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techniques use the patented TALEN editing process to modify the genes in the T cells to give the
CAR-T cells qualities that ordinary T cells would not have in the absence of TALEN editing.
1) Provide an off-the-shelf treatment for each specific type of cancer.
Cellectis has pioneered the technique of using foreign donor cells from healthy patients with the
aim of creating a ready-to-use stock of CAR-T cells engineered to treat specific cancer types. This
can only be made possible if the host fails to recognise the graft T cells as foreign and accepts them
as its own cells rather than rejecting them as foreign cells. The key to this rejection is the TCR gene
which gives a signature to the graft cell's origin. Using TALEN, Cellectis edits out the TCR gene, so
that the CAR-T cell is no longer identified as foreign is not attacked by the host immune system. In
principle such cells would be immortal and protected from what is known as Graft vs Host Disease
(GvHD). The use of foreign donor cells opens the door to the development of an economically
viable range of CAR engineered T cells capable of targeting not only cancer but a whole range of
diseases including chronic viral infections.
3) Protect against self destruction/co-destruction
The CAR component built into the CAR-T cell will target an antigen found predominantly on the
targeted cancer cell. However the T cell itself carries its own antigens. When used in combination
with other treatments (chemotherapy) it may be susceptible to being attacked either by host T cells
or by combination chemotherapy agents. The TALEN gene editing technique can be used to protect
the CAR-T cells from such attack.
In the Cellectis UCART-CS1 programme, donor T cells are engineered to target the CS1 antigen
found on the surface of Multiple Myeloma cells. The allogenic (donor) T cells are first of all edited
to remove the TCR gene and so remove the risk of GvHD. However human T cells also carry the
CSI gene and so would be likely targets for self targeting by the engineered CAR-T cells. TALEN
gene editing was therefore used to remove the CSI gene from the engineered CAR-T cells to
eliminate self attack by other CAR-T cells and so potentially give the cells a longer and more
effective life.
In the UCART19 program, third party donor cells were engineered to target the CD19 antigen on Bcell Leukaemia. The TCR gene was first edited out to avoid GvHD. A common therapy for this
disease is Alemtuzumab, which targets the antigen CD52. The CD52 gene was therefore edited out
of the CAR-T cell to avoid resistance to Alemtuzumab when used in co-therapy with UCART 19.
3) Build in controlled regulation/controlled destruction
In order to modulate the activity of the CAR-T cells in case of over-reaction resulting in a violent
cytokine attack, the TALEN technique can also be used to introduce a specific suicide gene into the
CAR-T cell to render it sensitive to deactivation by a specific agent. As part of the CD123 target for
Acute Myeloid Leukemia (AML) and the UCART19 program, the T cells are designed to coexpress the RQR8 gene as a safety feature rendering them sensitive to the monoclonal antibody
rituximab.
All of these techniques were successfully demonstrated in the three communications presented by
Cellectis to the European Hematology Association (EHA) 2015. In all cases anti-tumor activity
was demonstrated in in-vivo mouse models.