scholarly journals Sustained treatment‐free remission in chronic myeloid leukaemia is associated with an increased frequency of innate CD8(+) T‐cells

2019 ◽  
Vol 186 (1) ◽  
pp. 54-59 ◽  
Author(s):  
Emilie Cayssials ◽  
Florence Jacomet ◽  
Nathalie Piccirilli ◽  
Lucie Lefèvre ◽  
Lydia Roy ◽  
...  
Keyword(s):  
T Cells ◽  
Chronic Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Cd8 T Cells ◽  
Treatment Free Remission

Clinical BCR-ABL Peptide Vaccination in Chronic Myeloid Leukaemia: Results of the EPIC Study.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2197-2197
Author(s):  
Jose M. Rojas ◽  
Katy Knight ◽  
Li-Hui Wang ◽  
Richard E. Clark
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Chronic Myeloid Leukaemia ◽  
Immune Responses ◽  
Myeloid Leukaemia ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Peptide Vaccination ◽  
Molecular Responses ◽  
Junctional Region

Abstract Chronic myeloid leukaemia (CML) is characterised by the BCR-ABL oncoprotein. The amino-acid sequences spanning the junctional region are completely leukaemia-specific. In vitro pulsing of antigen presenting cells elicits immune response to CML cells. Vaccination of CML patients with peptides from this junctional region could therefore elicit/augment immune responses to CML cells. In our Evaluation of Peptide Immunisation in CML (EPIC) study, the patient’s entry requirements were as follows: first chronic phase of CML, expression of e14a2 (b3a2) BCR-ABL transcript, and prior treatment with imatinib daily (at least 400mg) at a stable dose for at least 6 months. Each patient received intradermally a cocktail of 3 BCR-ABL peptides: a 9-mer spanning the e14a2 region, the same 9-mer linked to PADRE (a 15-mer non-natural peptide shown to activate CD4+ T cells), and a 13-mer consensus e14a2 junctional peptide linked to PADRE. Peptides were administered at either 100 (5 patients), 300 (5 patients), 600 (5 patients), or 1000μg (4 patients) with sargramostim on 6 occasions over 2 months. Immune responses to the vaccine were monitored by IFN-γ and IL-5 ELISPOT assays on peripheral blood mononuclear cells. Molecular responses were assessed by quantitative real-time PCR of BCR-ABL mRNA. At entry no patient showed a detectable immune response to PADRE, but all 19 patients had detectable CD4+ T cells responses within 3 months of commencing vaccination. This indicated that the vaccination protocol was capable of stimulating T cell responses in all 19 patients. Immune responses to the 9-mer BCR-ABL junctional peptide used in the vaccine were detected in 11/19 patients, and demonstrated to be CD8+ T cells by cytokine analysis in flow cytometry. BCR-ABL immune responses were also assessed against a longer 18-mer peptide spanning the whole e14a2 junctional region. CD4+ T cells specific for this 18-mer peptide were detected in 14/19 patients. Interestingly, immunophenotyping indicated that these BCR-ABL-specific T cells were of a memory phenotype (CD45RO+). Serial molecular responses were available for at least 12 months on all cases. Of the 6 patients not in major cytogenic response (MCR) at baseline, molecular improvement was only observed in one case. However 12/13 patients in at least MCR at baseline had at least a 1 log fall in BCR–ABL transcripts, though this occurred several months after completing vaccination. Moreover, vaccination improved the fall in BCR–ABL transcripts in patients who had received imatinib for more than 12 months. These data show that peptide immunisation in CML can elicit anti-BCR-ABL peptide responses in CD4+ and CD8+ T cells. It also demonstrates that BCR-ABL peptide vaccination may improve control of CML, especially in patients responding well to imatinib.

scholarly journals Treatment-Free Remission in Chronic Myeloid Leukaemia: Can We Identify Prognostic Factors?

2021 ◽  
Author(s):  
Hilbeen Hisham Saifullah ◽  
Claire Marie Lucas
Keyword(s):  
Prognostic Factors ◽  
Chronic Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Molecular Response ◽  
Predicting Success ◽  
Treatment Free Remission ◽  
Almost All ◽  
Tki Discontinuation

Following the development of tyrosine kinase inhibitors (TKI), the survival of patients with chronic myeloid leukaemia (CML) drastically improved. With the introduction of these agents, CML is now considered a chronic disease, for some patients. Taking into consideration the side effects, toxicity, and high cost, discontinuing TKIs became a goal for patients with chronic phase CML. Patients who achieved deep molecular response (DMR) and discontinued TKI, remained in treatment-free remission (TFR). Currently, the data from the published literature demonstrate that 40-60% of patients achieve TFR, with relapses occurring within the first six months. In addition, almost all patients who relapsed regained a molecular response upon re-treatment, indicating TKI discontinuation is safe. However, there is still a gap in the understanding the mechanisms behind TFR, and whether there are prognostic factors that can predict the best candidates who qualify for TKI discontinuation with a view to keeping them in TFR. Furthermore, the information about a second TFR attempt and the role of gradual de-escalation of TKI before complete cessation is limited. This review highlights the factors predicting success or failure of TFR. In addition, it ex-amines the feasibility of a second TFR attempt after the failure of the first one, and the current guidelines concerning TFR in clinical practice.

Immunomodulatory Effects of STI571 in Chronic Myeloid Leukaemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2198-2198
Author(s):  
Dagmar Bund ◽  
Ting Yang ◽  
Raymund Buhmann ◽  
Hans-Jochem Kolb
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Chronic Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Cellular Immune Response ◽  
Myeloid Cells ◽  
Dependent Manner ◽  
Activation Markers ◽  
Cellular Immune ◽  
Antigen Presenting

Abstract Background: The tyrosine kinase inhibitor imatinib (imatinib, STI571, Glivec, and Gleevec) is highly effective in the treatment of chronic myeloid leukaemia (CML) and has already been shown to be effective in the setting of allogeneic stem cell transplantation. But until now, less is known with respect to its immunomodulating effects. Objective: In the present survey we investigated, whether imatinib could modify the antigen-presenting capacity of myeloid cells and in turn affects the cellular immune response. Method: For this purpose, patient derived chronic myeloid cells were incubated with different concentrations of imatinib (0, 1, 2, or 5microM), characterized for their antigen-presenting profile and their stimulatory capacity in the context of HLA-matched and mismatched T-cells. After 5 days, the proliferative immune response was evaluated in presence or absence of different concentrations of imatinib and altered effector-to-target ratios. Thereby, proliferation was detected via a CFDA, SE (5,6-carboxyfluorescein diacetate succinimidyl ester) based assay. Result: The proliferative capacity of the T- cells (allogeneic, HLA-mismatched) was inhibited by imatinib in a dose-dependent manner. Also, the expression of the activation markers was reduced in the presence of the different STI571 concentrations. Moreover, myeloid blasts were sensitized for T cell mediated effector functions by pre-treatment with increasing concentrations of imatinib. Conclusion: Taken together, imatinib can interfere with the T cellular immune response in vitro, and its impact on graft-versus-leukemia (GvL) and graft-versus-host (GvH) reactions will be further investigated.

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