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I'm a haematologist who is involved with patients who have CAR-T (I don't do it myself, but do other types of transplant and I look after the patients before an
by dm319 4y ago
I'm a haematologist who is involved with patients who have CAR-T (I don't do it myself, but do other types of transplant and I look after the patients before and after) and my research area is in the way T cells target cancer.
This study isn't CAR-T. It is more similar to adoptive TIL therapy because it is using the T cell receptor (TCR) to target the cancer's mutations. This has a huge advantage over CAR-T.
At the moment we use CAR-T to target, mostly, B cell cancers. These cancers have CD19 and CD20 on their cell surface, as do most B cells. We can safely target these cells because it turns out your B cells aren't critical for life. Think of it like an amputation. Your B cells went rogue, you wipe them out.
The problem is this doesn't translate to other cancers, which don't have an obvious cell protein you can target specific to a group of cells you can do without.
All cancer cells have mutations, and all cells in the human body have to display a sample of its proteins on its cell surface. This way our immune system regularly identifies cancer and removes it. Cancers that get established have somehow leveraged local immunosuppression to hold off the immune system, and so the immune system and cancer become a stalemate, or worse the cancer takes off and kills the person.
If we can target the mutations of the cancer, then we can get at the heart of the cancer itself.
You might ask why the cancer just doesn't display it's antigens on the surface. If a cell does this it gets removed by NK cells (natural killers) - our body's fail safe.
What I find interesting is that I didn't think we were close to predicting what TCRs can bind to to a peptide on MHC on the cell surface. I'm going to need to look at the article to findout how they did this. I suspect they used a library of known TCR-antigen interactions.
- readittwice 4y agoSince there are people here that seem to know a bit about this stuff, I will take the chance to ask some naive questions ;) Do I have this right that CAR T-cells have this engineered B-cell/antibody like receptor that recognizes antigens only on the cell membrane. While the regular T-cell receptor can look into cells as well? And that's why the T-cell receptor is potentially better at recognizing solid cancers? So cancers usually create this immunosuppresive environment, wouldn't this stop this engineered T-cells as well?
- dm319 4y agoYes, CAR-Ts are really a B cell receptor (otherwise known as an antibody) grafted onto a T cell. Antibody directly binds things like proteins, and usually targeted to things found on cell membranes. Also on the cell membrane is MHC-1, which shows a short (9-11 amino acid) fragment of protein produced from inside the cell. Our T cells are trained in our T cell kindergarten (the thymus) to not identify our usual self proteins, but detects anything different. They have already been demonstrated to identify single amino acid changes from normal. Yes, the micro-environment means the immune cells reach a dynamic equibrium. This is because when a cancer presents to healthcare, it is already a chronic process. The T cells are termed 'exhausted', but it's debatable whether this is a good term for it, because they are still active. A lot of cancer treatment 'shakes up' the microenvironment. This can be enough to tip into a cure. When you make CAR-Ts and adoptive TILS you either pick healthy T cells not involved in the cancer or buff them up in the lab, both in numbers and health. The hope is that a refreshed army of T cells will push that dynamic equilibrium towards a cure.
- acchow 4y ago9-11 amino acids sounds very short - only 18-22 bits of information. How do we decide something has gone wrong from only an 18 bit slice?
- dm319 4y agoI think there is more information than that. There are 20 amino acids, so around 1x10^13 possible sequences. This is also a clue as to why we don't have a perfectly rigid system, as a library of T cells capable of recognising every combination would weigh 600+ kg.
- acchow 4y agoI had a brain fart. I was thinking of DNA base pairs not amino acids :) Thanks for that. There are 20 amino acids. Each AA in a sequence represents approx 4.3 bits. So 9-11 AA would be 38.7-47.3 bits. Not quite as much as an MD5 hash (128 bits), but still quite a bit of info.