Showing papers by "Hugues de Lavallade published in 2022"
TL;DR: The humoral and T cell responses induced by sequential doses of vaccination against SARS-Cov-2 in patients with chronic myeloproliferative neoplasms are reported as well as the early protective effect on infection in these patients.
7 citations
TL;DR: T‐cell exhaustion and a pro‐inflammatory state at diagnosis in CML are demonstrated, likely secondary to leukaemia‐associated antigenic overload associated with increased disease burden.
Abstract: The search for novel targets in chronic myeloid leukaemia (CML) is ongoing, to improve treatment efficacy in refractory disease and increase eligibility for tyrosine kinase inhibitor (TKI) discontinuation. Increased frequency of Tregs and effector Tregs was evident at diagnosis, together with increased expression of T‐cell exhaustion markers, including in regulatory T cells at diagnosis and in patients with refractory disease. Plasma analysis revealed significantly increased levels of cytokines including tumour necrosis factor (TNF)‐a and interleukin (IL)‐6 at diagnosis, in keeping with a pro‐inflammatory state prior to treatment. We hence demonstrate T‐cell exhaustion and a pro‐inflammatory state at diagnosis in CML, likely secondary to leukaemia‐associated antigenic overload associated with increased disease burden.
6 citations
5 citations
TL;DR: Vodobatinib, a selective novel BCR::ABL1 inhibitor effective against wild-type and mutated BCR-ABL 1 isoforms was evaluated in Phase 1 open label study enrolling pts progressing or intolerant to ≥ 3 prior TKIs as discussed by the authors .
2 citations
TL;DR: Cortes et al. as discussed by the authors presented a post hoc analysis of long-term outcomes (progression-free survival [PFS] and overall survival [OS]) of patients in the OPTIC trial who reached landmark clinical responses (≤1, >1-≤10%, and >10% BCR::ABL1IS by Months 3, 6, or 12).
1 citations
TL;DR: The OPTIC trial as discussed by the authors evaluated the efficacy and safety of ponatinib using a novel response-based dose-adjustment strategy in patients with CP-CML whose disease is resistant to ≥2 TKIs or who harbor T315I.
1 citations
TL;DR: In this paper , the authors discuss conflict and conflict resolution in conflict resolution, and propose conflict-free conflict resolution strategy, including conflict-resolution strategy, and conflict-avoiding strategy.
DOI•
TL;DR: Studies have shown that rux inhibits T cell proliferation and reduces CD4+ cell cytokine secretion, suggesting off target kinase inhibition is implicated in the impairment of TCR signalling.
Abstract: Background: Background: Ruxolitinib (rux) is a JAK1/JAK2 inhibitor with varied immune effects including on T cell, NK cell and dendritic cell function. Therapeutic effects are largely attributed to marked reduction in pro-inflammatory cytokines. Aims: Aims: We hypothesised that impairment of T cell receptor (TCR) signalling through off-target binding of Src kinases, including Lck, would be an additional mechanism of immune dysfunction. Methods: Methods: We performed phosphoflow cytometry in Tregs, T effectors and NK cells to assess the effect on signalling downstream from the TCR and activating NK cell receptors. 11-colour flow cytometry was performed after cells were activated with H2O2 for 15 minutes, due to its activity as a potent phosphatase inhibitor and cells were analysed for phosphorylation of ZAP70 as a surrogate of TCR signalling and STAT5. A gating strategy of CD4+/CD25+/FOXP3+/CD127 lo cells was used for identification of Tregs. Results: Results: Phosphoflow analysis was performed in 7 patients with a diagnosis of MF managed with rux and compared with 7 healthy controls (HC). 4 (57%) of patients were male and mean age was 61 (range 44-76). Patients were taking a median rux dosage of 30mg daily (10-50). Three patients had a DIPPS+ Summary/Conclusion: Summary/Conclusion: Studies have shown that rux inhibits T cell proliferation and reduces CD4+ cell cytokine secretion. Previous in vitro analysis of rux on CD4+ cells failed to identify an effect on TCR signalling after CD3/CD28 stimulation. In our ex-vivo analysis, using H2O2 stimulation, we observe TCR signalling inhibition in CD4+, CD8+ and NK cells, although reduced compared with effects on STAT5. It has been shown that rux inhibits Lck with an IC50 of 3.6uM. Whilst this is significantly less than the inhibitory effect on JAK kinases, there is ~34% sequency homology between Src and JAK family kinases in the kinase domain, suggesting off target kinase inhibition is implicated in the impairment of TCR signalling.
TL;DR: In this paper , the authors report a comprehensive immunological evaluation of the response to SARS-CoV-2 vaccination in patients with chronic myeloid neoplasms (MPN).
Abstract: Background: Background: Concerns remain over the response to vaccination against SARS-CoV-2 in patients with haematological malignancy. Aims: Aims: Herein, we report a comprehensive immunological evaluation of the response to SARS-CoV-2 vaccination in patients with chronic myeloid neoplasms (MPN). Methods: Methods: Antibody response was assessed using anti-Spike (anti-S) IgG with anti-nucleocapsid (anti-N) IgG used to determine previous infection. Neutralising antibody analysis was performed assessing inhibitory effect of plasma on entry of HIV-1 particles expressing Wuhan and omicron variant spike proteins into cells expressing ACE-2 receptor. T cell response was assessed using flow cytometric evaluation of intracellular pro-inflammatory cytokines and surface exhaustion markers upon re-exposure to S peptides (Miltenyi) in T cell subsets. Subsequently, T cell response was evaluated using a fluorospot assay assessing IFNg/IL-2 secretion upon re-exposure to S peptides (Mabtech). Plates were analysed Summary/Conclusion: Summary/Conclusion: We show overall high frequency of seroconversion and memory T cell responses but demonstrate the need for alternative strategies in some groups, including patients taking ruxolitinib. The increase in T cell reactivity after 3 doses is of particular significance in view of the reduced neutralisation of the now dominant omicron variant, with studies showing T cell functionality is maintained against omicron. Updated results will be presented.