Abstracts (complete list) - Wissenschaft Online

Elisa Kieback, Jehad Charo, Daniel Sommermeyer, Thomas Blankenstein, Wolfgang
Uckert
A new safeguard eliminates TCR gene-modified autoimmunereactive
T cells after adoptive therapy
The T cell specificity can be redirected by the transfer of TCR genes. The modified T
cells can elicit effector functions against the new target, and adoptive transfer of
redirected T lymphocytes into cancer patients has recently led to clinical success.
However, the adoptive transfer of TCR gene-modified lymphocytes is associated with
potential risks. First, many tumor antigens are also expressed in normal tissue.
Recognition of these antigens on non-tumor cells might lead to autoimmunity. Second,
the introduced TCR chains might form heterodimers with the alpha and beta chains of
the endogenous TCR. The specificity of these mispaired TCRs cannot be predicted and
they might have autoimmune capacity. Third, it has been shown that activation of the
introduced TCR might also trigger signal transduction of the endogenous receptor.
Therefore, it is essential to have the possibility to eliminate autoreactive T cells in vivo
in case of severe side effects.
The strategies developed so far include suicide genes or apoptosis-inducing fusion
constructs. However, they either do not lead to efficient depletion or require purification
of gene-modified cells which might hamper their functionality.
Here, we introduce a novel method to eliminate autoreactive TCR-redirected T cells. By
introducing a myc-tag into the murine OT-I and P14 TCR or the human gp100 TCR it
was possible to deplete T cells in vitro and in vivo with a tag-specific antibody. Tagmodified
TCRs exhibited equal functionality compared to the wild type receptor
concerning MHC-multimer binding and cytokine secretion. In vivo depletion of
adoptively transferred cells entirely prevented disease in an autoimmune mouse model.
Here, OT-I/myc TCR-transduced splenocytes were injected into RIP-mOVA mice which
express the OT-I specific antigen ovalbumin in the beta-islet cells of the pancreas.
Destruction of these cells by the adoptively transferred T lymphocytes led to severe
diabetic disease in untreated control mice. Mice receiving a dose of myc-antibody after
T cell transfer remained healthy and showed no increase in blood glucose levels.