BackgroundLeukemia-associated macrophages (LAMs) represent an important cell population within th... more BackgroundLeukemia-associated macrophages (LAMs) represent an important cell population within the tumor microenvironment, but little is known about the phenotype, function, and plasticity of these cells. The present study provides an extensive characterization of macrophages in patients with acute myeloid leukemia (AML).MethodsThe phenotype and expression of coregulatory markers were assessed on bone marrow (BM)-derived LAM populations, using multiparametric flow cytometry. BM and blood aspirates were obtained from patients with newly diagnosed acute myeloid leukemia (pAML, n=59), patients in long-term remission (lrAML, n=8), patients with relapsed acute myeloid leukemia (rAML, n=7) and monocyte-derived macrophages of the blood from healthy donors (HD, n=17). LAM subpopulations were correlated with clinical parameters. Using a blocking anti-T-cell immunoreceptor with Ig and ITIM domains (TIGIT) antibody or mouse IgG2α isotype control, we investigated polarization, secretion of cyto...
The main objective of this study was to compare the long-term health-related quality of life of p... more The main objective of this study was to compare the long-term health-related quality of life of patients with acute promyelocytic leukemia (APL) treated with all-trans retinoic acid (ATRA) plus arsenic trioxide (ATO) vs ATRA plus standard chemotherapy. Patients previously enrolled in the randomized controlled trial APL0406 were considered eligible for this follow-up study. The following patient-reported outcome measures were used: the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core30 (EORTC QLQ-C30), the EORTC Quality of Life Questionnaire Chemotherapy-Induced Peripheral Neuropathy 20 (QLQ-CIPN20), and the Short Form Health Survey 36 (SF-36). The prevalence of late comorbidities and health problems was also assessed. The clinical significance of differences was evaluated based on predefined thresholds. A total of 161 of 232 potentially eligible patients were analyzed, of whom 83 were treated with ATRA-ATO and 78 were treated with ATRA ch...
The majority of publications regarding SARS-CoV-2 infections in adult patients with acute leukemi... more The majority of publications regarding SARS-CoV-2 infections in adult patients with acute leukemia (AL) refer to hematological patients in general and are not focused on acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL). We herein report a review of the current literature on adult AL patients infected with SARS-CoV-2. Overall, SARS-CoV-2-associated mortality ranges from 20–52% in patients with adult AL. AML patients have a particularly high COVID-19-related mortality. Of note, most of the available data relate to the pre-vaccination era and to variants before Omicron. The impact of COVID-19 infections on AL treatment is rarely reported. Based on the few studies available, treatment delay does not appear to be associated with an increased risk of relapse, whereas therapy discontinuation was associated with worse outcomes in AML patients. Therefore, the current recommendations suggest delaying systemic AL treatment in SARS-CoV-2-positive patients until SARS-CoV-2 nega...
Despite therapeutic advances in the prevention and treatment of febrile neutropenia, acute leukem... more Despite therapeutic advances in the prevention and treatment of febrile neutropenia, acute leukemia (AL) patients still have considerable febrile neutropenia-related mortality. However, the diagnostic yield of flexible bronchoscopy (FB) and bronchoalveolar lavage (BAL) in acute leukemia patients is unclear. In this retrospective single-center study, we analyzed 88 BAL samples of patients with acute leukemia and pulmonary infiltrates in spite of treatment with broad-spectrum anti-infective agents. The aim was to investigate the impact of FB with BAL on detecting causative organisms, which would result in a change in treatment regimens. The median age was 59 years, and 86% had acute myeloid leukemia. In 47%, pathogens were detectable in BAL fluid (pathogen bacteria, viruses, and fungi in 2, 15, and 18%, respectively), with Aspergillus fumigatus detected most frequently. BAL-guided anti-infective therapy changes were performed in 15%. The detection of herpes simplex and influenza virus...
This study aimed to characterize different natural killer (NK) cell phenotypes on bone marrow and... more This study aimed to characterize different natural killer (NK) cell phenotypes on bone marrow and peripheral blood cells from acute myeloid leukemia (AML) patients and healthy donors (HDs). Our data show that CD56dimCD16− and CD56brightCD16− NK cells represent the predominant NK cell subpopulations in AML, while the CD56dimCD16+ NK cells are significantly reduced compared to HDs. Moreover, TIGIT+ and PVRIG+ cells cluster on the CD56dimCD16+ subset whereas CD39+ and CD38+ cells do so on CD56brightCD16− NK cells in AML. Furthermore, functional effects of (co-)blockade of TIGIT and CD39 or A2AR on NK cell functionality were analyzed. These experiments revealed that the single blockade of the TIGIT receptor results in an increased NK-92 cell-mediated killing of AML cells in vitro. Combined targeting of CD39 or A2AR significantly augments the anti-TIGIT-mediated lysis of AML cells. Our data indicate that distinct NK cell subsets in AML exhibit different immunosuppressive patterns (via th...
Phenotypic characterization of γδ T cells in the MALs (malignant ascites lymphocytes), TILs (tumo... more Phenotypic characterization of γδ T cells in the MALs (malignant ascites lymphocytes), TILs (tumor infiltrating lymphocytes), and PBLs (peripheral blood lymphocytes) of ovarian cancer (OvCA) patients is lacking. Therefore, we quantified γδ T cell prevalence in MAL, TIL, and PBL specimens from n = 18 OvCA patients and PBL from age-matched healthy donors (HD, n = 14). Multicolor flow cytometry was performed to evaluate the expression of inhibitory receptors (TIGIT, PD-1 and TIM-3), stimulatory receptors (Ox40), and purinergic ectoenzymes (CD39 and CD73) on γδ T cell subsets. We identified an abundant infiltration of Vδ1 T cells in the MALs and TILs. These cells varied in their differentiation: The majority of Vδ1 TILs displayed an effector memory (EM) phenotype, whereas Vδ1 MALs had a more mature phenotype of terminally differentiated effector memory cells (TEMRA) with high CD45RA expression. TIGIT and TIM-3 were abundantly expressed in both MALs and PBLs, whereas Vδ1 TILs exhibited t...
Severe infectious complications remain the main cause of mortality in leukemia patients due to a ... more Severe infectious complications remain the main cause of mortality in leukemia patients due to a long period of profound neutropenia. Standardized regimens for antimicrobial, antifungal, and antiviral prophylaxis and therapy in neutropenic patients have improved infection-associated mortality. Nevertheless, many patients are refractory to these multidrug approaches. Tigecycline is a last-resort antibiotic with a broad-spectrum activity; unfortunately, clinical experience in multidrug-resistant febrile neutropenia is limited. The aim was to evaluate the efficacy of tigecycline treatment in comparison to standard treatment in this patient cohort. In this single center analysis, we analyzed the clinical courses of 73 patients with acute leukemia and diagnosis of febrile neutropenia resistant to hospital-based multidrug escalation levels who continued on a standard approach without antibiotics as the last resort (n = 30) or were switched to tigecycline in addition to carbapenem treatmen...
Purpose: To evaluate efficacy and safety of venetoclax + azacitidine among treatment-naïve patien... more Purpose: To evaluate efficacy and safety of venetoclax + azacitidine among treatment-naïve patients with IDH1/2-mutant (mut) acute myeloid leukemia (AML). Patients and Methods: Data were pooled from patients enrolled in a phase III study (NCT02993523) that compared patients treated with venetoclax + azacitidine or placebo + azacitidine and a prior phase Ib study (NCT02203773) where patients were treated with venetoclax + azacitidine. Enrolled patients were ineligible for intensive therapy due to age ≥75 years and/or comorbidities. Patients on venetoclax + azacitidine received venetoclax 400 mg orally (days 1–28) and azacitidine (75 mg/m2; days 1–7/28-day cycle). Results: In the biomarker-evaluable population, IDH1/2mut was detected in 81 (26%) and 28 (22%) patients in the venetoclax + azacitidine and azacitidine groups. Composite complete remission [CRc, complete remission (CR)+CR with incomplete hematologic recovery (CRi)] rates (venetoclax + azacitidine/azacitidine) among patients...
Cilengitide induces cellular detachment and apoptosis in endothelial and glioma cells mediated by... more Cilengitide induces cellular detachment and apoptosis in endothelial and glioma cells mediated by inhibition of FAK/src/AKT pathway
High mobility group box 1 (HMGB1) is a non-histone protein which is predominantly localised in th... more High mobility group box 1 (HMGB1) is a non-histone protein which is predominantly localised in the cell nucleus. However, stressed, dying, injured or dead cells can release this protein into the extracellular matrix passively. In addition, HMGB1 release was observed in cancer and immune cells where this process can be triggered by various endogenous as well as exogenous stimuli. Importantly, released HMGB1 acts as a so-called “danger signal” and could impact on the ability of cancer cells to escape host immune surveillance. However, the molecular mechanisms underlying the functional role of HMGB1 in determining the capability of human cancer cells to evade immune attack remain unclear. Here we report that the involvement of HMGB1 in anti-cancer immune evasion is determined by Toll-like receptor (TLR) 4, which recognises HMGB1 as a ligand. We found that HGMB1 induces TLR4-mediated production of transforming growth factor beta type 1 (TGF-β), displaying autocrine/paracrine activities....
Background: γδ T cells represent a unique T cell subpopulation due to their ability to recognize ... more Background: γδ T cells represent a unique T cell subpopulation due to their ability to recognize cancer cells in a T cell receptor- (TCR) dependent manner, but also in a non-major histocompatibility complex- (MHC) restricted way via natural killer receptors (NKRs). Endowed with these features, they represent attractive effectors for immuno-therapeutic strategies with a better safety profile and a more favorable anti-tumor efficacy in comparison to conventional αβ T cells. Also, remarkable progress has been achieved re-activating exhausted T lymphocytes with inhibitors of co-regulatory receptors e.g., programmed cell death protein 1 (PD-1), T cell immunoreceptor with Ig and ITIM domains (TIGIT) and of the adenosine pathway (CD39, CD73). Regarding γδ T cells, little evidence is available. This study aimed to immunophenotypically characterize γδ T cells from patients with diagnosed acute myeloid leukemia (AML) in comparison to patients with multiple myeloma (MM) and healthy donors (HD)...
Key Points Patients with acute leukemia present with a prolonged and severe course of COVID-19, w... more Key Points Patients with acute leukemia present with a prolonged and severe course of COVID-19, which is paralleled by high rates of viremia. Low-intensive chemotherapy seems to be more feasible in patients with acute myeloid leukemia and concomitant SARS-CoV-2 infection.
The version in the Kent Academic Repository may differ from the final published version. Users ar... more The version in the Kent Academic Repository may differ from the final published version. Users are advised to check http://kar.kent.ac.uk for the status of the paper. Users should always cite the published version of record.
Acute myeloid leukemia (AML), a blood/bone marrow cancer, is a severe and often fatal malignancy.... more Acute myeloid leukemia (AML), a blood/bone marrow cancer, is a severe and often fatal malignancy. AML cells are capable of impairing the anti-cancer activities of cytotoxic lymphoid cells. This includes the inactivation of natural killer (NK) cells and killing of T lymphocytes. Here we report for the first time that V-domain Ig-containing suppressor of T cell activation (VISTA), a protein expressed by T cells, recognizes galectin-9 secreted by AML cells as a ligand. Importantly, we found that soluble VISTA released by AML cells enhances the effect of galectin-9, most likely by forming multiprotein complexes on the surface of T cells and possibly creating a molecular barrier. These events cause changes in the plasma membrane potential of T cells leading to activation of granzyme B inside cytotoxic T cells, resulting in apoptosis.
Isolated myeloid sarcoma (MS) is a rare malignancy in which myeloid blast forms tumors at various... more Isolated myeloid sarcoma (MS) is a rare malignancy in which myeloid blast forms tumors at various locations while the bone marrow (BM) remains cytomorphologically free from disease. We analyzed isolated MS from four patients and their BMs at initial diagnosis and follow-up, using a custom next-generation sequencing (NGS) panel. We observed possible clonal evolution and a clonal hematopoiesis of indeterminate potential (CHIP)-like finding in the BM of one of three cases with detectable mutations. Clinical presentation of one patient suggested extramedullary confined homing of blasts to distal sites in the relapse situation still sparing the BM. In summary, our findings shall motivate future work regarding signals of extramedullary blast trafficking and clonal evolution in MS.
Background: Acute myeloid leukemia (AML) with t(8;21)(q22;q22) results in the formation of the RU... more Background: Acute myeloid leukemia (AML) with t(8;21)(q22;q22) results in the formation of the RUNX1-RUNX1T1 fusion transcript which can be used to monitor minimal residual disease (MRD) by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). Early identification of patients (pts) with a high risk of relapse will allow pre-emptive therapy including allogeneic hematopoietic cell transplantation (alloHCT). Recent studies in AML with NPM1 mutation or the CBFB-MYH11 gene fusion revealed that MRD persistence is significantly associated with a high risk of relapse. However, the prognostic impact of MRD assessment in RUNX1-RUNX1T1-positive AML is not well established. Aims: To assess the prognostic impact of qRT-PCR-based MRD monitoring in bone marrow (BM) of pts with t(8;21)/RUNX1-RUNX1T1-positive AML obtained at defined time-points (diagnosis, first and second cycle of chemotherapy, end of treatment). Methods: In total, 120 pts were included based on the availability o...
Immune checkpoints are intensively investigated as targets in cancer therapy. T-cell immunorecept... more Immune checkpoints are intensively investigated as targets in cancer therapy. T-cell immunoreceptor with immunoglobulin (Ig) and ITIM domains (TIGIT) and its ligand poliovirus receptor (PVR) are recently emerging as novel promising targets in immunotherapy. Here, we show that high expression of PVR represents an independent prognostic marker being associated with poor outcome for breast cancer patients. Furthermore, PVR mRNA, as well as protein expression, is associated with more aggressive breast cancer subtypes such as HER2 positive and triple-negative breast cancer. In vitro, blocking TIGIT or PVR resulted in enhanced immune cell-mediated lysis of breast cancer cell lines SKBR-3, MDA-MB-231, MDA-MB-468, and BT549 and additionally increased the cytotoxic effects of a bispecific T cell engager BiTE® antibody construct targeting EGFR. Taken together, our data identify the immune checkpoint factor PVR as a novel prognostic marker in breast cancer and indicate that blocking the TIGIT-PVR axis might represent a novel therapeutic option for the treatment of breast cancer patients.
Immune checkpoints are promising targets in cancer therapy. Recently, poliovirus receptor (PVR) a... more Immune checkpoints are promising targets in cancer therapy. Recently, poliovirus receptor (PVR) and poliovirus receptor-related 2 (PVRL2) have been identified as novel immune checkpoints. In this investigation we show that acute myeloid leukemia (AML) cell lines and AML patient samples highly express the T-cell immunoreceptor with Ig and ITIM domains (TIGIT) ligands PVR and PVRL2. Using two independent patient cohorts, we could demonstrate that high PVR and PVRL2 expression correlates with poor outcome in AML. We show for the first time that antibody blockade of PVR or PVRL2 on AML cell lines or primary AML cells or TIGIT blockade on immune cells increases the anti-leukemic effects mediated by PBMCs or purified CD3 cells in vitro. The cytolytic activity of the BiTE® antibody construct AMG 330 against leukemic cells could be further enhanced by blockade of the TIGIT-PVR/PVRL2 axis. This increased immune reactivity is paralleled by augmented secretion of Granzyme B by immune cells. Em...
BackgroundLeukemia-associated macrophages (LAMs) represent an important cell population within th... more BackgroundLeukemia-associated macrophages (LAMs) represent an important cell population within the tumor microenvironment, but little is known about the phenotype, function, and plasticity of these cells. The present study provides an extensive characterization of macrophages in patients with acute myeloid leukemia (AML).MethodsThe phenotype and expression of coregulatory markers were assessed on bone marrow (BM)-derived LAM populations, using multiparametric flow cytometry. BM and blood aspirates were obtained from patients with newly diagnosed acute myeloid leukemia (pAML, n=59), patients in long-term remission (lrAML, n=8), patients with relapsed acute myeloid leukemia (rAML, n=7) and monocyte-derived macrophages of the blood from healthy donors (HD, n=17). LAM subpopulations were correlated with clinical parameters. Using a blocking anti-T-cell immunoreceptor with Ig and ITIM domains (TIGIT) antibody or mouse IgG2α isotype control, we investigated polarization, secretion of cyto...
The main objective of this study was to compare the long-term health-related quality of life of p... more The main objective of this study was to compare the long-term health-related quality of life of patients with acute promyelocytic leukemia (APL) treated with all-trans retinoic acid (ATRA) plus arsenic trioxide (ATO) vs ATRA plus standard chemotherapy. Patients previously enrolled in the randomized controlled trial APL0406 were considered eligible for this follow-up study. The following patient-reported outcome measures were used: the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core30 (EORTC QLQ-C30), the EORTC Quality of Life Questionnaire Chemotherapy-Induced Peripheral Neuropathy 20 (QLQ-CIPN20), and the Short Form Health Survey 36 (SF-36). The prevalence of late comorbidities and health problems was also assessed. The clinical significance of differences was evaluated based on predefined thresholds. A total of 161 of 232 potentially eligible patients were analyzed, of whom 83 were treated with ATRA-ATO and 78 were treated with ATRA ch...
The majority of publications regarding SARS-CoV-2 infections in adult patients with acute leukemi... more The majority of publications regarding SARS-CoV-2 infections in adult patients with acute leukemia (AL) refer to hematological patients in general and are not focused on acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL). We herein report a review of the current literature on adult AL patients infected with SARS-CoV-2. Overall, SARS-CoV-2-associated mortality ranges from 20–52% in patients with adult AL. AML patients have a particularly high COVID-19-related mortality. Of note, most of the available data relate to the pre-vaccination era and to variants before Omicron. The impact of COVID-19 infections on AL treatment is rarely reported. Based on the few studies available, treatment delay does not appear to be associated with an increased risk of relapse, whereas therapy discontinuation was associated with worse outcomes in AML patients. Therefore, the current recommendations suggest delaying systemic AL treatment in SARS-CoV-2-positive patients until SARS-CoV-2 nega...
Despite therapeutic advances in the prevention and treatment of febrile neutropenia, acute leukem... more Despite therapeutic advances in the prevention and treatment of febrile neutropenia, acute leukemia (AL) patients still have considerable febrile neutropenia-related mortality. However, the diagnostic yield of flexible bronchoscopy (FB) and bronchoalveolar lavage (BAL) in acute leukemia patients is unclear. In this retrospective single-center study, we analyzed 88 BAL samples of patients with acute leukemia and pulmonary infiltrates in spite of treatment with broad-spectrum anti-infective agents. The aim was to investigate the impact of FB with BAL on detecting causative organisms, which would result in a change in treatment regimens. The median age was 59 years, and 86% had acute myeloid leukemia. In 47%, pathogens were detectable in BAL fluid (pathogen bacteria, viruses, and fungi in 2, 15, and 18%, respectively), with Aspergillus fumigatus detected most frequently. BAL-guided anti-infective therapy changes were performed in 15%. The detection of herpes simplex and influenza virus...
This study aimed to characterize different natural killer (NK) cell phenotypes on bone marrow and... more This study aimed to characterize different natural killer (NK) cell phenotypes on bone marrow and peripheral blood cells from acute myeloid leukemia (AML) patients and healthy donors (HDs). Our data show that CD56dimCD16− and CD56brightCD16− NK cells represent the predominant NK cell subpopulations in AML, while the CD56dimCD16+ NK cells are significantly reduced compared to HDs. Moreover, TIGIT+ and PVRIG+ cells cluster on the CD56dimCD16+ subset whereas CD39+ and CD38+ cells do so on CD56brightCD16− NK cells in AML. Furthermore, functional effects of (co-)blockade of TIGIT and CD39 or A2AR on NK cell functionality were analyzed. These experiments revealed that the single blockade of the TIGIT receptor results in an increased NK-92 cell-mediated killing of AML cells in vitro. Combined targeting of CD39 or A2AR significantly augments the anti-TIGIT-mediated lysis of AML cells. Our data indicate that distinct NK cell subsets in AML exhibit different immunosuppressive patterns (via th...
Phenotypic characterization of γδ T cells in the MALs (malignant ascites lymphocytes), TILs (tumo... more Phenotypic characterization of γδ T cells in the MALs (malignant ascites lymphocytes), TILs (tumor infiltrating lymphocytes), and PBLs (peripheral blood lymphocytes) of ovarian cancer (OvCA) patients is lacking. Therefore, we quantified γδ T cell prevalence in MAL, TIL, and PBL specimens from n = 18 OvCA patients and PBL from age-matched healthy donors (HD, n = 14). Multicolor flow cytometry was performed to evaluate the expression of inhibitory receptors (TIGIT, PD-1 and TIM-3), stimulatory receptors (Ox40), and purinergic ectoenzymes (CD39 and CD73) on γδ T cell subsets. We identified an abundant infiltration of Vδ1 T cells in the MALs and TILs. These cells varied in their differentiation: The majority of Vδ1 TILs displayed an effector memory (EM) phenotype, whereas Vδ1 MALs had a more mature phenotype of terminally differentiated effector memory cells (TEMRA) with high CD45RA expression. TIGIT and TIM-3 were abundantly expressed in both MALs and PBLs, whereas Vδ1 TILs exhibited t...
Severe infectious complications remain the main cause of mortality in leukemia patients due to a ... more Severe infectious complications remain the main cause of mortality in leukemia patients due to a long period of profound neutropenia. Standardized regimens for antimicrobial, antifungal, and antiviral prophylaxis and therapy in neutropenic patients have improved infection-associated mortality. Nevertheless, many patients are refractory to these multidrug approaches. Tigecycline is a last-resort antibiotic with a broad-spectrum activity; unfortunately, clinical experience in multidrug-resistant febrile neutropenia is limited. The aim was to evaluate the efficacy of tigecycline treatment in comparison to standard treatment in this patient cohort. In this single center analysis, we analyzed the clinical courses of 73 patients with acute leukemia and diagnosis of febrile neutropenia resistant to hospital-based multidrug escalation levels who continued on a standard approach without antibiotics as the last resort (n = 30) or were switched to tigecycline in addition to carbapenem treatmen...
Purpose: To evaluate efficacy and safety of venetoclax + azacitidine among treatment-naïve patien... more Purpose: To evaluate efficacy and safety of venetoclax + azacitidine among treatment-naïve patients with IDH1/2-mutant (mut) acute myeloid leukemia (AML). Patients and Methods: Data were pooled from patients enrolled in a phase III study (NCT02993523) that compared patients treated with venetoclax + azacitidine or placebo + azacitidine and a prior phase Ib study (NCT02203773) where patients were treated with venetoclax + azacitidine. Enrolled patients were ineligible for intensive therapy due to age ≥75 years and/or comorbidities. Patients on venetoclax + azacitidine received venetoclax 400 mg orally (days 1–28) and azacitidine (75 mg/m2; days 1–7/28-day cycle). Results: In the biomarker-evaluable population, IDH1/2mut was detected in 81 (26%) and 28 (22%) patients in the venetoclax + azacitidine and azacitidine groups. Composite complete remission [CRc, complete remission (CR)+CR with incomplete hematologic recovery (CRi)] rates (venetoclax + azacitidine/azacitidine) among patients...
Cilengitide induces cellular detachment and apoptosis in endothelial and glioma cells mediated by... more Cilengitide induces cellular detachment and apoptosis in endothelial and glioma cells mediated by inhibition of FAK/src/AKT pathway
High mobility group box 1 (HMGB1) is a non-histone protein which is predominantly localised in th... more High mobility group box 1 (HMGB1) is a non-histone protein which is predominantly localised in the cell nucleus. However, stressed, dying, injured or dead cells can release this protein into the extracellular matrix passively. In addition, HMGB1 release was observed in cancer and immune cells where this process can be triggered by various endogenous as well as exogenous stimuli. Importantly, released HMGB1 acts as a so-called “danger signal” and could impact on the ability of cancer cells to escape host immune surveillance. However, the molecular mechanisms underlying the functional role of HMGB1 in determining the capability of human cancer cells to evade immune attack remain unclear. Here we report that the involvement of HMGB1 in anti-cancer immune evasion is determined by Toll-like receptor (TLR) 4, which recognises HMGB1 as a ligand. We found that HGMB1 induces TLR4-mediated production of transforming growth factor beta type 1 (TGF-β), displaying autocrine/paracrine activities....
Background: γδ T cells represent a unique T cell subpopulation due to their ability to recognize ... more Background: γδ T cells represent a unique T cell subpopulation due to their ability to recognize cancer cells in a T cell receptor- (TCR) dependent manner, but also in a non-major histocompatibility complex- (MHC) restricted way via natural killer receptors (NKRs). Endowed with these features, they represent attractive effectors for immuno-therapeutic strategies with a better safety profile and a more favorable anti-tumor efficacy in comparison to conventional αβ T cells. Also, remarkable progress has been achieved re-activating exhausted T lymphocytes with inhibitors of co-regulatory receptors e.g., programmed cell death protein 1 (PD-1), T cell immunoreceptor with Ig and ITIM domains (TIGIT) and of the adenosine pathway (CD39, CD73). Regarding γδ T cells, little evidence is available. This study aimed to immunophenotypically characterize γδ T cells from patients with diagnosed acute myeloid leukemia (AML) in comparison to patients with multiple myeloma (MM) and healthy donors (HD)...
Key Points Patients with acute leukemia present with a prolonged and severe course of COVID-19, w... more Key Points Patients with acute leukemia present with a prolonged and severe course of COVID-19, which is paralleled by high rates of viremia. Low-intensive chemotherapy seems to be more feasible in patients with acute myeloid leukemia and concomitant SARS-CoV-2 infection.
The version in the Kent Academic Repository may differ from the final published version. Users ar... more The version in the Kent Academic Repository may differ from the final published version. Users are advised to check http://kar.kent.ac.uk for the status of the paper. Users should always cite the published version of record.
Acute myeloid leukemia (AML), a blood/bone marrow cancer, is a severe and often fatal malignancy.... more Acute myeloid leukemia (AML), a blood/bone marrow cancer, is a severe and often fatal malignancy. AML cells are capable of impairing the anti-cancer activities of cytotoxic lymphoid cells. This includes the inactivation of natural killer (NK) cells and killing of T lymphocytes. Here we report for the first time that V-domain Ig-containing suppressor of T cell activation (VISTA), a protein expressed by T cells, recognizes galectin-9 secreted by AML cells as a ligand. Importantly, we found that soluble VISTA released by AML cells enhances the effect of galectin-9, most likely by forming multiprotein complexes on the surface of T cells and possibly creating a molecular barrier. These events cause changes in the plasma membrane potential of T cells leading to activation of granzyme B inside cytotoxic T cells, resulting in apoptosis.
Isolated myeloid sarcoma (MS) is a rare malignancy in which myeloid blast forms tumors at various... more Isolated myeloid sarcoma (MS) is a rare malignancy in which myeloid blast forms tumors at various locations while the bone marrow (BM) remains cytomorphologically free from disease. We analyzed isolated MS from four patients and their BMs at initial diagnosis and follow-up, using a custom next-generation sequencing (NGS) panel. We observed possible clonal evolution and a clonal hematopoiesis of indeterminate potential (CHIP)-like finding in the BM of one of three cases with detectable mutations. Clinical presentation of one patient suggested extramedullary confined homing of blasts to distal sites in the relapse situation still sparing the BM. In summary, our findings shall motivate future work regarding signals of extramedullary blast trafficking and clonal evolution in MS.
Background: Acute myeloid leukemia (AML) with t(8;21)(q22;q22) results in the formation of the RU... more Background: Acute myeloid leukemia (AML) with t(8;21)(q22;q22) results in the formation of the RUNX1-RUNX1T1 fusion transcript which can be used to monitor minimal residual disease (MRD) by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). Early identification of patients (pts) with a high risk of relapse will allow pre-emptive therapy including allogeneic hematopoietic cell transplantation (alloHCT). Recent studies in AML with NPM1 mutation or the CBFB-MYH11 gene fusion revealed that MRD persistence is significantly associated with a high risk of relapse. However, the prognostic impact of MRD assessment in RUNX1-RUNX1T1-positive AML is not well established. Aims: To assess the prognostic impact of qRT-PCR-based MRD monitoring in bone marrow (BM) of pts with t(8;21)/RUNX1-RUNX1T1-positive AML obtained at defined time-points (diagnosis, first and second cycle of chemotherapy, end of treatment). Methods: In total, 120 pts were included based on the availability o...
Immune checkpoints are intensively investigated as targets in cancer therapy. T-cell immunorecept... more Immune checkpoints are intensively investigated as targets in cancer therapy. T-cell immunoreceptor with immunoglobulin (Ig) and ITIM domains (TIGIT) and its ligand poliovirus receptor (PVR) are recently emerging as novel promising targets in immunotherapy. Here, we show that high expression of PVR represents an independent prognostic marker being associated with poor outcome for breast cancer patients. Furthermore, PVR mRNA, as well as protein expression, is associated with more aggressive breast cancer subtypes such as HER2 positive and triple-negative breast cancer. In vitro, blocking TIGIT or PVR resulted in enhanced immune cell-mediated lysis of breast cancer cell lines SKBR-3, MDA-MB-231, MDA-MB-468, and BT549 and additionally increased the cytotoxic effects of a bispecific T cell engager BiTE® antibody construct targeting EGFR. Taken together, our data identify the immune checkpoint factor PVR as a novel prognostic marker in breast cancer and indicate that blocking the TIGIT-PVR axis might represent a novel therapeutic option for the treatment of breast cancer patients.
Immune checkpoints are promising targets in cancer therapy. Recently, poliovirus receptor (PVR) a... more Immune checkpoints are promising targets in cancer therapy. Recently, poliovirus receptor (PVR) and poliovirus receptor-related 2 (PVRL2) have been identified as novel immune checkpoints. In this investigation we show that acute myeloid leukemia (AML) cell lines and AML patient samples highly express the T-cell immunoreceptor with Ig and ITIM domains (TIGIT) ligands PVR and PVRL2. Using two independent patient cohorts, we could demonstrate that high PVR and PVRL2 expression correlates with poor outcome in AML. We show for the first time that antibody blockade of PVR or PVRL2 on AML cell lines or primary AML cells or TIGIT blockade on immune cells increases the anti-leukemic effects mediated by PBMCs or purified CD3 cells in vitro. The cytolytic activity of the BiTE® antibody construct AMG 330 against leukemic cells could be further enhanced by blockade of the TIGIT-PVR/PVRL2 axis. This increased immune reactivity is paralleled by augmented secretion of Granzyme B by immune cells. Em...
Uploads
Papers by Walter Fiedler