T cells targeted to TdT kill leukemic lymphoblasts while sparing normal lymphocytes
Muhammad Ali, Eirini Giannakopoulou, Yingqian Li, Madeleine Lehander, Stina Virding Culleton, Weiwen Yang, Cathrine Knetter, Mete Can Odabasi, Ravi Chand Bollineni, Xinbo Yang, Zsófia Földvári, Maxi-Lu Böschen, Eli Taraldsrud, Erlend Strønen, Mireille Toebes, Amy Hillen, Stefania Mazzi, Arnoud H. de Ru, George M. C. Janssen, Arne Kolstad, Geir E. Tjønnfjord, Benedicte A. Lie, Marieke Griffioen, Sören Lehmann, Liv Osnes, Jochen Buechner, K. Christopher García, Ton N. Schumacher, Peter A. van Veelen, Matthias Leisegang, Sten Eirik W. Jacobsen, Petter Woll, Johanna Olweus
Abstract
Unlike chimeric antigen receptors, T-cell receptors (TCRs) can recognize intracellular targets presented on human leukocyte antigen (HLA) molecules. Here we demonstrate that T cells expressing TCRs specific for peptides from the intracellular lymphoid-specific enzyme terminal deoxynucleotidyl transferase (TdT), presented in the context of HLA-A*02:01, specifically eliminate primary acute lymphoblastic leukemia (ALL) cells of T- and B-cell origin in vitro and in three mouse models of disseminated B-ALL. By contrast, the treatment spares normal peripheral T- and B-cell repertoires and normal myeloid cells in vitro, and in vivo in humanized mice. TdT is an attractive cancer target as it is highly and homogeneously expressed in 80-94% of B- and T-ALLs, but only transiently expressed during normal lymphoid differentiation, limiting on-target toxicity of TdT-specific T cells. TCR-modified T cells targeting TdT may be a promising immunotherapy for B-ALL and T-ALL that preserves normal lymphocytes.