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Won't the cancer cells mutate again after it figures out that the immune system is working successfully against it ? If they won't mutate why can't the body ch

Won't the cancer cells mutate again after it figures out that the immune system is working successfully against it ? If they won't mutate why can't the body choose the white blood cells which are effective against it and amplify them ? Why does it have to be done externally in a lab ? If they do mutate again, what makes this treatment effective ? Excuse me for the basic questions,I have no experience in Biology or how antibiotics work.

dm319 9y ago
No, those are excellent questions. Our immune system is a force to be reckoned with for any cancers - we don't have figures on how many cancers our immune system clears before it meets one it cannot clear. So for cancer to survive, it has to thwart our immune system somehow, and one of the ways it does this is to use signalling pathways which dampen down the immune response. It communicates to the cancer 'calm down, don't call your friends'. The immune cells don't go away - instead they switch to a mode where they control rather than clear the cancer. Adoptive TIL therapy (which is not the same thing as the article is talking about, though they are both T cells) takes the immune cells from the cancer. These cells recognise the cancer as being foreign ('non-self') and in need of clearing, but they have been suppressed by signals from the cancer. In the lab the cells are selected and bred so that you have a pool of hyped-up cytotoxic T cells, which when transfused back into the patient are so aggressive even the suppressive signals from the cancer don't stop the killing. In fact, it's the mutations in the cancer which allow this therapy to work. Mutations are what makes the cancer 'non-self' - the more they have, the more attention they get from the immune system. If they try to hide their mutations (all cells must present the products of their DNA on the cell surface), they get removed by natural killer cells (so called because they naturally kill cells unless they display what they are meant to on the cell surface). The article actually talks about another type of treatment called CAR-T cell therapy. This is a bit different. What you do in this case is you take a T cell from the patient (not a tumour-infiltrating T cell - instead you want an effective T-killer cell), and they graft an antibody which is specific* for the tumour onto the cell. There are a few other steps to make sure that the cell survives in the patient, but essentially when you infuse this cell (ok they give more than one) into the patient, it recognises the target (hopefully the tumour), divides and kills, divides and kills etc etc until the tumour is gone. Then hopefully it stops dividing, or you end up with a T cell tumour. In this case - your question is right on target. The cancer can and does mutate to avoid this therapy. In this particular case the antibody is for CD19/CD20 (I can't remember), and it was able to clear the tumour before it could evolve to drop CD19/20 from the cell surface. In other patients subsequently treated, a proportion of them have relapse with tumour cells not displaying CD19 on the surface. In fact, this is the achille's heal of CAR-T cell treatment. It is essentially a very powerful antibody, but for it to work it needs a few things - 1. The tumour must have the target marker on all of its cells - i.e. it can't evolve out, 2. You must be happy to lose any healthy cells which also have this marker. In this case the patient lost all of his B cells. This is a powerful component of the immune system, but actually, you can get away without it, thankfully. This treatment wouldn't work for a T cell leukaemia/lymphoma. Removing all of your T cells gives you AIDS, which is no better than having a terminal cancer (when it's not caused by HIV, that is).
- epmaybe 9y ago
  I just want to say that you have a fantastic way of writing that explains these therapies extremely well. I've learned about these therapies in class, but your explanations felt even more fluid.
  - dm319 9y ago
    Thank you for telling me that - much appreciated :)
- kittiepryde 9y ago
  Can this treatment be designed to target the mutations? ( So you didn't lose healthy cells ) I'm assuming the mutations present on the cell surface as well, but I am unsure. In that case, would any cell that mutated to avoid there treatment, de-cancer itself?
  - dm319 9y ago
    That would be a sort-of holy grail of cancer therapy. The problem is that the best equipment to develop a high-affinity antibody, or find the correct T cell receptor to the mutation is the patient's immune system - and they've already done it. Predicting what sort of antibody or T cell receptor will bind a specific mutation (more technically a piece of protein with the mutation in it - about 10 amino acids long) is hugely difficult - it requires a very good understanding of how all the amino acids fold and interact in a 3D spatial model, and we simply aren't there yet. Your last question really depends on the mutations. Further mutations would stimulate more of an immune response, but a mutation could, for example, increase the ways a tumour cell hides from the immune system. On the other hand, it would be hard for the tumour cells to de-mutate itself to avoid TILs already specific for that mutation.
- rgejman 9y ago
  Just a clarifying note: mutations and foreign proteins are not always responsible for the effectiveness of TILs in all cases. For instance, in a report from this year, patients with HPV (Human Papilloma Virus) positive cervical cancer were treated with TILs. It was expected that most of the TILs would be directed to HPV antigens or mutated protein (neo-antigens) because both would be maximally foreign to the immune system. However, it was determined that T cells against the wild-type protein CT83 (also known as KK-LC-1; which is a wild-type cancer associated antigen) dominated the response in at least one patient. http://science.sciencemag.org/content/356/6334/200.full http://science.sciencemag.org/content/356/6334/200.full

dm319 9y ago

No, those are excellent questions. Our immune system is a force to be reckoned with for any cancers - we don't have figures on how many cancers our immune system clears before it meets one it cannot clear. So for cancer to survive, it has to thwart our immune system somehow, and one of the ways it does this is to use signalling pathways which dampen down the immune response. It communicates to the cancer 'calm down, don't call your friends'. The immune cells don't go away - instead they switch to a mode where they control rather than clear the cancer. Adoptive TIL therapy (which is not the same thing as the article is talking about, though they are both T cells) takes the immune cells from the cancer. These cells recognise the cancer as being foreign ('non-self') and in need of clearing, but they have been suppressed by signals from the cancer. In the lab the cells are selected and bred so that you have a pool of hyped-up cytotoxic T cells, which when transfused back into the patient are so aggressive even the suppressive signals from the cancer don't stop the killing. In fact, it's the mutations in the cancer which allow this therapy to work. Mutations are what makes the cancer 'non-self' - the more they have, the more attention they get from the immune system. If they try to hide their mutations (all cells must present the products of their DNA on the cell surface), they get removed by natural killer cells (so called because they naturally kill cells unless they display what they are meant to on the cell surface). The article actually talks about another type of treatment called CAR-T cell therapy. This is a bit different. What you do in this case is you take a T cell from the patient (not a tumour-infiltrating T cell - instead you want an effective T-killer cell), and they graft an antibody which is specific* for the tumour onto the cell. There are a few other steps to make sure that the cell survives in the patient, but essentially when you infuse this cell (ok they give more than one) into the patient, it recognises the target (hopefully the tumour), divides and kills, divides and kills etc etc until the tumour is gone. Then hopefully it stops dividing, or you end up with a T cell tumour. In this case - your question is right on target. The cancer can and does mutate to avoid this therapy. In this particular case the antibody is for CD19/CD20 (I can't remember), and it was able to clear the tumour before it could evolve to drop CD19/20 from the cell surface. In other patients subsequently treated, a proportion of them have relapse with tumour cells not displaying CD19 on the surface. In fact, this is the achille's heal of CAR-T cell treatment. It is essentially a very powerful antibody, but for it to work it needs a few things - 1. The tumour must have the target marker on all of its cells - i.e. it can't evolve out, 2. You must be happy to lose any healthy cells which also have this marker. In this case the patient lost all of his B cells. This is a powerful component of the immune system, but actually, you can get away without it, thankfully. This treatment wouldn't work for a T cell leukaemia/lymphoma. Removing all of your T cells gives you AIDS, which is no better than having a terminal cancer (when it's not caused by HIV, that is).

epmaybe 9y ago
I just want to say that you have a fantastic way of writing that explains these therapies extremely well. I've learned about these therapies in class, but your explanations felt even more fluid.
- dm319 9y ago
  Thank you for telling me that - much appreciated :)
kittiepryde 9y ago
Can this treatment be designed to target the mutations? ( So you didn't lose healthy cells ) I'm assuming the mutations present on the cell surface as well, but I am unsure. In that case, would any cell that mutated to avoid there treatment, de-cancer itself?
- dm319 9y ago
  That would be a sort-of holy grail of cancer therapy. The problem is that the best equipment to develop a high-affinity antibody, or find the correct T cell receptor to the mutation is the patient's immune system - and they've already done it. Predicting what sort of antibody or T cell receptor will bind a specific mutation (more technically a piece of protein with the mutation in it - about 10 amino acids long) is hugely difficult - it requires a very good understanding of how all the amino acids fold and interact in a 3D spatial model, and we simply aren't there yet. Your last question really depends on the mutations. Further mutations would stimulate more of an immune response, but a mutation could, for example, increase the ways a tumour cell hides from the immune system. On the other hand, it would be hard for the tumour cells to de-mutate itself to avoid TILs already specific for that mutation.
rgejman 9y ago
Just a clarifying note: mutations and foreign proteins are not always responsible for the effectiveness of TILs in all cases. For instance, in a report from this year, patients with HPV (Human Papilloma Virus) positive cervical cancer were treated with TILs. It was expected that most of the TILs would be directed to HPV antigens or mutated protein (neo-antigens) because both would be maximally foreign to the immune system. However, it was determined that T cells against the wild-type protein CT83 (also known as KK-LC-1; which is a wild-type cancer associated antigen) dominated the response in at least one patient. http://science.sciencemag.org/content/356/6334/200.full http://science.sciencemag.org/content/356/6334/200.full