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  • Perspective
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Targeting the roots of myeloid malignancies with T cell receptors

Nature Reviews Cancer (2025)Cite this article

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Abstract

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.

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Fig. 1: Target recognition in standard immunotherapies in haematological malignancies.
Fig. 2: Technologies to assess normal and malignant human haematopoiesis.
Fig. 3: Clinical trials employing T cell receptor-engineered T cells.
Fig. 4: Clonal evolution and assessment of leukaemic stem cells.
Fig. 5: In vivo safety and efficacy testing of T cell receptor-engineered T cells.

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Data availability

The data used for the generation of Table 1, Fig. 3 and Supplementary Table 1 are available in Supplementary Table 2. Information on the TCR T cell clinical trials in malignant diseases was collected using a manually curated database of cellular therapies under development with commercial intent (Beacon Cell Therapy, Hanson Wade Group). These data were reviewed by the authors as described in Supplementary Methods.

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Acknowledgements

The authors acknowledge the constructive expert feedback of J. E. Dick, D. H. Busch, A. J. Mead, M. S. Leisegang, F. Lund-Johansen and E. H. Rustad on the pre-final draft of this manuscript. This work was delivered as part of projects supported by grants to S.E.W.J. from the Knut and Alice Wallenberg Foundation (2016.0105 and 2023.0263), the Swedish Research Council (538-2013-8995), the Swedish Cancer Society (23 3138 PJ), the Torsten Söderberg Foundation and the UK Medical Research Council, to M.S.B. from the Swedish Cancer Society (21 0355 PT) and to J.O. from the Research Council of Norway through its Centres of Excellence scheme (332727) and research grant (316060), the Norwegian Cancer Society (216135-2020), South-Eastern Regional Health Authority Norway (2021074), the Cancer Grand Challenges partnership financed by CRUK (CGCATF-2023/100011), the National Cancer Institute (1OT2CA297513-01) and The Mark Foundation for Cancer Research, as members of the MATCHMAKERS team, the University of Oslo and Oslo University Hospital and the Novo Nordisk Foundation. The authors apologize to colleagues whose relevant work has not been cited due to space restrictions guiding the preparation of this Perspective.

Author information

Author notes

  1. These authors contributed equally: Zsofia Foldvari, Margs S. Brennan.

  2. These authors jointly supervised this work: Sten Eirik W Jacobsen, Johanna Olweus.

Authors and Affiliations

  1. Department of Cancer Immunology, Oslo University Hospital Radiumhospitalet, Oslo, Norway

    Zsofia Foldvari, Aleksei Titov & Johanna Olweus

  2. Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway

    Zsofia Foldvari, Aleksei Titov & Johanna Olweus

  3. Department of Medicine Huddinge, Center for Hematology and Regenerative Medicine, Karolinska Institutet, Stockholm, Sweden

    Margs S. Brennan & Sten Eirik W. Jacobsen

  4. Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden

    Sten Eirik W. Jacobsen

  5. Department of Hematology, Karolinska University Hospital, Stockholm, Sweden

    Sten Eirik W. Jacobsen

  6. MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK

    Sten Eirik W. Jacobsen

Authors
  1. Zsofia Foldvari
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  2. Margs S. Brennan
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  3. Aleksei Titov
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  4. Sten Eirik W. Jacobsen
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  5. Johanna Olweus
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Contributions

S.E.W.J. and J.O. contributed equally and jointly supervised this work. All authors contributed to all aspects of this article.

Corresponding authors

Correspondence to Sten Eirik W. Jacobsen or Johanna Olweus.

Ethics declarations

Competing interests

J.O. is an inventor on several patents and patent applications protecting TCR sequences owned by Oslo University Hospital/University of Oslo; is on the scientific advisory board of Asgard Therapeutics; and is cofounder of T-Rx therapeutics. Z.F., M.S.B., A.T. and S.E.W.J. declare no competing interests.

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Nature Reviews Cancer thanks Sebastian Kobold and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Related links

Beacon Cell Therapy, Hanson Wade Group: https://beacon-intelligence.com/solutions/cell-therapy-database/

Genotype-Tissue Expression (GTEx): https://www.gtexportal.org/home/

GoCART Coalition: https://www.ebmt.org/research/gocart-coalition

Structural T-Cell Receptor Database (STCRDab): https://opig.stats.ox.ac.uk/webapps/stcrdab-stcrpred/

T2Eolve: https://t2evolve.com/

Supplementary information

Glossary

Affinity

The strength of the monovalent interaction between an antigen (for example, a peptide–major histocompatibility complex (pMHC) complex) and a receptor complex (for example, T cell receptor (TCR)); contributes to antigen sensitivity.

Allogeneic haematopoietic stem cell transplantation

(allo-HSCT). A procedure in which a patient receives healthy blood-forming cells (stem cells) from a donor to replace their own stem cells that have been destroyed by treatment with radiation or high doses of chemotherapy, and to attack remaining malignant haematopoietic cells in the patient.

Antigens

In the context of a B cell, molecules that specifically bind to an antibody or a B cell receptor expressed by a B cell; or in the context of a T cell, peptide–major histocompatibility complex (pMHC) molecules that specifically bind a T cell receptor (TCR), which evokes an immune response against the molecule or pMHC.

Bispecific antibodies

Engineered antibodies designed to bind to two different antigens or two epitopes on the same antigen simultaneously, for example CD3 on T cells and CD19 on B cells and B cell malignancies, to bring immune effector cells into close proximity to cancer cells.

Bispecific proteins

Engineered proteins that can bind to two different targets simultaneously, for example, bispecific antibodies, and soluble, affinity-enhanced T cell receptors (TCRs) fused to anti-CD3 to redirect T cells to target cells expressing a particular peptide–human leucocyte antigen (pHLA) complex.

Catch bonds

Biological interactions that become stronger when mechanical forces act to pull a ligand–receptor complex apart, which in the context of T cell receptor (TCR)–peptide–major histocompatibility complex (pMHC) interactions can enhance TCR-antigen recognition and promote effective T cell activation.

Clonal haematopoiesis

A common aging-related condition observed in healthy individuals with normal blood parameters, where a recurrent genetic mutation in a haematopoietic stem cell (HSC) results in clonal expansion of cells originating from the HSC clone.

Epitopes

Short peptides that derive from a protein, bind to a major histocompatibility complex (MHC) molecule and are recognized by a particular T cell receptor (TCR) expressed on a T cell.

Functional avidity

Refers to the sensitivity of a T cell receptor (TCR) to its cognate peptide–major histocompatibility complex (pMHC), typically measured by the amount of peptide needed to trigger T cell activation (peptide sensitivity), integrating TCR–pMHC binding affinity, TCR density, TCR signalling efficiency, co-receptor engagement and cellular context.

Graft-versus-host disease

(GVHD). A potentially fatal condition whereby the donor immune cells recognize and attack patient non-haematopoietic cells after allogeneic haematopoietic stem cell transplantation (allo-HSCT).

Graft-versus-leukaemia (GVL) effect

An immune response to a patient’s leukaemic cells by donor immune cells, as observed after allogeneic haematopoietic stem cell transplantation (allo-HSCT).

Haematopoietic progenitor cells

An undifferentiated cell population that is highly proliferative and can replenish one, some or all the different blood cell types, but unlike haematopoietic stem cells (HSCs) possesses limited or no self-renewal ability.

Haematopoietic stem cells

(HSCs). Immature blood-forming cells capable of both self-renewal and multi-lineage differentiation into all blood cell lineages, ensuring their replenishment throughout the lifetime of an organism.

Human leukocyte antigen

(HLA). The set of major histocompatibility complex (MHC) molecules in humans comprising cell surface receptors expressed on all nucleated cells (HLA class I) and on antigen-presenting cells (HLA class II), specialized to present antigenic peptides to T cells.

Immune privileged

Indicating that certain immunogenic cells in the body are protected from immune attack.

Immunoediting

The process whereby the immune system can both constrain and promote tumour development, often leading to the tumour being able to evade detection by immune cells.

Immunogenic

The ability of an antigen to provoke an immune response.

Immunoproteasome

A specialized form of the proteasome responsible for degrading proteins in immune cells, with altered cleavage activity favouring the generation of peptides that are presented by major histocompatibility complex (MHC) class I molecules.

Leukaemia-propagating cells

(LPCs). Populations of leukaemic cells that possess the ability to self-renew, and sustain the growth of the leukaemia.

Leukaemic stem cells

(LSCs). Leukaemic cells residing at the top of the cellular hierarchy of a leukaemic clone, possessing extensive self-renewal potential and ability to replenish all other cell types constituting the leukaemic clone, including other leukaemia-propagating cells (LPCs).

Measurable residual disease

(MRD; previously termed minimal residual disease). Denotes the detection of rare cancer cells with advanced molecular methods while patients remain in complete clinical remission after therapy, a finding with prognostic and therapeutic implications.

Myeloid cells

A heterogeneous group of white blood cells involved in antigen presentation and innate immunity that include monocytes, macrophages, granulocytes, dendritic cells, erythrocytes and megakaryocytes.

Neoantigens

New antigens with an amino acid sequence that is not present in the normal human proteome and that can evoke an immune response (that is, a neoepitope); a private neoantigen is unique to an individual tumour and patient, whereas a public neoantigen is shared among tumours and patients.

Quiescent

A state of reversible growth arrest in which cells have exited the cell cycle but remain capable of renewed division upon stimulation.

Self-renewal

The process by which haematopoietic stem cells (HSCs) divide to sustain or make more HSCs, perpetuating the HSC pool and multi-lineage blood replenishment throughout life.

Self-tolerance

The ability of the immune system to identify and not react against self-produced antigens.

T cell receptor (TCR)-engineered T cells

T cells that have been genetically engineered to express a specific T cell receptor (TCR) that recognizes a defined antigen.

Transposons

DNA sequences that can move from one location in the genome to another, also known as transposable elements (TEs), which in gene therapy are used to deliver and stably integrate therapeutic genes into target cells, using a transposase enzyme.

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Foldvari, Z., Brennan, M.S., Titov, A. et al. Targeting the roots of myeloid malignancies with T cell receptors. Nat Rev Cancer (2025). https://doi.org/10.1038/s41568-025-00857-0

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