Medicine (RMH) - Research Publications
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ItemDysregulation of immune cell and cytokine signalling correlates with clinical outcomes in myelodysplastic syndrome (MDS)(WILEY, 2022-04)OBJECTIVES: Myelodysplastic syndromes (MDS) are characterised by ineffective haematopoiesis. Although hypomethylating agents (HMA) have improved survival in higher-risk MDS, most patients eventually succumb to progressive disease. Utilising samples collected prospectively from three MDS clinical trials, we analysed genetic and immunological biomarkers and correlated them with clinical outcomes. METHODS: A hundred and fifty four samples were analysed from 133 de novo MDS patients for T-cell and myeloid cell immunophenotyping and gene expression analysis. Treatments were with HMA or immunomodulatory drug (IMiD) alone or in combination. RESULTS: We observed differences in immune cell subsets between lower- and higher-risk IPSS groups with NKT cells, MDSCs, intermediate-proinflammatory and non-classical monocytes being higher in the latter group, while naïve CD4+ T cells were reduced. Intermediate-proinflammatory monocytes were increased in non-responders and those failing to achieve at least a haematological improvement. Proinflammatory NKT cells were increased at diagnosis for patients failing to derive clinical benefit after 12 months of treatment. Gene expression analysis of paired bone marrow (BM) colony-forming units (CFUs) from diagnosis and 4 cycles post-treatment confirmed that genes involved in cytokine signalling were downregulated in C4 normal colonies. CONCLUSIONS: These findings support the central roles of dysregulation in innate immunity and inflammatory signalling in the pathogenesis of MDS which correlated with clinical outcomes post-treatment.
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Item[18F]FDG-PET-CT compared with CT for persistent or recurrent neutropenic fever in high-risk patients (PIPPIN): a multicentre, open-label, phase 3, randomised, controlled trial(ELSEVIER SCI LTD, 2022-08)BACKGROUND: Management of neutropenic fever in high-risk haematology patients is challenging; there are often few localising clinical features, and diagnostic tests have poor sensitivity and specificity. We aimed to compare how [18F]flurodeoxyglucose ([18F]FDG)-PET-CT scans and conventional CT scans affected the guidance of antimicrobial management and the outcomes of patients with persistent or recurrent neutropenic fever. METHODS: We did a multicentre, open-label, phase 3, randomised, controlled trial in two tertiary referral hospitals in Australia. We recruited adults aged 18 years or older who were receiving conditioning chemotherapy for haematopoietic stem-cell transplantation or chemotherapy for acute leukaemia and had persistent (>72 h) or recurrent (new fever beyond 72 h of initial onset interspersed with >48 h defervescence) neutropenic fever. Exclusion criteria were pregnancy, allergy to iodinated contrast, or estimated glomerular filtration rate of less than 30 mL/min. Patients were randomly assigned by computer-generated randomisation chart (1:1) to [18F]FDG-PET-CT or conventional CT. Masking was not possible because of the nature of the investigation. Scans were done within 3 days of random assignment. The primary endpoint was a composite of starting, stopping, or changing the spectrum (broadening or narrowing) of antimicrobial therapy-referred to here as antimicrobial rationalisation-within 96 h of the assigned scan, analysed per protocol. This trial is registered with clinicaltrials.gov, NCT03429387, and is complete. FINDINGS: Between Jan 8, 2018, and July 23, 2020, we assessed 316 patients for eligibility. 169 patients were excluded and 147 patients were randomly assigned to either [18F]FDG-PET-CT (n=73) or CT (n=74). Nine patients did not receive a scan per protocol, and two participants in each group were excluded for repeat entry into the study. 65 patients received [18F]FDG-PET-CT (38 [58%] male; 53 [82%] White) and 69 patients received CT (50 [72%] male; 58 [84%] White) per protocol. Median follow up was 6 months (IQR 6-6). Antimicrobial rationalisation occurred in 53 (82%) of 65 patients in the [18F]FDG-PET-CT group and 45 (65%) of 69 patients in the CT group (OR 2·36, 95% CI 1·06-5·24; p=0·033). The most frequent component of antimicrobial rationalisation was narrowing spectrum of therapy, in 28 (43%) of 65 patients in the [18F]FDG-PET-CT group compared with 17 (25%) of 69 patients in the CT group (OR 2·31, 95% CI 1·11-4·83; p=0·024). INTERPRETATION: [18F]FDG-PET-CT was associated with more frequent antimicrobial rationalisation than conventional CT. [18F]FDG-PET-CT can support decision making regarding antimicrobial cessation or de-escalation and should be considered in the management of patients with haematological diseases and persistent or recurrent high-risk neutropenic fever after chemotherapy or transplant conditioning. FUNDING: National Health and Medical Research Council Centre of Research Excellence (APP1116876), Melbourne Health foundation, Gilead Research Fellowship grants supported this study.
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ItemPretransplant FLT3-ITD MRD assessed by high-sensitivity PCR-NGS determines posttransplant clinical outcome(AMER SOC HEMATOLOGY, 2022-12-01)
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ItemIntratumoural administration of an NKT cell agonist with CpG promotes NKT cell infiltration associated with an enhanced antitumour response and abscopal effect(TAYLOR & FRANCIS INC, 2022-12-31)Intratumoural administration of unmethylated cytosine-phosphate-guanine motifs (CpG) to stimulate toll-like receptor (TLR)-9 has been shown to induce tumour regression in preclinical studies and some efficacy in the clinic. Because activated natural killer T (NKT) cells can cooperate with pattern-recognition via TLRs to improve adaptive immune responses, we assessed the impact of combining a repeated dosing regimen of intratumoural CpG with a single intratumoural dose of the NKT cell agonist α-galactosylceramide (α-GalCer). The combination was superior to CpG alone at inducing regression of established tumours in several murine tumour models, primarily mediated by CD8+ T cells. An antitumour effect on distant untreated tumours (abscopal effect) was reliant on sustained activity of NKT cells and was associated with infiltration of KLRG1+ NKT cells in tumours and draining lymph nodes at both injected and untreated distant sites. Cytometric analysis pointed to increased exposure to type I interferon (IFN) affecting many immune cell types in the tumour and lymphoid organs. Accordingly, antitumour activity was lost in animals in which dendritic cells (DCs) were incapable of signaling through the type I IFN receptor. Studies in conditional ablation models showed that conventional type 1 DCs and plasmacytoid DCs were required for the response. In tumour models where the combined treatment was less effective, the addition of tumour-antigen derived peptide, preferably conjugated to α-GalCer, significantly enhanced the antitumour response. The combination of TLR ligation, NKT cell agonism, and peptide delivery could therefore be adapted to induce responses to both known and unknown antigens.
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ItemExercise in allogeneic bone marrow transplantation: a qualitative representation of the patient perspective(SPRINGER, 2022-06)PURPOSE: Exercise is emerging as a vital aspect of care to alleviate the physical and psychosocial symptom burden associated with allogeneic bone marrow transplantation (BMT). Understanding the patient perspective regarding exercise is important to move towards implementation. This study aimed to characterise experiences and views regarding participation in an exercise program in adults receiving treatment for haematological disease with allogeneic BMT. METHODS: Individual semi-structured interviews were conducted with 35 participants from either an early- or late-commencing supervised group-based exercise program. Using an inductive, conventional approach to qualitative content analysis data were independently analysed by two researchers. RESULTS: Six major themes and 33 sub-themes were identified: this encompassed motivation, physical opportunity and capability to exercise; psychosocial effects of group-based exercise; experienced impact of participation in an exercise program; and intervention design considerations. Key barriers to exercise included symptom severity and fluctuating health and distance or difficult access to an exercise facility or equipment, whilst facilitators included encouragement from staff; peer support in the group-based setting; flexibility; education; and ability to measure change. CONCLUSION: This study highlights the importance of a flexible approach to exercise with consideration of individual symptoms and preferences. The perceived psychological impact of exercise should not be underestimated; future exercise programs should be designed in partnership with patients, with consideration of group-based activities to reduce social isolation if this is feasible in the treatment context. Intervention design should also acknowledge the individual's physical and psychological capability, opportunity and automatic and reflective motivation to direct and sustain exercise behaviours following BMT.
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ItemT Cell Fitness and Autologous CAR T Cell Therapy in Haematologic Malignancy(FRONTIERS MEDIA SA, 2021-11-25)A range of emerging therapeutic approaches for the treatment of cancer aim to induce or augment endogenous T cell responses. Chimeric antigen receptor (CAR) T cell therapy (CTT) is one such approach that utilises the patient's own T cells, engineered ex vivo to target cell surface antigens, to eliminate haematological malignancies. Despite mediating high rates of responses in some clinical trials, this approach can be limited by dysfunctional T cells if they are present at high frequencies either in the starting material from the patient or the CAR T cell product. The fitness of an individual's T cells, driven by age, chronic infection, disease burden and cancer treatment, is therefore likely to be a crucial limiting factor of CTT. Currently, T cell dysfunction and its impact on CTT is not specifically quantified when patients are considering the therapy. Here, we review our current understanding of T cell fitness for CTT, how fitness may be impacted by age, chronic infection, malignancy, and treatment. Finally, we explore options to specifically tailor clinical decision-making and the CTT protocol for patients with more extensive dysfunction to improve treatment efficacy. A greater understanding of T cell fitness throughout a patient's treatment course could ultimately be used to identify patients likely to achieve favourable CTT outcomes and improve methods for T cell collection and CTT delivery.
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ItemDissection of the bone marrow microenvironment in hairy cell leukaemia identifies prognostic tumour and immune related biomarkers(NATURE PORTFOLIO, 2021-09-24)Hairy cell leukaemia (HCL) is a rare CD20+ B cell malignancy characterised by rare "hairy" B cells and extensive bone marrow (BM) infiltration. Frontline treatment with the purine analogue cladribine (CDA) results in a highly variable response duration. We hypothesised that analysis of the BM tumour microenvironment would identify prognostic biomarkers of response to CDA. HCL BM immunology pre and post CDA treatment and healthy controls were analysed using Digital Spatial Profiling to assess the expression of 57 proteins using an immunology panel. A bioinformatics pipeline was developed to accommodate the more complex experimental design of a spatially resolved study. Treatment with CDA was associated with the reduction in expression of HCL tumour markers (CD20, CD11c) and increased expression of myeloid markers (CD14, CD68, CD66b, ARG1). Expression of HLA-DR, STING, CTLA4, VISTA, OX40L were dysregulated pre- and post-CDA. Duration of response to treatment was associated with greater reduction in tumour burden and infiltration by CD8 T cells into the BM post-CDA. This is the first study to provide a high multiplex analysis of HCL BM microenvironment demonstrating significant immune dysregulation and identify biomarkers of response to CDA. With validation in future studies, prospective application of these biomarkers could allow early identification and increased monitoring in patients at increased relapse risk post CDA.
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ItemVenetoclax or Ruxolitinib in Pre-Transplant Conditioning Lowers the Engraftment Barrier by Different Mechanisms in Allogeneic Stem Cell Transplant Recipients(FRONTIERS MEDIA SA, 2021-09-24)Allogeneic stem cell transplantation (alloSCT) is utilised to cure haematological malignancies through a combination of conditioning regimen intensity and immunological disease control via the graft versus tumour (GVT) effect. Currently, conventional myeloablative chemotherapeutic or chemoradiation conditioning regimens are associated with significant side effects including graft versus host disease (GVHD), infection, and organ toxicity. Conversely, more tolerable reduced intensity conditioning (RIC) regimens are associated with unacceptably higher rates of disease relapse, partly through an excess incidence of mixed chimerism. Improvement in post-alloSCT outcomes therefore depends on promotion of the GVT effect whilst simultaneously reducing conditioning-related toxicity. We have previously shown that this could be achieved through BCL-2 inhibition, and in this study, we explored the modulation of JAK1/2 as a strategy to lower the barrier to donor engraftment in the setting of RIC. We investigated the impact of short-term treatment of BCL2 (venetoclax) or JAK1/2 (ruxolitinib) inhibition on recipient natural killer and T cell immunity and the subsequent effect on donor engraftment. We identified striking differences in mechanism of action of these two drugs on immune cell subsets in the bone marrow of recipients, and in the regulation of MHC class-II and interferon-inducible gene expression, leading to different rates of GVHD. This study demonstrates that the repurposed use of ruxolitinib or venetoclax can be utilised as pre-transplant immune-modulators to promote the efficacy of alloSCT, whilst reducing its toxicity.
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ItemIbrutinib protects T cells in patients with CLL from proliferation-induced senescence(BMC, 2021-11-22)BACKGROUND: The development of Bruton's tyrosine kinase inhibitors (BTKi) for the treatment of chronic lymphocytic leukaemia (CLL) has provided a highly effective and relatively non-toxic alternative to conventional chemotherapy. Some studies have shown that BTKi can also lead to improvements in T cell immunity in patients despite in vitro analyses suggesting an immunosuppressive effect of BTKi on T cell function. METHODS: In this study, we examined both the in vitro effect and long-term in vivo effect of two clinically available BTKi, ibrutinib and zanubrutinib. Additional in vitro assessments were undertaken for a third BTKi, acalabrutinib. Immune subset phenotyping, cytokine secretion, T cell degranulation and proliferation assays were performed on peripheral blood mononuclear cells isolated from untreated CLL patients, and CLL patients on long-term (> 12 months) BTKi treatment. RESULTS: Similar to prior studies we observed that long-term BTKi treatment normalises lymphocyte subset frequency and reduces PD-1 expression on T cells. We also observed that T cells from patients taken prior to BTKi therapy showed an abnormal hyper-proliferation pattern typical of senescent T cells, which was normalised by long-term BTKi treatment. Furthermore, BTKi therapy resulted in reduced expression of the T cell exhaustion markers PD-1, TIM3 and LAG3 in late generations of T cells undergoing proliferation. CONCLUSIONS: Collectively, these findings indicate that there are critical differences between the in vitro effects of BTKi on T cell function and the effects derived from long-term BTKi exposure in vivo. Overall long-term exposure to BTKi, and particularly ibrutinib, resulted in improved T cell fitness in part due to suppressing the abnormal hyper-proliferation of CLL T cells and the associated development of T cell senescence.
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