Clinically relevant doses of FLT3-kinase inhibitors quizartinib and midostaurin do not impair T-cell reactivity and function

Wolleschak, Denise; Mack, Thomas Sebastian; Perner, Florian; Frey, Stephanie; Schnöder, Tina M.; Wagner, Marie-Christine; Höding, Christine; Pils, Marina C.; Parkner, Andreas; Kliche, Stefanie; Schraven, Burkhart; Hebel, Katrin; Brunner‐Weinzierl, Monika C.; Ranjan, Satish; Isermann, Berend; Lipka, Daniel B.; Fischer, Thomas

doi:10.3324/haematol.2014.104331

Cited by 17 publications

(14 citation statements)

References 15 publications

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“…As GvHD is primarily a T-cell driven disease we next explored aPC’s effect on T-cell activation using in vitro mixed lymphocyte reactions (MLRs) 23 . Co-culture of C57BL/6 wt pan T-cells with irradiated allogenic antigen-presenting cells (AgPC, BALB/c) for 96 h induced T-cell reactivity, which was markedly blunted in the presence of aPC (20 nM, every 12 h, Fig.…”

Section: Resultsmentioning

confidence: 99%

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Activated protein C protects from GvHD via PAR2/PAR3 signalling in regulatory T-cells

et al. 2017

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Graft-vs.-host disease (GvHD) is a major complication of allogenic hematopoietic stem-cell(HSC) transplantation. GvHD is associated with loss of endothelial thrombomodulin, but the relevance of this for the adaptive immune response to transplanted HSCs remains unknown. Here we show that the protease-activated protein C (aPC), which is generated by thrombomodulin, ameliorates GvHD aPC restricts allogenic T-cell activation via the protease activated receptor (PAR)2/PAR3 heterodimer on regulatory T-cells (Tregs, CD4+FOXP3+). Preincubation of pan T-cells with aPC prior to transplantation increases the frequency of Tregs and protects from GvHD. Preincubation of human T-cells (HLA-DR4−CD4+) with aPC prior to transplantation into humanized (NSG-AB°DR4) mice ameliorates graft-vs.-host disease. The protective effect of aPC on GvHD does not compromise the graft vs. leukaemia effect in two independent tumor cell models. Ex vivo preincubation of T-cells with aPC, aPC-based therapies, or targeting PAR2/PAR3 on T-cells may provide a safe and effective approach to mitigate GvHD.

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Section: Resultsmentioning

confidence: 99%

“…The effect of aPC on allogenic activation of human T-cells was next assessed 23 . Conducting the MLR using human T-cells and AgPC in the presence of aPC (20 nM, every 12 h) reduced T-cell reactivity to 67% as compared to the MLR without aPC (Fig.…”

Section: Resultsmentioning

confidence: 99%

Activated protein C protects from GvHD via PAR2/PAR3 signalling in regulatory T-cells

et al. 2017

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“…These preclinical data suggest that midostaurin and quizartinib may be used with immunosuppressive therapies and might not inhibit T-cell function. The authors concluded that the use of FLT3 TKIs may help prevent relapse, although prospective clinical studies are needed to confirm this [78].…”

Section: Published Data On Flt3 Tkis Given After Transplantationmentioning

confidence: 99%

Allogeneic Hematopoietic Stem Cell Transplantation in FLT3 -ITD–Positive Acute Myelogenous Leukemia: The Role for FLT3 Tyrosine Kinase Inhibitors Post-Transplantation

Schiller

Tuttle

Desai

2016

Biology of Blood and Marrow Transplantation

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In recent years, allogeneic hematopoietic stem cell transplantation (allo-HSCT) has become increasingly common in patients with acute myelogenous leukemia (AML) due to improved donor availability and the use of nonmyeloablative regimens. However, despite the potential clinical gains with allo-HSCT, the post-transplantation outcomes for many patients, especially those with high-risk disease, remain dismal. Patients with AML who have internal tandem duplication mutations in the tyrosine kinase receptor FLT3 (FLT3-ITD) face particularly poor outcomes, even after allo-HSCT, which appears to only partially mitigate the poor prognosis associated with this mutation. Experimental treatments to reduce the likelihood of relapse and improve survival following allo-HSCT include maintenance with FLT3-specific tyrosine kinase inhibitors (TKIs), several of which are currently being evaluated in clinical studies. Preliminary data and case reports suggest that FLT3 TKIs can be effective in the post-transplantation setting, particularly for patients with FLT3-ITD mutations. Improvements in donor matching, transplantation procedures, and supportive care have allowed a greater number of patients to undergo allo-HSCT than ever before. For these patients, it is essential to identify effective post-transplantation therapies to reduce the risk of relapse and improve disease-free survival.

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“…Indeed, it has recently been shown that the mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitor cobimetinib increased major histocomaptibility complex (MHC) class I molecule expression on cancer cells and induced a 17% response rate in colorectal cancer patients treated with the anti-PDL1 mAb atezolizumab [85]. Midostaurin, an flt-3 inhibitor with a broad kinase inhibition dendrogram, increases OS in AML patients (when added to daunorubicin and cytarabine) [86], yet does not hamper TCR signaling or T-cell activation [87]. Its effect on expression and function of checkpoint molecules on the cell surface of T-cells of AML patients has not yet been analyzed, although the combination of flt-3 inhibition with checkpoint inhibitors is currently being tested in Phase I to III trials in this disease.…”

Section: Synergistic Opportunities With Other Therapiesmentioning

confidence: 99%

Reactivation of dormant anti-tumor immunity – a clinical perspective of therapeutic immune checkpoint modulation

et al. 2017

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In favor of their outgrowth, cancer cells must resist immune surveillance and edit the immune response. Cancer immunoediting is characterized by fundamental changes in the cellular composition and the inflammatory cytokine profiles in the microenvironment of the primary tumor and metastatic niches, with an ever increasing complexity of interactions between tumor cells and the immune system. Recent data suggest that genetic instability and immunoediting are not necessarily disparate processes. Increasing mutational load may be associated with multiple neoepitopes expressed by the tumor cells and thus increased chances for the immune system to recognize and combat these cells. At the same time the immune system is more and more suppressed and exhausted by this process. Consequently, immune checkpoint modulation may have the potential to be most successful in genetically highly altered and usually extremely unfavorable types of cancer. Moreover, the fact that epitopes recognized by the immune system are preferentially encoded by passenger gene mutations opens windows of synergy in targeting cancer-specific signaling pathways by small molecules simultaneously with antibodies modifying T-cell activation or exhaustion.This review covers some aspects of the current understanding of the immunological basis necessary to understand the rapidly developing therapeutic endeavours in cancer treatment, the clinical achievements made, and raises some burning questions for translational research in this field.

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Clinically relevant doses of FLT3-kinase inhibitors quizartinib and midostaurin do not impair T-cell reactivity and function

Abstract: LETTERS TO THE EDITOR © F e r r a t a S t o r t i F o u n d a t i o n

Cited by 17 publications

References 15 publications

Activated protein C protects from GvHD via PAR2/PAR3 signalling in regulatory T-cells

Activated protein C protects from GvHD via PAR2/PAR3 signalling in regulatory T-cells

Allogeneic Hematopoietic Stem Cell Transplantation in FLT3 -ITD–Positive Acute Myelogenous Leukemia: The Role for FLT3 Tyrosine Kinase Inhibitors Post-Transplantation

Reactivation of dormant anti-tumor immunity – a clinical perspective of therapeutic immune checkpoint modulation

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