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Msg  24983 of 25208  at  9/26/2021 11:50:15 AM  by

dnmun


 In response to msg 24982 by  dachmeister4u
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Re: CAR T Cells: Off the Shelf and On the Mark

 sleeping beauty is not used because it has  the ability to increase replication of effector T cells. it is used because it is simpler and safer to use a transposon to put the genes needed for the TCR into the cell rather than using the retrovirus as dr Rosenberg has always used. because his lab developed the use of the retrovirus for that.
 
the SB as no effect on replication, it is the activation of the transduced lymphocyte by exposure to it's 'cognate' antigen in the context of the HLA, which we call the MHC major histocompatability complex.
 
maybe i can cover this by going into fundamentals. every person has a different MHC, or blood type. when a ceell in the body has a mutation then the amino acid madde by that mutated gene is different from the normal AA so the protein with that AA is different and when that protein is digested into small pieces by the proteosome (the cellular garbage digestor/disposal function)  then when the new small 8-11 AA pieces that the MHC picks up as it enters the endoplasmic reticulum ER and is presented through the Golgi complex to the surface in the the care of the TAP transporter of antigenic protein.
 
so when this unusual protein in the grasp of the MHC reaches the surface of the cell, then it is recognized by the T cell which has been randomly assigned recognition of that unusual MHC-peptide complex, called the tetramer.
 
when that Teff cell recogniizes that unusual tetramer which was determined in the thyus to be non normal, or non self, then that Teff cell is activated. it is this activation which causes the Teff cell to begin reproducing as fast as possible so it rapidly grows to overrtake the presence of the the unusua cells. either because they are infected by virus or bacteria or if they just have a different AA being produced because of the mutation in the genome that causes that MHC-peptide complex to be recognized as non self.
 
this is why using the activation signals present on the cell surface, OX40 being the one most well recognized, but other techniques, such as the rapid clning technique, also provide  path to identify where the position of that mutated AA is in the sequencee of AA in that 8-11 AA piece picked up by the selection technique to be able to then program the naive lymphocyte with the TCR we introduce with the SB transposon. 
 
dr Rosenberg uses the retrovirus to introduce this new TCR into the naive lymphocytes, but that takes a long time and has risks of introducing a malignant retrovirus when reintroduced into the patient. 
 
our focus on these 'hotspot' mutations is to identify what is the AA changed when that 'hotspot' gene is mutated, and where is the position of that mutated AA in the sequence of 8-11 AA in the peptide of the tetramer which the patient already has a lymphocyte which will recognize that MHC-peptide complex .
 
ths is why it is so difficlut, finding the TCR coding of the lymphocyte that the body aready produces to bind to that unusual tetrmer complex in the saame individual with the tumor.
 
i don't follow FATE but i assume they redose with multiple courses of their engineered Teff cells because the Teff cells lack the ability to reproduce because they aree not activated by the mutated tumor protein MHC complex of the patient. so they have to be expanded in the IL-2 added solution. 


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Msg # Subject Author Recs Date Posted
24984 Re: CAR T Cells: Off the Shelf and On the Mark dachmeister4u 3 9/26/2021 12:16:25 PM


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