Development and dynamics of robust T-cell responses to CML under imatinib treatment

Chen, Christiane I-U; Maecker, Holden T.; Lee, Peter P.

doi:10.1182/blood-2007-12-128397

Cited by 80 publications

(102 citation statements)

References 35 publications

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“…However, imatinib does not seem to be among the most detrimental agents active on immune cells, as autologous bcr/abl-specific T-cell immunity may emerge and persist in patients with chronic myeloid leukemia treated with this tyrosine-kinase inhibitor. 30 Therefore, we believe that, in our patient, restoration of JCV-specific immunity was promoted by immunosuppression discontinuation and enhanced by the adoptive infusion of virus-specific cell lines. Indeed, no JCV-specific cytotoxicity was detectable after discontinuation of immune-suppressive therapy and before CTL infusion, a finding that would have predicted an unfavorable outcome, given JCV persistence in CSF.…”

Section: Discussionmentioning

confidence: 74%

Polyomavirus JC-targeted T-cell therapy for progressive multiple leukoencephalopathy in a hematopoietic cell transplantation recipient

Balduzzi

Lucchini

Hirsch

et al. 2010

Bone Marrow Transplant

115

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Progressive multifocal leukoencephalopathy (PML) associated with polyomavirus JC (JCV) infection has been reported to be usually fatal in allogeneic hematopoietic SCT (HSCT) recipients. We present the case of a 19-year-old HSCT patient diagnosed with JCV-associated PML after prolonged immunosuppression for severe GVHD. No short-term neurological improvement was observed after antiviral treatment and discontinuation of immunosuppressive therapy. Donor-derived JCV Ag-specific CTLs were generated in vitro after stimulation with 15-mer peptides derived from VP1 and large T viral proteins. After adoptive CTL infusion, virus-specific cytotoxic cells were shown in the peripheral blood, JCV-DNA was cleared in the cerebrospinal fluid and the patient showed remarkable improvement. Adoptive T-lymphocyte therapy with JCVspecific CTLs was feasible and had no side effects. This case suggests that adoptive transfer of JCV-targeted CTLs may contribute to restore JCV-specific immune competence and control PML in transplanted patients.

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Section: Discussionmentioning

confidence: 74%

Polyomavirus JC-targeted T-cell therapy for progressive multiple leukoencephalopathy in a hematopoietic cell transplantation recipient

Balduzzi

Lucchini

Hirsch

et al. 2010

Bone Marrow Transplant

115

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“…15 Cytotoxic T lymphocytes specific for leukemia-associated antigens have been demonstrated in patients treated with both interferon-a 16,17 and imatinib. 18 Further investigation is warranted to determine whether immunological reactivity against CML modifies the risk or timing of relapse when imatinib treatment is withdrawn. Kinetic data using RQ-PCR have shown that the average rate of decline in MRD is o0.5 log per annum beyond the second year of imatinib treatment.…”

Section: Discussionmentioning

confidence: 99%

Patients with chronic myeloid leukemia who maintain a complete molecular response after stopping imatinib treatment have evidence of persistent leukemia by DNA PCR

et al. 2010

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“…[27][28][29] Imatinib was shown to inhibit T-cell functions 30,31 but not NK-cell cytotoxicity and cytokine secretion. 29 Importantly, despite the immunosuppressive activities reported for both drugs in vitro, functional T-cell responses were reported to develop in CML patients on imatinib, [32][33][34] and clonal lymphoproliferation was observed in some patients on dasatinib and was associated with favorable clinical responses. [35][36][37][38] Thus, further in vivo studies are needed to discern the effects of TKIs on immune effector cells.…”

Section: Introductionmentioning

confidence: 99%

NK cells are dysfunctional in human chronic myelogenous leukemia before and on imatinib treatment and in BCR–ABL-positive mice

et al. 2011

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Although BCR-ABL þ stem cells in chronic myeloid leukemia (CML) resist elimination by targeted pharmacotherapy in most patients, immunological graft-versus-leukemia effects can cure the disease. Besides cytotoxic T cells, natural killer (NK) cells may have a role in immune control of CML. Here, we explored the functionality of NK cells in CML patients and in a transgenic inducible BCR-ABL mouse model. Compared with controls, NK-cell proportions among lymphocytes were decreased at diagnosis of CML and did not recover during imatinib-induced remission for 10-34 months. Functional experiments revealed limited in vitro expansion of NK cells from CML patients and a reduced degranulation response to K562 target cells both at diagnosis and during imatinib therapy. Consistent with the results in human CML, relative numbers of NK1.1 þ NK cells were reduced following induction of BCR-ABL expression in mice, and the defects persisted after BCR-ABL reversion. Moreover, target-induced degranulation by expanded BCR-ABL þ NK cells was compromised. We conclude that CML is associated with quantitative and functional defects within the NK-cell compartment, which is reproduced by induced BCR-ABL expression in mice. Further work will aim at identifying the mechanisms of NK-cell deficiency in CML and at developing strategies to exploit NK cells for immunotherapy.

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Development and dynamics of robust T-cell responses to CML under imatinib treatment

Cited by 80 publications

References 35 publications

Polyomavirus JC-targeted T-cell therapy for progressive multiple leukoencephalopathy in a hematopoietic cell transplantation recipient

Polyomavirus JC-targeted T-cell therapy for progressive multiple leukoencephalopathy in a hematopoietic cell transplantation recipient

Patients with chronic myeloid leukemia who maintain a complete molecular response after stopping imatinib treatment have evidence of persistent leukemia by DNA PCR

NK cells are dysfunctional in human chronic myelogenous leukemia before and on imatinib treatment and in BCR–ABL-positive mice

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