[HTML][HTML] An improved bicistronic CD20/tCD34 vector for efficient purification and in vivo depletion of gene-modified T cells for adoptive immunotherapy

I Vogler, S Newrzela, S Hartmann, N Schneider… - Molecular Therapy, 2010 - cell.com
I Vogler, S Newrzela, S Hartmann, N Schneider, D Von Laer, U Koehl, M Grez
Molecular Therapy, 2010cell.com
T-cell-based adoptive immunotherapy is widely used to treat graft rejection and relapse after
stem cell transplantation (SCT). However, this approach is hampered by a high risk of life-
threatening graft-versus-host-disease (GvHD). Clinical trials have demonstrated the value of
suicide genes to modify T cells for the effective control of GvHD. Herewith, we show that the
combination of a codon-optimized B-cell antigen (CD20op) with a selection marker based
on a cytoplasmic truncated version of the human stem cell antigen CD34 (tCD34) allows the …
T-cell-based adoptive immunotherapy is widely used to treat graft rejection and relapse after stem cell transplantation (SCT). However, this approach is hampered by a high risk of life-threatening graft-versus-host-disease (GvHD). Clinical trials have demonstrated the value of suicide genes to modify T cells for the effective control of GvHD. Herewith, we show that the combination of a codon-optimized B-cell antigen (CD20op) with a selection marker based on a cytoplasmic truncated version of the human stem cell antigen CD34 (tCD34) allows the generation of highly enriched gene-modified T cells. We demonstrate coordinate co-expression of both transgenes and high expression of CD20op resulting in an increased susceptibility to Rituximab (RTX)-induced cell death. In addition, T cells partially retained their alloreactive potential and their CD4/CD8 ratio after transduction and expansion. Long-lasting transgene expression was sustained in vivo after adoptive transfer into Rag-1−/− mice. Moreover, gene-modified T cells were quickly and efficiently depleted from peripheral blood (PB) and secondary lymphoid organs of transplanted animals after RTX treatment. These results warrant further steps toward a clinical application of CD20op as a suicide gene for adoptive immunotherapy.
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