9 research outputs found
Lenalidomide maintenance treatment after imatinib discontinuation:results of a phase 1 clinical trial in chronic myeloid leukaemia
No full textLink to a related website: https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/bjh.15894, Open Access via UnpaywallAbstract not availableDavid M. Ross, Ilaria S. Pagani, Yazad D. Irani, Jade Clarson, Tamara Leclercq, Phuong Dang, Jennifer McLean, Verity A. Saunders, Lisa Carne, John Reynolds, David S. Ritchie, Deborah L. White, Susan Branford, Timothy P. Hughes, Agnes S. M. Yon
Successful treatment-free remission in chronic myeloid leukaemia and its association with reduced immune suppressors and increased natural killer cells
No full textData source: Supporting information, https://doi.org/10.1111/bjh.16718There is currently no biomarker that reliably predicts treatment-free remission (TFR) in chronic myeloid leukaemia (CML). We characterised effector and suppressor immune responses at the time of tyrosine kinase inhibitor (TKI) cessation in patients from the CML8 and CML10 clinical studies. Natural killer (NK) cells with increased expression of activating NK receptors were higher in patients who achieved TFR. There was no difference in the proportion of CD4+ or CD8+ T cells. Furthermore, we found that FoxP3+ regulatory T cells (T reg) and monocytic myeloid-derived suppressor cells (Mo-MDSCs) were concomitantly decreased in TFR patients, suggesting that the effector and suppressor arms of the immune system work in concert to mediate TFR. A discovery cohort (CML10) was used to generate a predictive model, using logistic regression. Patients classified into the high-risk group were more likely to relapse when compared with the low-risk group (HR 7·4, 95% CI 2·9-19·1). The model was successfully validated on the independent CML8 cohort (HR 8·3, 95% CI 2·2-31·3). Effective prediction of TFR success may be obtained with an effector-suppressor score, calculated using absolute NK cell, T reg, and Mo-MDSC counts, at TKI cessation, reflecting the contribution of both immune suppressors and effectors in the immunobiology underlying successful TFR.Yazad D. Irani, Amy Hughes, Jade Clarson, Chung H. Kok, Naranie Shanmuganathan, Deborah L. White, David T. Yeung, David M. Ross, Timothy P. Hughes, and Agnes S.M. Yon
CML patients with deep molecular responses to TKI have restored immune effectors and decreased PD-1 and immune suppressors
No full textImmunological control may contribute to achievement of deep molecular response in chronic myeloid leukemia (CML) patients on tyrosine kinase inhibitor (TKI) therapy and may promote treatment-free remission (TFR). We investigated effector and suppressor immune responses in CML patients at diagnosis (n = 21), on TKI (imatinib, nilotinib, dasatinib) before achieving major molecular response (pre-MMR, BCR-ABL1 >0.1%, n = 8), MMR (BCR-ABL1 ≤0.1%, n = 20), molecular response4.5 (MR4.5, BCR-ABL1 ≤0.0032%, n = 16), and sustained TFR (BCR-ABL1 undetectable following cessation of TKI therapy, n = 13). Aberrant immune-inhibitory responses (myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), and programmed death-1 (PD-1) inhibitory molecule expression on CD4+/CD8+ T cells were increased in CML patients at diagnosis. Consequent quantitative and functional defects of innate effector natural killer (NK) cells and cytotoxic T-lymphocyte responses to leukemia-associated antigens WT1, BMI-1, PR3, and PRAME were observed at diagnosis. Treg and PD-1+CD4+/CD8+ T cells persisted in pre-MMR CML patients on TKI. Patients in MMR and MR4.5 had a more mature, cytolytic CD57+CD62L- NK cell phenotype, consistent with restoration of NK cell activating and inhibitory receptor repertoire to normal healthy donor levels. Immune responses were retained in TFR patients off-therapy, suggesting the restored immune control observed in MMR and MR4.5 is not an entirely TKI-mediated effect. Maximal restoration of immune responses occurred only in MR4.5, as demonstrated by increased NK cell and effector T-cell cytolytic function, reduced T-cell PD-1 expression and reduced numbers of monocytic MDSCs.Amy Hughes, Jade Clarson, Carine Tang, Ljiljana Vidovic, Deborah L. White, Timothy P. Hughes and Agnes S. M. Yon
Association of TIM-3 checkpoint receptor expression on T cells with treatment-free remission in chronic myeloid leukemia
No full textDysregulation of immune checkpoint receptors has been reported at diagnosis of chronic myeloid leukemia (CML), but their role in the maintenance of remission after tyrosine kinase inhibitor (TKI) cessation is unclear. We assessed PD-1, TIM-3, CTLA-4, LAG-3 and TIGIT expression on T-cell subsets, regulatory T cells (T-regs), and natural killer (NK) cells at the time of TKI cessation in 44 patients (22 who sustained treatment-free remission (TFR), 22 who experienced molecular relapse (MolR)). We confirmed our previous finding that absolute numbers of T-regs are increased in MolR patients compared to TFR. The immune checkpoint receptors PD-1, CTLA-4, LAG-3 and TIGIT on T or NK cells were not differentially expressed between the MolR and TFR groups. However, TIM-3 was consistently upregulated on bulk T-cells (CD3+), and T-cell subsets including, CD4+T-cells, CD8+T-cells, and T-regs, in patients who relapsed in comparison to those who maintained TFR after discontinuation. Furthermore, gene expression analysis from publicly available datasets showed increased TIM-3 expression on CML stem cells compared with normal hematopoietic stem cells. These findings suggest that among the targetable immune checkpoint molecules, TIM-3 blockade may potentially improve effector immune response in CML patients stopping TKI, whilst concomitantly targeting leukemic stem cells, and could be a promising therapeutic strategy for preventing relapse after cessation of TKI in CML patients.Yazad D. Irani, Chung H. Kok, Jade Clarson, Naranie Shanmuganathan, Susan Branford, David T. Yeung, David M. Ross, Timothy P. Hughes and Agnes S. M. Yon
Successful treatment‐free remission in chronic myeloid leukaemia and its association with reduced immune suppressors and increased natural killer cells
No full textSynthesis of conducting graphite-like nanometer wires via soluble precursors
No full textGraphite - like conducting materials were
encapsulated in the channels of new mesoporous MCM-
41 materials with typical channel diameters of 30-40 Ä.
Acrylonitrile was introduced into the hosts via vapor
transport, then polymerized with external radical
initiators, K2S2O8 and HNaSOß. The polymers in the host
cavities were further pyrolyzed at different temperatures
under vacuum or nitrogen atmosphere. The properties of
the polymer systems were studied while encapsulated or
after dissolution of the host. The crystallinity of the hosts
is intact after insertion of the polymer (even after
pyrolysis at 800°C). The formation of conducting
graphite - like materials inside the hosts was
demonstrated with Raman and UV spectra. The nitrogen
to carbon ratio of the pyrolyzed polymers depends on the
pyrolysis temperature and the polymer environment.
Most interestingly, the normalized AC absorption of
pyrolyzed polyacrylonitrile in MCM-41 (at 800°C) is
comparable to graphite
Demethylating therapy increases anti-CD123 CAR T cell cytotoxicity against acute myeloid leukemia
No full textThe success of CAR-T cells for treating acute myeloid leukaemia (AML) is hampered by toxicity to normal cells and low CAR-T cell persistence. Here, the authors show that the demethylating compound 5′-Azacitdine increases anti-CD123 CAR-T cell cytotoxicity against AML
Demethylating therapy increases anti-CD123 CAR T cell cytotoxicity against acute myeloid leukemia
No full textSuccessful treatment of acute myeloid leukemia (AML) with chimeric antigen receptor (CAR) T cells is hampered by toxicity on normal hematopoietic progenitor cells and low CAR T cell persistence. Here, we develop third-generation anti-CD123 CAR T cells with a humanized CSL362-based ScFv and a CD28-OX40-CD3ζ intracellular signaling domain. This CAR demonstrates anti-AML activity without affecting the healthy hematopoietic system, or causing epithelial tissue damage in a xenograft model. CD123 expression on leukemia cells increases upon 5′-Azacitidine (AZA) treatment. AZA treatment of leukemia-bearing mice causes an increase in CTLA-4negative anti-CD123 CAR T cell numbers following infusion. Functionally, the CTLA-4negative anti-CD123 CAR T cells exhibit superior cytotoxicity against AML cells, accompanied by higher TNFα production and enhanced downstream phosphorylation of key T cell activation molecules. Our findings indicate that AZA increases the immunogenicity of AML cells, enhancing recognition and elimination of malignant cells by highly efficient CTLA-4negative anti-CD123 CAR T cells
Acute coronary syndrome rule-out strategies in the emergency department: an observational evaluation of clinical effectiveness and current UK practice
No full text\ua9 Author(s) (or their employer(s)) 2025. Background: Numerous strategies have been developed to rapidly rule-out acute coronary syndrome (ACS) using high-sensitivity troponin. We aimed to establish their performance in terms of emergency care length of stay (LOS) in real-world practice. Methods: A multicentre observational cohort study in 94 UK sites between March and April 2023. Recruitment was preferably prospective, with retrospective recruitment also allowed. Adults presenting to the ED with chest pain triggering assessment for possible ACS were eligible. Primary outcome was emergency care LOS. Secondary outcomes were index rate of acute myocardial infarction (MI), time to be seen (TTBS), disposition and discharge diagnosis. Details of ACS rule-out strategies in use were collected from local guidelines. Mixed effects linear regression models tested the association between rule-out strategy and LOS. Results: 8563 eligible patients were recruited, representing 5.3% of all ED attendances. Median LOS for all patients was 333 min (IQR 225, 510.5), for admitted patients was 460 min (IQR 239.75, 776.25) and for discharged patients was 313 min (IQR 221, 451). Heterogeneity was seen in the rule-out strategies with regard to recommended troponin timing. There was no significant difference in LOS in discharged patients between rule-out strategies defined by single and serial troponin timing (p=0.23 and p=0.41). The index rate of acute MI was 15.2% (1301/8563). Median TTBS was 120 min (IQR 57, 212). 24.4% (2087/8563) of patients were partly managed in a same day emergency care unit and 70% (5934/8563) of patients were discharged from emergency care. Conclusion: Despite heterogeneity in the ACS rule-out strategies in use and widespread adoption of rapid rule-out approaches, this study saw little effect on LOS in real-world practice. Suspected cardiac chest pain still accounts for a significant proportion of UK ED attendances. ED system pressures are likely to be explanatory, but further research is needed to understand the reasons for the unrealised potential of these strategies
