Targeting the roots of myeloid malignancies with T cell receptors

Myeloid malignancies are clonal diseases of haematopoietic stem cell or haematopoietic progenitor cell origin, for which allogeneic haematopoietic stem cell transplantation remains the only curative treatment for most patients. However, the severe side effects and high relapse rates underscore the need for novel therapies. The success of adoptive transfer of chimeric antigen receptor (CAR) T cells targeting B cell-specific cell surface molecules in B cell cancers has not been replicated in myeloid malignancies. T cells engineered to express cancer-directed T cell receptors (TCRs) could provide an alternative, enabling targeting also of the intracellular proteome. In this Perspective, we have collated and reviewed available data from clinical trials exploiting TCR-engineered T cells for the treatment of haematological malignancies and discuss specific characteristics that make myeloid malignancies attractive candidates for TCR-based therapies. We also highlight the need to efficiently target the rare and notoriously therapy-resistant leukaemic stem cells, which represent the roots of myeloid malignancies, to achieve cures. This will require identification of novel targets and TCRs, and we discuss different target categories and strategies that can be applied towards this goal. We also highlight the importance of standardized preclinical testing and publicly available data to enable rapid identification and clinical advancement of promising TCRs towards clinical application.