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Msg  35449 of 35852  at  12/1/2023 6:40:04 PM  by

dnmun

The following message was updated on 12/1/2023 6:50:28 PM.

 In response to msg 35442 by  dachmeister4u
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Re: FWIW a look back into what Dr, Rosenberg is focused upon -- TCR-T

 
not sure what to say to add to this. first, we know it works from the response shown in the first patient before she lost the ability of her cancerous cells to express their surface antigens. the most common way is loss of part of chromosome 6 which carries part of the code that makes the protein that carries the antigenic protein to the surface of the cancerous cell.
 
what we are doing is to find the cells that are cancerous in solid tissue. but the CAR-T cell therapies are directed at the B cells of the blood, lymphocytes that go around the body looking for invading viruses and bacteria sorta things. 
 
these B cells are found in the lymph nodes and circulating throughout the body where blood and lymph flows. these cancers are called lymphomas, leukemias to reflect that.
 
on the surface of  B cell is a signature protein complex called CD19 (forgot the real name, complex of differentiation?),  but anyway the CAR T cell carries a manufactured antibody that can bind to these CD19 ANTIGENS when the cell carrying the has tons of them piled up in one place on the cell, and lymphoid cells like B cells do have a lot on the surface.
 
so the trick with these other CAR T cell therapies is to find the best match of the monoclonal antibody that the manufacturer can place on their otherwise ignorant T cells, (meaning that without the added CAR monoclonal antibody they would not recognize a B cell and bind to it, and monoclonal just means all of these newly minted T cells have the same CAR chimeric antigen receptor on them.) 
 
in order to convince the T cell to bind and kill these B cells these CAR antibody receptors have to find a high density, (BIG PILE), of these B cell antigens all in one place so that only some of the B cells will be bound and destroyed by the T cells with these CAR antibodies on them. this where the CAR T cell therapies fail.
 
most cancers are not these types of B cell cancers. only about 10% of all cancers are this type, the remainder are cancers in the solid tissues that make up the body, muscle and structural tissues and organs. 
 
our body has an organ called the thymus that just randomly makes up T cells and has a mechanism to prevent these randomly created T cells from attacking our normal tissues, and these self destructive T cells are destroyed in the thymus before they can leave, but the other newly, randomly, created T cells which do not attack normal tissue are allowed to exit the thymus and go hunting for something to kill that they recognize as been non self, or defective cancerous cells, and have the T cell receptor that will bind to that cell and activate the killing mechanism of that cell.
 
this is the beauty of the T cell receptor because it only take a few strange, not normal, proteins on the surface of the cancerous cell to cause the T cell that can bind to it to destroy the cell wall of the strange, (cancerous), so that the cancerous cell is removed by the normal junk removal organs of the body. i think about 3 or so is the lower limit whereas CAR T cells require thousands of the B cell antigens in a small area where the CAR T cell can bind with it's multitude of CAR's on the the T cell.
 
so the trick to finding these T cells with that ability to kill cancerous cells is to look for the T cells that did already try to kill the cancerous cells but just wore themselves out because there were not enough new T cells created by subdividing of the progenitor T cells that recognized the cancerous cells. so what our technique does is to go look in the blood for T cells that show this exhaustion from fighting off the cancer, and then use the genes for the receptors on that T cell to make new T cells , new T cells with the same programming of the cell to make the alpha and beta chains of the TCR on some otherwise useless young energetic T cells, we call them PBL, by using a genetic insertion tool called a transposase which used to be the way the Salmonid fishes that are now extinct, would randomly make changes to their body in order to evolve rapidly to meet changing environments in which the salmon would live in. as you know salmon do stupid stuff to reproduce, in an ancient very harsh world which allowed them to survive over time and eventually they lost the need for this TRANSPOSASE.
 
many years ago dr Rosenberg seems to have coaxed dr Laurence Cooper into trying to use it to insert genes into lymphocytes to create T cells with the ability to recognize and kill cancerous cells.
 
the way i picture this is to rationalize that dr Rosenberg could not do that himself in his lab because he is limited to working within the NCI, on real patients, and Cooper was kinda looking for something to do to make a name for himself to add to his credentials, and he could do this at MDAnderson where he had a big lab. jmho. 
 
so that was how we got started, but the technique for finding the genetic program of the  TCR that recognizes and binds to the cancerous cell surface antigen now uses equipment not available then.
 
we use a machine now called a sequencer, by Illumina, which can read out the genetic code of these alpha chains of the TCR from cells that we know have been fighting cancerous cells for a long time because they express a protein on their surface that indicates they are worn out from fighting cancer cells and are gonna die. known as NR4a, a signal of cellular exhaustion. 
 
we can identify these cells in the cancer patient's blood by using a monoclonal antibody that binds to the NR4a and this monoclonal antibody has attached to it a fluorescent die will will be excited to fluoresce when exposed to light of a specific frequency inside a machine called a FACS florescence activated cell sorter.
 
we know the frequency of the light that will excite the die bearing mAb attaching itself to these exhausted T cells with that NR4a surface molecule and each individual cell with the fluorescent label is then separated from the millions of others and placed into one of the little wells in the separation plate inside the FACS by the most tiny little autonomous pipettes you can imagine paying millions of dollars for. so that is how we find the T cells which can recognize the tumor cells and have been fighting it to their own exhaustion, and then we use the genetic code of that alpha chain of these cells to program the PBL.
 
this is where we differ from dr Rosenberg's technique because he uses a virus to insert the gene for the alpha chains of the TCR and we use the SB transposase. the other part of the TCR called the beta chains is taken from the mouse because it works just as well as the human beta chains to make the new TCR, but because it is mouse DNA then it does not bind to any of the other alpha chains of naturally synthetized TCRs in that cell we use from the PBL that might attack normal tissue in the body by accidently combining into a TCR that would attack normal tissue.
 
sorry to run on, doubt if i helped d4u much by rambling, but many here really do not know how we do what we do and why it is really the best way to do this way of finding and killing cancerous cells in solid tissues in the body. really the only way at present and i don't see any new ideas besides this in the literature i run though.
 
the risk of using a virus for the alpha chain  gene insertion step for this is hard to quantify and using the virus to insert the genes takes a long time and is very expensive, which is why dr Rosenberg has also decided to try using SB as well to see if he can get results like he does with his virus based technique. 
 
i sure wish Arie would recognize the limits of CAR now with the recent (SCATTERED and maybe overhyped) news about cancer caused in CAR patients by the therapy and make an offer. the sooner the better, but i know they will drag it out forever to get it as cheap as possible. fuck. 
 
 
 


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