Antibodies againts the CD19 marker on B cells can clear out B cells from the blood and to some extent the lymph glands, but antibody doesn’t get into the brain very well and so will not clear out the brain very well. Even if it did get in the brain, as the antibodies often need natural killer cells/neutrohils to mediate the destuction and these cells are not attracted into the brain.
T cells can get into any tissue in any part of the body and if acrivated have no problem in getting into the brain. T cells have targets due to their antigen receptors, but you can engineer them to have new targets by inserting an antibody into them.
This antibody is engineered to exhibit T cell activation machinery and is called a CAR = chimeric antigen receptor. You put it into a CD8 kiler cell and the result is CAR-T-cell. This is specifically developed for each individual patient and involves reprogramming the patient’s own immune system cells which are then used to destroy their target.
So if you want to get the T cells to kill B cells you can give them a CD19 chimeric antigen receptor (an antibdoy on the cell surface and a T celll receptor signalling element). If you wan to kill plasma cells (antibody secreting cells you can make a BCMA (B-cell maturation antigen known as tumor necrosis factor receptor superfamily member 17) as it expressed by plasma cells. If you wanted to targetmemory B cells you could go APRIL receptor (Transmembrane activator and CAML interactor (TACI), also known as tumor necrosis factor receptor superfamily member 13B (TNFRSF13B).
CART-19 is being used against B cell and plasma cell cancers and CAR-T therapy can cure people of their cancers. They can clear out the brain the bone marrow etc. But once you have made these T cells they will not only root out the B cell cancers where ever they are lurking but they will destroy ever B cell in the body……forever. Therefore, it is a potentially risky treatment and so used in people with life threatening problems. However, it has real potential if you could get rid of the CAR T cells once they have done the business to get rid of the pathogenic B cells or if you want T cells or ThGM, Th1 or Th17 etc. It would mean perhaps that you would have to re vaccinate your childhood infections if you remove plasma cells but remember you are not destroying the stem cells,early B cells so a new repertoire can regenerate.
In animals it has been shown that you can get rid of the anti B cell CAR-T -B cells using antibodies. They get them to express a molecule (which is designed not to bind to its natural target or signal), which can be targeted a commercially available antibody. Will this become a reality for humans?`Is this going to be good enough becuase will those CART cells be lurching in the places antibodies can’t reach
Not in animals only..
https://www.scripps.edu/news-and-events/press-room/2020/20200203-calibr-cartIND.html
Interesting
CAR-T was one of the first thing I thought when I came across this blog but aware of the potential risks it is a clear no go. Then I read this post and I immediately thought that we can fight fire with fire. We make CAR-T that target CD19 and BCMA. Both types expressing another non immunogenic protein. Them we make a third CAR-T targeting that protein. First you infuse the CD19 and BCMA CAR-T. Once they have done their business you infuse the third CAR-T that clearing out the first two types restore the normal function of the immune system.
Expensive but in principle resolutive and quite safe.
There are already CAR-T against CD19 and BCMA available in the pipelines
The downside is the cost of CAR-T-cells and that they will take out all B-cells expressing the antigen being targeted.
“In a July 2020 comment on the Centers for Medicare & Medicaid Services (CMS) Hospital Inpatient Prospective Payment System proposed rule, the American Society of Clinical Oncology noted the average cost of a CAR-T cell product at $373,000, with the estimated cost of CAR-T cell therapy and related services at $419,238“.
That’s true! I know that. But… what is the cost of second line DMTs? Ocrevus should be in the 60k per year plus the cost of the related services. And prices for MS drugs usually increase with time. So in 7 years one of the car t would be payed back depending on the pricing.
We should not consider the price of the drug and related service alone but the whole costs for the management of the disease and for the average duration.
Also we should consider that people will keep working and pay taxes etc.
I think that in this view the costs could become more appealing.
When will the phase 3 trial of higher dose of ocrevus for relapsing remitting patients be completed ( in what year ) ?
And what difference do you think it will make to the pathogen of MS? Other than increase the revenue for roche and all the little fishes that feed.
A ray of sunshine as ever………………………
😂
CAR-T can be activated and deactivated by pulsed light like a switch.
https://advances.sciencemag.org/content/6/8/eaay9209
One of the first talks i heard about car-t cell theraphy was by Stephan A. Grupp one of the first pioneers of this theraphy
He was presenting some slides from patients infused with the cells and one of them ferritin was at
250 000
Normal range
Men 18–270 nanograms per milliliter (ng/mL)
Women 18–160 ng/mL
He said that they had to redesign the lab sensor because they could´ ´nt reach those values
Caneco
MD, can you kindly share some link to papers where CAR-T cell removal was achieved in animals, please? Thank you in advance!