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SLIDES
& TRANSCRIPTS
Monday,
May 12, 2003
Allogeneic
and autologous SCT
Stephen
J. Forman, M.D.
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| Slide
1: |
 In
adults the autologous and the allogeneic approach, I wanted to
present an idea that we were working on as it concerns adoptive
T cell therapy for B cell or pre-B ALL.
TOP
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| Slide
2: |
|  It
is focused on basically designing genetically modified T cells that
express a chimeric immunoreceptor, the idea being that, to introduce
this receptor into the cell endows it with a capacity to recognize,
in an antigen-specific way, as a way of overcoming the requirement
of isolating cells that either focus on minor antigens or other
antigen-specific T cells. I am going to show you how we have done
this.
We have focused
on, as the antigenic target, CD19.
TOP
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| Slide
3: |
|  As
you know, CD19 is expressed basically on the majority, if not all,
pre-B ALLs. It is really lost during the process of neoplastic transformation,
and specifically is not expressed on the hematopoietic stem cell,
and is not shed in the circulation.
Based on a
lot of the data we have looked at in getting ready for this project,
and in discussion with John Kersey at Minnesota, we concluded that
the cytogenetic progenitor cell at pre-B ALL still retains expression
of CD19.
TOP
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| Slide
4: |
|  So,
we thought it was an appropriate target.
Basically,
this is work that Mike Jenson and Lawrence Cooper have done at the
City of Hope, concerning a genetic approach.
What they have
done is, they have designed a chimeric immunoreceptor, the top portion
of which represents the antigen recognition site for CD19.
It is fused
to a CD4 transmembrane linker, and then connects to the intracellular
zeta chain of the T cell receptor so that, when antigen is bound
by the immunoglobulin component of the receptor, it turns on the
T cell.
TOP
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| Slide
5: |
|  This
is the plasmid that was designed, showing the CD19 component and
it is under our control of high tech. We have not taken out these
genes yet, for obvious reasons, wanting to maintain some control
over the fate of these cells, should there be problems after their
infusion.
TOP
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| Slide
6: |
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 This
is done by a non-viral electroporation. Basically, it takes approximately
six weeks from the time you first transduce the cells to have enough
cells to do three infusions at 109 cells.
TOP
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| Slide
7: |
|  What
I can show you is some data about the capacity for these clones.
These are CD8 specific CD8 clones, specific for CD19, and these
are two cell lines showing you the specificity.
The CD19 lines
are sensitive to the T cells and actually are a remarkably low ET
target. For those of you who do these sorts of assays, this is about
as low, I think, as we have seen for these kinds of assays.
TOP
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| Slide
8: |
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 There
aren't CD4 cytolytic T cells and it looks very much the same, with
the same specificity.
TOP
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| Slide
9: |
|  If
you look at primary cells, the more important target, these also
serve as targets for these cells.
TOP
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| Slide
10: |
|  So,
our goal, in essence, would be to try to augment the graft versus
leukemia effect by the adoptive transfer of donor derived B ALL
specific T cell clones, as a way of trying to decrease the relapse
after both allogeneic and autologous setting.
Working with
my pediatric colleagues, we have discussed the possibility of actually
making these cells for kids as part of their therapy to help prevent
the relapse in an antigen specific way, and I will stop there. Thank
you very much.
TOP
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