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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 off-target toxicities.
iCells are marketed by Cellular Dynamics International Inc.
(See Sleuthing for toxicity, page 1.)

SciBX 6(33); doi:10.1038/scibx.2013.905
Published online Aug. 29, 2013

Unpatented; licensing 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.