Thursday, August 29, 2013
This week in techniques
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Assays & screens
Strategy to decrease
off-target peptide recognition by affinity-enhanced, T cell receptor (TCR)-based T cell therapies
Amino acid scanning and
cell culture screens could be used to decrease the risk of off-target
toxicity from TCR-based T cell therapies to treat cancer. Clinical use of T
cells engineered to express affinity-enhanced TCRs targeting melanoma-associated antigen A3
(MAGEA3) led to two patients
dying of cardiac failure. An in silico scan of non-MAGEA3 protein
sequences identified three proteins containing a peptide motif that could be
recognized by the TCRs targeting MAGEA3. In cell lines individually pulsed
with each of the three non-MAGEA3 peptides, only the cells pulsed with a
peptide derived from the muscle protein titin (TTN) induced activation of
MAGEA3-targeting T cells. In 3D beating cultures of iCell cardiomyocytes and
in five independent human cardiac tissue samples, titin expression was
confirmed, suggesting the off-target clinical toxicity was a result of the T
cells targeting titin. Next steps include using the strategy to avoid future
iCells are marketed by Cellular Dynamics International Inc.
for toxicity, page 1.)
Published online Aug. 29, 2013
status not applicable
Cameron, B.J. et al.
Sci. Transl. Med.; published online Aug. 7, 2013;
Contact: Bent K. Jakobsen, Immunocore Ltd., Abingdon, U.K.
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