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IMMUNOTHERAPY

Persistence of ex vivo expanded tumour and pathogen specific T-cells after allogeneic stem cell transplant for myeloid malignancies (the INTACT study)

Leukemia volume 37, pages 2330–2333 (2023)Cite this article

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Disease relapse and infections cause significant morbidity and mortality post-allogeneic stem cell transplant (aHSCT) [1, 2] for myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML). One approach to address this is to infuse lymphocytes specific for pathogens and tumour associated antigens (TAA). Wilms’ tumour 1 antigen (WT1) and preferentially expressed antigen in melanoma (PRAME) are TAAs expressed in myeloid malognancies [3, 4] and have low expression in healthy tissues, making them attractive targets for immunotherapy.

T-cell products were manufactured from transplant donors; 10 multipathogen products containing equal proportions of pathogen specific components, 8 WT1-specific products and 6 PRAME-specific products. Detailed product information is shown in Fig. S3. Products expanded briskly from the CD137+ fraction (median expansion 9188-fold for TAA products vs 3335-fold for multipathogen products, p = 0.008). The target cell dose for all multipathogen and PRAME-specific products was reached. Culture failure for WT1 occurred in 4 of 9 (inadequate cell dose n = 2, no antigen specific activity n = 2) and these products were not infused.

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Fig. 1: Study schema and clinical outcomes.
Fig. 2: Tracking antigen-specific T-cell responses by tetramer and TCR sequencing.

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Acknowledgements

This study was funded by the Australian National Health and Medical Research Council (NHMRC) (PG1088118). E.B. was an NHMRC Early Career Fellow (ECF1089398), a NSW Cancer Institute Early Career Fellow (ECF181576) and a current NSW Health Cell and Gene Therapy Fellow. WJ was supported by a scholarship from the Haematology Society of Australia and New Zealand and Leukaemia Foundation Australia, and is a current Leukaemia Foundation Australia Fellow. We are grateful to Gillian Huang and Elissa Atkins for clinical trial management. Microchimerism assays, DNA quantification, and flow cytometry were performed at the Westmead Scientific Platforms, which are supported by the Westmead Research Hub, the Westmead Institute for Medical Research the Cancer Institute of New South Wales, the National Health and Medical Research Council, and the Ian Potter Foundation.

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Authors and Affiliations

  1. Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Camperdown, NSW, Australia

    Wei Jiang, Selmir Avdic, Koon H. Lee, Renee Simms, Caroline M. Bateman, Ken Micklethwaite, David J. Gottlieb & Emily Blyth

  2. Westmead Institute for Medical Research, The University of Sydney, Westmead, NSW, Australia

    Wei Jiang, Selmir Avdic, Koon H. Lee, Janine Street, Gloria Castellano-González, Renee Simms, Ellis Patrick, Nadav Myers, Brian S. Gloss, Caroline M. Bateman, Ken Micklethwaite, David J. Gottlieb & Emily Blyth

  3. Blood Transplant and Cell Therapies Program, Department of Haematology, Westmead Hospital, Westmead, NSW, Australia

    Koon H. Lee, Richard Blennerhassett, Ken Micklethwaite, David J. Gottlieb & Emily Blyth

  4. Research and Education Network, Western Sydney Area Health Service, Westmead, NSW, Australia

    Leighton E. Clancy

  5. School of Mathematics and Statistics, Faculty of Science, University of Sydney, Camperdown, NSW, Australia

    Ellis Patrick & Adam S. Chan

  6. Charles Perkins Centre, The University of Sydney, Camperdown, NSW, Australia

    Adam S. Chan & Helen M. McGuire

  7. Infection, Immunity and Inflammation Theme, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia

    Helen M. McGuire

  8. Blood Transplant and Cell Therapies Unit, The Children’s Hospital at Westmead, Westmead, NSW, Australia

    Melissa Gabriel & Caroline M. Bateman

  9. Blood Transplant and Cell Therapies Laboratory, Institute for Pathology and Medical Research, NSW Health Pathology, Westmead, NSW, Australia

    Ken Micklethwaite

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  1. Wei Jiang
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Contributions

EB and DJG designed the study and wrote the trial protocol. WJ, MG, CMB, KM, DJG and EB recruited and treated patients on the study. SA, RS and LEC performed T-cell product manufacturing. WJ, JS, KHL, GC-G, RS, RB and HMM performed correlative studies. WJ, SA, RS, EP, AC, NM, BG and EB performed data analysis. All authors contributed to the writing of and approved the final manuscript.

Corresponding author

Correspondence to Emily Blyth.

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Competing interests

LEC, KM, EB, and DJG hold patents in adoptive cell therapy for opportunistic infection and malignancy. EB declares advisory board membership for IQVIA, Abbvie, MSD, Astellas, Novartis, BMS, Bastion Education and research funding from MSD. The remaining authors declare no competing interests.

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Jiang, W., Avdic, S., Lee, K.H. et al. Persistence of ex vivo expanded tumour and pathogen specific T-cells after allogeneic stem cell transplant for myeloid malignancies (the INTACT study). Leukemia 37, 2330–2333 (2023). https://doi.org/10.1038/s41375-023-02033-5

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