Is the end state of this to eventually modify people's bone marrow to produce modified T cells, or do they envision treating people with infusions of modified T cells? On one hand, permanently modifying people's immune systems seams fraught with challenges. On the other, a steady supply of cancer killing T cells sounds like a strong protection against recurrence.
This is an ongoing discussion in CAR-T. At the moment we only have 'autologous' CAR-T, which means they are manufactured from our own cells. The big advantage to 'allogeneic' CAR-T is that we don't have to take the time (several weeks) to modify T cells for adminstration, during which patients can die of the disease. 'Off the shelf' would be preferable, but there are lots of problems with trying to use someone else's T cells for the job.
The main issue is that our immune system is very good at removing non-self, so a lot of work would need to go into stopping the immune system doing this.
The article isn't talking about CAR-T though, rather TCR-modified T cells. These are very patient-specific because we have a unique MHC signature (this is why we have to find a 'match' for a transplant recipient). Previously people have taken the T cells from the tumour site, boosted them in the lab, and re-infused with some remarkable and curative results. The outcomes in this trial weren't so great but it is novel to splice in a new TCR.
CAR T-cells are cytotoxic T-cells modified so they do not cooperate with the rest of your immune system (they do reproduce inside your body, they just don't care what your "normal" immune system thinks on the matter). They do not listen to instructions from your immune system. They are modified from your own immune system so they don't get attacked, your immune system can't tell the difference between its own cells and CAR T-cells.
They are then further modified to go looking for specific targets (they go through your body, randomly, and check for specific molecules on cell membranes), and become "cytotoxic" towards them (they fire exploding acidic "bubbles" that digest a target cell).
Needless to say, this is a very dangerous treatment (uncontrolled killer T-cells roaming around inside your body multiplying ... not hard to imagine what happens if they target normal cells) and small mistakes will kill patients. In addition to directly killing off important cells, they may can also make the immune system overactive (which in fact happened in this study to three of the patients). They have a bad reputation in research for killing off entire batches of test animals when making a small mistake in less time than you'll need to diagnose the problem and, uh, "fix" it (you're supposed to kill test animals when a treatment doesn't work so they don't suffer). This is not allowed, and has to be explained to the authorities when it does happen and has ended research careers.
Normally, or should I say ideally, after multiplying a more-or-less set number of times, they die off and are removed by the body.
So no, this does not modify the bone marrow of the patient. Not at all. It just attacks and digests specific cells inside your body and dies off.
I think the fact they rapidly multiply while killing cells, inside your body, without any form of control beyond the initial "programming" deserves a, huge, honking, warning sign somewhere in that sentence. Once they go in, they may cure cancer, they may kill you in less than an hour, they can destroy your immune system and they can have your immune system destroy you.
Just to make clear this treatment will always be in the "you'll survive next week? This treatment is too risky" class.
Don't get too excited, this is medicine right? Surgeons literally cut people open -- don't try this at home.
CAR-T these days is indicated after hugely toxic therapies like BMT have failed. Plus they understand the danger of the cytokine storm responses and are at the ready to mitigate. A successful CAR-T therapy is massively less toxic overall.
If you really want to get freaked out: CAR-T uses a modified, neutered virus to reprogram the T cells. Today that's some lentivirus, but in the 2000s when this was a new therapy, it was a modified HIV. Things get safer over time!
The end state might be a little machine inside that does all of it without specific treatment, i.e. an enhanced immune system that knows what "cancer" is.
Someone makes a copy of your consciousness, runs millions of ads by this copy until it perfectly predicts your responses to various advertising strategies. Fast forward 2 months and you are broke.
An oppressive government makes a copy of your consciousness, tortures it. Learns everything. You never know it happened.
I made it up. I like the idea of taking Biblical stories and putting them into a sci-fi setting and trying to make a believable scenario. Like black mirror meets religion. Thanks for the message!
