Abstract
Allogeneic haematopoietic stem cell transplantation (allo-HSCT) was the first successful therapy for patients with haematological malignancies, predominantly owing to graft-versus-tumour (GvT) effects. Dramatic methodological changes, designed to expand eligibility for allo-HSCT to older patients and/or those with comorbidities, have led to the use of reduced-intensity conditioning regimens, in parallel with more aggressive immunosuppression to better control graft-versus-host disease (GvHD). Consequently, disease relapse has become the major cause of death following allo-HSCT. Hence, the prevention and treatment of relapse has come to the forefront and remains an unmet medical need. Despite >60 years of preclinical and clinical studies, the immunological requirements necessary to achieve GvT effects without promoting GvHD have not been fully established. Herein, we review learnings from preclinical modelling and clinical studies relating to the GvT effect, focusing on mechanisms of relapse and on immunomodulatory strategies that are being developed to overcome disease recurrence after both allo-HSCT and autologous HSCT. Emphasis is placed on discussing current knowledge and approaches predicated on the use of cell therapies, cytokines to augment immune responses and dual-purpose antibody therapies or other pharmacological agents that can control GvHD whilst simultaneously targeting cancer cells.
Key points
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Autologous haematopoietic stem cell transplantation (HSCT) might present the optimal platform for immunotherapies, particularly for myeloma and lymphoma; future approaches to improve allogeneic HSCT will require the introduction of innovative immune and/or targeted therapies to prevent relapse, following effective prevention of graft-versus-host disease (GvHD).
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In initial clinical trials, freshly isolated or in vitro expanded donor regulatory T cell infusions have been associated with low GvHD rates; in preclinical models and in preliminary clinical studies, donor regulatory T cell infusion does not seem to increase leukaemia relapse rates as had been feared, although more extensive, controlled trials are needed.
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Immune system-targeted approaches to treat disease relapse after autologous or allogeneic HSCT now include pharmacological agents that block pathways essential for tumour cell survival and at the same time, for allogeneic HSCT, suppress GvHD.
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Immune-checkpoint inhibitors targeting inhibitory signalling pathways in T cells or infusion of T cells genetically modified to express chimeric antigen receptors or T cell receptors reactive with tumour cells might prove advantageous in autologous HSCT, but the risk of GvHD warrants careful consideration in allogeneic HSCT.
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Preclinical models used to delineate graft-versus-tumour from GvHD responses as well as to assess potential therapeutic interventions often use inbred laboratory mouse strains, which offer many advantages mechanistically, but crucial caveats beyond immunological differences between species need to be acknowledged during clinical extrapolation.
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Nature killer (NK) cells are increasingly being examined for their ability to mediate graft-versus-tumour effects whilst having minimal effects on GvHD after HSCT, including the use of third-party chimeric antigen receptor NK cell products and the use of targeted biologic agents to exploit the ability of NK cells to mediate antibody-dependent cellular cytotoxicity.
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B.R.B. is a founder of Tmunity Therapeutics, and receives research support and is a member of the Scientific Advisory Board for BlueRock Therapeutics. G.R.H. has received research funding from Compass Therapeutics and Roche. W.J.M. declares no competing interests.
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Blazar, B.R., Hill, G.R. & Murphy, W.J. Dissecting the biology of allogeneic HSCT to enhance the GvT effect whilst minimizing GvHD. Nat Rev Clin Oncol 17, 475–492 (2020). https://doi.org/10.1038/s41571-020-0356-4
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DOI: https://doi.org/10.1038/s41571-020-0356-4
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