But I do not see how stem cell transplants would get rid of memory antigen experienced subsets
Ah yeah I wasn’t being clear. For an autologous SCT for like myeloma, the idea is you save some stem cells ex vivo then go on super duper harsh chemo to try to eliminate the cancer, as a side effect this wipes out your entire immune system, then you reinject the stem cells that you saved. Notably, after an ASCT you have to get re-vaccinated against everything because the chemo eliminates most of your immunological memory. But if the chemo wipes out the good memory then it should wipe out the bad/autoimmune memory too!
Hi Rux, I enjoyed this piece, particularly the first part.
I am less convinced that long covid will turn out to be an autoimmune disease. The phenotype is very similar to chronic fatigue syndrome, which does show not consistent evidence of autoimmunity.
To say very speculative is an understatement. Given the context of management in its various forms, this discussion has an up hill battle and doesn't begin well. As a fantasy piece, it may work. External reality isn't so kind.
It may be true that we will see such spill overs but I’m not so sure this makes sense from an economic perspective. Autoimmune therapies are one of the few areas more attractive for Pharma than oncology. Consider the case of adalimumab (Humira), largest revenue drug in the world for several years. Anti-aging would be one of the few indications that would be even more lucrative than that! So you would expect spill overs to tend to be in the other direction. Does this just reflect the skew in basic research funding? Assuming all that research in mice is worth anything…
The reason I'm saying this is speculative is because we don't know for sure this is the mechanism behind immune aging and which subpopulations matter. But I think there's a lot of scattered data here and there that's suggestive. To be fair the subset of cells doesn't have to be autoimmune it just has to be a subset of immune cells that's bad and pro inflammatory and we know we wanna get rid of it. I do strongly believe there's are subpopulations of immune cells that are bad.
We could do it with tools we use for autoimmune disease after they had been perfected -- that's my point.
Yeah those are some really interesting studies you pointed to. CAR-T for autoimmune is something I hadn’t noticed. I do think if some of these trials are positive then a large amount of funding could shift from oncology to autoimmune. The economics of CAR-T in oncology aren’t great. The actual survival benefits are a little underwhelming. But in many situations in autoimmune disease this will look much better because you will avoid the costs of life time immunosuppressive therapies.
which ones are underwhelming? There are several CAR-T therapies for which we see complete remission in a subset of patients.
I was mainly thinking about NICE in England rejecting Yescarta a few years back. And subsequent approvals were only with some very favourable commercial arrangements. But perhaps what I should have said that CAR-T has not produced overwhelming evidence yet. The complete remission numbers are indeed good. But long term survival data are very limited. Often the promise in oncology dries up going from responses and progression to overall survival as you probably know. I just looked at the ZUMA-7 trial for an example. Axi-cel for large B cell lymphoma, reported 60% vs 30% difference in complete response but only 54.6% vs 46.0% difference in overall survival at 4 years. You can see why payers might be reluctant to spend $400,000 per patient for that. But really it is still too early to say definitively that these are underwhelming so I retract that. I guess I was hoping for more good quality RCT results faster.
Do you have any theories on why it is that women are more prone to autoimmune disorders? Given pregnancy, it seems like there should be an evolutionary drive towards being less aggressive when confronted with something on the border of self and foreign, rather than more.
Because their immune systems need to be stronger
there is a paper on this: https://pmc.ncbi.nlm.nih.gov/articles/PMC7980266/
Ruxandra, have you read any of Uri Alon's work?
He's been categorizing and analyzing different physiological circuit motifs and using them to make testable predictions that seem really promising, making connections between different disease states including many of the diseases of aging.
He's got two textbooks out, *An Introduction to Systems Biology* (https://a.co/d/8YyZXKs) and *Systems Medicine* (https://a.co/d/1soHeXF), the latter of which is more readable and more obviously related to these sorts of problems.
(You can also watch his lectures from Fall 2024 that cover much of his recent book: https://www.weizmann.ac.il/mcb/alon/courses/systems-aging-autumn-2024)
Yes I'm familiar with him. Tho I'm a bit skeptical biology is so amenable to physics like reductions, unfortunately
What does the aging profile look like for people who get autologous stem cell transplants like as part of cancer treatment? Per your hypothesis this should be effective anti-aging therapy as it would wipe out the accumulated subclinical virally induced auto immune response. To be fair it’s confounded by the cancer that would cause the transplant to be necessary in the first place but there should still be some signal like for atherosclerosis risk post transplant or something
It's a good question though I'm not sure what control you'd use here. Like the ppl who have the cancer and don't get the treatment would die and members of the general population without cancer... well they don't have cancer
1. You could do a CAC scan (or epigenetic age measurements etc if you buy that sort of thing) before and after the SCT so patients would be their own controls, 2. Compare CAC/epigenetic age to cancer patients who don’t get stem cell transplants, imperfect control but decent. Needing SCT is more dependent on evolution of resistance to chemo drugs than physiologic state of patient so idk if there would be that many non tumor differences between the groups. Also I’m not sure the evidence for SCT is all that amazing anyway so maybe not much difference in progression between the two groups.
Sorry it was late when we last talked.
so these cells that are responsible for the progression of the plaque are memory, antigen experienced ones. I think you need to "kill" those ones, not add new stem cells. I mean, it's somewhat complicated because some of the reason why you have accumulation of pro-inflammatory immune cells in plaques is mutations at stem cell level (e.g. those seen in CHIP). So there would be a benefit from that. But I do not see how stem cell transplants would get rid of memory antigen experienced subsets
Ah yeah I wasn’t being clear. For an autologous SCT for like myeloma, the idea is you save some stem cells ex vivo then go on super duper harsh chemo to try to eliminate the cancer, as a side effect this wipes out your entire immune system, then you reinject the stem cells that you saved. Notably, after an ASCT you have to get re-vaccinated against everything because the chemo eliminates most of your immunological memory. But if the chemo wipes out the good memory then it should wipe out the bad/autoimmune memory too!
Hi Rux, I enjoyed this piece, particularly the first part.
I am less convinced that long covid will turn out to be an autoimmune disease. The phenotype is very similar to chronic fatigue syndrome, which does show not consistent evidence of autoimmunity.
I don't think it's an "autoimmune disease".
I think it shows increases in autoantibodies which are also seen in autoimmune diseases so I think it shows an autoimmune-like phenotype.
Btw, the researcher who looked into long covid is also studying CFS as part of her immunology program: https://medicine.yale.edu/news-article/post-acute-infection-syndromes-will-be-the-focus-of-new-ysm-center/
https://medicine.yale.edu/news-article/new-evidence-supports-autoimmunity-as-one-of-long-covids-underlying-drivers/
Sorry I misread you.
I'm still skeptical that long covid or chronic fatigue syndrome will have an autoimmune basis but time will tell!
To say very speculative is an understatement. Given the context of management in its various forms, this discussion has an up hill battle and doesn't begin well. As a fantasy piece, it may work. External reality isn't so kind.