4 ms·

I don't understand why they can't do it again if a person relapses. Why is it a one time only event? Or, to put it another way, when the efficacy wears off, why

I don't understand why they can't do it again if a person relapses. Why is it a one time only event? Or, to put it another way, when the efficacy wears off, why does it persist?

justsocrateasin 5y ago
This may be an oversimplification, and I could be wrong, but the way I understand it is this: Relapse events are often triggered by an alternative mutation in the cancer. So let's say your skin cell becomes cancerous because gene 1111 mutates. You have, let's say, a million other genes that dictate your skin cell, and maybe like a few dozen mutations that could be cancerous (some mutations are harmless). So the T cell targets that gene 1111 mutation, but as a response, either that same mutated cell mutates again, or a healthy cell mutates. Now it's gene 1232 that mutates, but your T cells are modified to only recognize that gene 1111 mutation, so the new gene 1232 mutation sneaks by without being killed by the T cell. There are a lot of intuitions I have about why you can't just do it again, and ultimately I think it depends. Maybe gene 1232 doesn't change a protein that T cells can target without killing your other cells. Maybe your skin cell has dozens of mutations but 99% of them aren't cancerous, and we don't yet have the right signal/noise reduction in sequencing / the right AI to determine the mutation that is causing the cancer. Here we need to keep in mind that these proteins are very small and very hard to determine the structure of. Cancer cells can be very hard to differentiate from normal cells in a way that you can target them, so a new mutation is a whole new puzzle to solve. If I am wrong please correct me - my degree is in chemistry / applied math and not genetics/biology and this info comes from domain knowledge I pick up at my job (SDE for a cancer company) + books I've read.
- omarhaneef 5y ago
  So let's say you're targetting cd19 (the protein). You're saying that the target might stop emitting cd19. Okay, but then why not target cd21 or another target that the cancer is emitting, and run CAR-T again?
  - arjvik 5y ago
    Sometimes the cancer doesn't emit any marker proteins, or maybe the ones it does are difficult to detect/create antibodies to bind to. (I'm in the same situation as 2 above, I'm a software engineer with domain knowledge from working in a cancer research lab at a university; I may be entirely wrong.)
  - PeterisP 5y ago
    You need to choose a marker that you can "afford" to use for destruction - which either doesn't exist at all in healthy cells, or, more likely, it exists but losing all your healthy cells with the same marker won't kill you (but is still likely to harm you, just in ways that can be treated). Such markers are scarce, and not guaranteed to exist; if we find one for this cancer (like CD19) that works, but if it fails, then it's exceedingly likely that targeting "cd21 or another target" will simply kill you because it will also destroy some vital cells in your liver or veins or brain.
    - omarhaneef 5y ago
      You typically have a choice of a few “safer” markers like cd19, 21, 22 etc Even 19 will knock out your B cells and has to be managed with various treatments.
- s1artibartfast 5y ago
  My understanding is a little different: All skin cells have gene 1111, and you CAR-T goes after cells expressing gene 1111, killing all your skin. Some of the cancerous skin cells mutate to not express gene 1111, evading the CAR-T efficacy.
mlyle 5y ago
Short, incomplete answer: Cancer evolves. After a therapy has failed, you've effectively selected the proportion of the cancer most resistant to that therapy.
- inter_netuser 5y ago
  can't it be sequenced again and again and custom treatment prepared every time? cancer in general an umbrella term for 100s of different diseases.
  - mlyle 5y ago
    It all comes down to what surface receptors the cancer is presenting on whether you can get T cells to attack it. If the B-specific receptors are gone on your B-cell lymphoma, there may not be a great target left that isn't also on a bunch of cells you need. Each thing you do that targets "weird" characteristics of cancer (or bacterial infection, or pests) selects for cancer (or bacteria, or pests) that is presenting as less weird relative to everything else around.
f6v 5y ago
One reason would be that CD4 and CD8 populations undergo major changes with age. There’s a shift towards exhausted phenotype. Immune system produces fewer and fewer naive T cells in the bone marrow, thymus is less efficient in adulthood as well. I’d imagine CAR-Ts are less efficient in older adults. So getting in relapse after a decade would put a patient in a different position.
polski-g 5y ago
Luckily you can still go with a bone marrow transplant.
doctoring 5y ago
There's a couple of reasons for why a person may relapse after CAR-T therapy, and much is still under investigation. One large category is that the attack on the CD19 target has selected for B-cells which have a mutated CD19 or do not express CD19. This part kind of makes sense, and is somewhat understandable. The other category is roughly that the CAR-T cells fucked up, and this is where things are a little murky. Sometimes the CAR-T cells kind of disappeared really quickly after infusion. Sometimes they're there but there's no significant immune response. Remember the therapy uses the patient's own T-cells which get "armed" outside the body and then re-infused. What if the patient's own T-cells are kind of uh, wimpy? Or their immune system overall is? (We know, for example, that T-cell immunity in general declines over age, which probably partly explains better results in younger patients than older). Anyways, for various reasons, you can see why just "doing it again" may not work due to some issue with the targeting and the immune reaction. Oh and also CAR-T therapy is not benign. You can get intense cytokine release syndrome where the (intended) activation of your immune system causes a ton of systemic effects (sometimes resulting in organ failure, seizures, death). Nevertheless, sometimes they do try it again. I've had patients they've attempted CAR-T two or three times on. As you may guess, it was not effective.
- omarhaneef 5y ago
  It seems it would be effective if the B-cells were still emitting CD-21 or some other target. I thought that they manage the CRS pretty well these days. Is it still a major risk? I would be very curious to know more about this wimpy or no response. I am doubly surprised that it doesn't help to just do more.
  - doctoring 5y ago
    Choosing another target is a good idea! But, as you can imagine, we've been trying a lot of targets and they don't seem to work as well. One issue is that CD19 is the only known target that is a) expressed throughout the entirety of the B-cell lifespan, b) fairly preserved under immunological pressure, and c) is not expressed on other cells. Other targets do not maintain those characteristics and as such either won't catch all the tumor cells or will catch too many other cells. (CD21, for example, is also expressed on T-cells.) That being said, there are studies ongoing for some of these targets in like "last last resort" capacity, as well as certain dual-target CAR-Ts looking at CD19 + another (CD22 or CD123, for example), to try to widen the net while tolerating a degree of on-target but non-tumor effects. One could also imagine a way to more rapidly alter a patient's CAR-Ts such that you could quickly switch targets, or update them if their malignant CD19 was mutating. Currently the manufacture and production of CAR-T cells is very slow and expensive process, but I do have some friends working on improving that. Some are also working on the idea of a sort of "blank slate" CAR-T cell line which could be used in anybody, rather than being harvested from the particular patient in question. re: CRS. It is still a significant risk, but our understanding has definitely dramatically improved over the past 10 years. We're getting better and better at anticipating, appropriately triaging, and providing necessary diagnostics & supportive care. That being said, severe outcomes and death do still occur. I don't know the numbers, to be honest. re: the wimpy response. I am less well-versed in the immunological complexities but there are just so many steps which could contribute. Part of the CAR-T cell success requires them to continue to clonally expand after infusion into the body, and sometimes after infusion they just... don't. Or only a tiny subpopulation of them does. Why? We're not sure. Sometimes they fail to recruit the body's immune response. Why? Also not sure. Maybe it has to do with the health of the T-cells when they were harvested? Maybe something went wrong with the CAR engineering? Maybe with the host immune system? Here's a decent overview of some mechanisms of relapse after CAR-T which might be a good jumping off point: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6863137/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6863137/
dna4cy 5y ago
In addition to what others have written (mainly, loss of tumor antigen target CD19) the antigen receptor (part of the CAR) can be recognized as foreign (FMC63 on human CD19 targeting CARs is mouse origin) and the body will generate an antibody response to it. Thus, the second time CAR-T is infused, they are quickly rejected.
diskzero 5y ago
Other good answers are here about additional mutations occurring, making the cells no longer receptive. Another reason is that receiving CAR-T itself is quite risky. Almost everyone experiences some level of neurotoxicity, decreased cognition and more. It is my hope that these negative effects caused by the treatment will vanish, as CAR-T itself is pretty amazing.

I don't understand why they can't do it again if a person relapses. Why is it a one time only event? Or, to put it another way, when the efficacy wears off, why does it persist?

justsocrateasin 5y ago

This may be an oversimplification, and I could be wrong, but the way I understand it is this: Relapse events are often triggered by an alternative mutation in the cancer. So let's say your skin cell becomes cancerous because gene 1111 mutates. You have, let's say, a million other genes that dictate your skin cell, and maybe like a few dozen mutations that could be cancerous (some mutations are harmless). So the T cell targets that gene 1111 mutation, but as a response, either that same mutated cell mutates again, or a healthy cell mutates. Now it's gene 1232 that mutates, but your T cells are modified to only recognize that gene 1111 mutation, so the new gene 1232 mutation sneaks by without being killed by the T cell. There are a lot of intuitions I have about why you can't just do it again, and ultimately I think it depends. Maybe gene 1232 doesn't change a protein that T cells can target without killing your other cells. Maybe your skin cell has dozens of mutations but 99% of them aren't cancerous, and we don't yet have the right signal/noise reduction in sequencing / the right AI to determine the mutation that is causing the cancer. Here we need to keep in mind that these proteins are very small and very hard to determine the structure of. Cancer cells can be very hard to differentiate from normal cells in a way that you can target them, so a new mutation is a whole new puzzle to solve. If I am wrong please correct me - my degree is in chemistry / applied math and not genetics/biology and this info comes from domain knowledge I pick up at my job (SDE for a cancer company) + books I've read.

omarhaneef 5y ago
So let's say you're targetting cd19 (the protein). You're saying that the target might stop emitting cd19. Okay, but then why not target cd21 or another target that the cancer is emitting, and run CAR-T again?
- arjvik 5y ago
  Sometimes the cancer doesn't emit any marker proteins, or maybe the ones it does are difficult to detect/create antibodies to bind to. (I'm in the same situation as 2 above, I'm a software engineer with domain knowledge from working in a cancer research lab at a university; I may be entirely wrong.)
- PeterisP 5y ago
  You need to choose a marker that you can "afford" to use for destruction - which either doesn't exist at all in healthy cells, or, more likely, it exists but losing all your healthy cells with the same marker won't kill you (but is still likely to harm you, just in ways that can be treated). Such markers are scarce, and not guaranteed to exist; if we find one for this cancer (like CD19) that works, but if it fails, then it's exceedingly likely that targeting "cd21 or another target" will simply kill you because it will also destroy some vital cells in your liver or veins or brain.
  - omarhaneef 5y ago
    You typically have a choice of a few “safer” markers like cd19, 21, 22 etc Even 19 will knock out your B cells and has to be managed with various treatments.
s1artibartfast 5y ago
My understanding is a little different: All skin cells have gene 1111, and you CAR-T goes after cells expressing gene 1111, killing all your skin. Some of the cancerous skin cells mutate to not express gene 1111, evading the CAR-T efficacy.

mlyle 5y ago

Short, incomplete answer: Cancer evolves. After a therapy has failed, you've effectively selected the proportion of the cancer most resistant to that therapy.

inter_netuser 5y ago
can't it be sequenced again and again and custom treatment prepared every time? cancer in general an umbrella term for 100s of different diseases.
- mlyle 5y ago
  It all comes down to what surface receptors the cancer is presenting on whether you can get T cells to attack it. If the B-specific receptors are gone on your B-cell lymphoma, there may not be a great target left that isn't also on a bunch of cells you need. Each thing you do that targets "weird" characteristics of cancer (or bacterial infection, or pests) selects for cancer (or bacteria, or pests) that is presenting as less weird relative to everything else around.

f6v 5y ago

One reason would be that CD4 and CD8 populations undergo major changes with age. There’s a shift towards exhausted phenotype. Immune system produces fewer and fewer naive T cells in the bone marrow, thymus is less efficient in adulthood as well. I’d imagine CAR-Ts are less efficient in older adults. So getting in relapse after a decade would put a patient in a different position.

polski-g 5y ago

Luckily you can still go with a bone marrow transplant.

doctoring 5y ago

There's a couple of reasons for why a person may relapse after CAR-T therapy, and much is still under investigation. One large category is that the attack on the CD19 target has selected for B-cells which have a mutated CD19 or do not express CD19. This part kind of makes sense, and is somewhat understandable. The other category is roughly that the CAR-T cells fucked up, and this is where things are a little murky. Sometimes the CAR-T cells kind of disappeared really quickly after infusion. Sometimes they're there but there's no significant immune response. Remember the therapy uses the patient's own T-cells which get "armed" outside the body and then re-infused. What if the patient's own T-cells are kind of uh, wimpy? Or their immune system overall is? (We know, for example, that T-cell immunity in general declines over age, which probably partly explains better results in younger patients than older). Anyways, for various reasons, you can see why just "doing it again" may not work due to some issue with the targeting and the immune reaction. Oh and also CAR-T therapy is not benign. You can get intense cytokine release syndrome where the (intended) activation of your immune system causes a ton of systemic effects (sometimes resulting in organ failure, seizures, death). Nevertheless, sometimes they do try it again. I've had patients they've attempted CAR-T two or three times on. As you may guess, it was not effective.

omarhaneef 5y ago
It seems it would be effective if the B-cells were still emitting CD-21 or some other target. I thought that they manage the CRS pretty well these days. Is it still a major risk? I would be very curious to know more about this wimpy or no response. I am doubly surprised that it doesn't help to just do more.
- doctoring 5y ago
  Choosing another target is a good idea! But, as you can imagine, we've been trying a lot of targets and they don't seem to work as well. One issue is that CD19 is the only known target that is a) expressed throughout the entirety of the B-cell lifespan, b) fairly preserved under immunological pressure, and c) is not expressed on other cells. Other targets do not maintain those characteristics and as such either won't catch all the tumor cells or will catch too many other cells. (CD21, for example, is also expressed on T-cells.) That being said, there are studies ongoing for some of these targets in like "last last resort" capacity, as well as certain dual-target CAR-Ts looking at CD19 + another (CD22 or CD123, for example), to try to widen the net while tolerating a degree of on-target but non-tumor effects. One could also imagine a way to more rapidly alter a patient's CAR-Ts such that you could quickly switch targets, or update them if their malignant CD19 was mutating. Currently the manufacture and production of CAR-T cells is very slow and expensive process, but I do have some friends working on improving that. Some are also working on the idea of a sort of "blank slate" CAR-T cell line which could be used in anybody, rather than being harvested from the particular patient in question. re: CRS. It is still a significant risk, but our understanding has definitely dramatically improved over the past 10 years. We're getting better and better at anticipating, appropriately triaging, and providing necessary diagnostics & supportive care. That being said, severe outcomes and death do still occur. I don't know the numbers, to be honest. re: the wimpy response. I am less well-versed in the immunological complexities but there are just so many steps which could contribute. Part of the CAR-T cell success requires them to continue to clonally expand after infusion into the body, and sometimes after infusion they just... don't. Or only a tiny subpopulation of them does. Why? We're not sure. Sometimes they fail to recruit the body's immune response. Why? Also not sure. Maybe it has to do with the health of the T-cells when they were harvested? Maybe something went wrong with the CAR engineering? Maybe with the host immune system? Here's a decent overview of some mechanisms of relapse after CAR-T which might be a good jumping off point: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6863137/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6863137/

dna4cy 5y ago

In addition to what others have written (mainly, loss of tumor antigen target CD19) the antigen receptor (part of the CAR) can be recognized as foreign (FMC63 on human CD19 targeting CARs is mouse origin) and the body will generate an antibody response to it. Thus, the second time CAR-T is infused, they are quickly rejected.

diskzero 5y ago

Other good answers are here about additional mutations occurring, making the cells no longer receptive. Another reason is that receiving CAR-T itself is quite risky. Almost everyone experiences some level of neurotoxicity, decreased cognition and more. It is my hope that these negative effects caused by the treatment will vanish, as CAR-T itself is pretty amazing.