Publications by authors named "Friedhelm Schuster"

31 Publications

Expression profiles of HMGB1 on B-CLL related leukocytes contribute to prediction of relapse.

Immunobiology 2021 Jan 16;226(1):152048. Epub 2020 Dec 16.

University Hospital of Munich, Dept. for Hematopoetic Cell Transplantation, Med. Dept. 3, 81377 Munich, Germany. Electronic address:

Background: The High Mobility Group Box 1 (HMGB1) is a nuclear protein that is frequently overexpressed in hematologic diseases and might be of relevance in immunogenic cancer control thus correlating with patients' (pts.) prognosis in diseases such as acute myeloid, acute lymphatic and chronic lymphocytic leukemia.

Materials And Methods: Expression profiles of blasts from AML (n = 21), ALL (n = 16) and of B-lymphocytes of CLL (n = 9) pts. were analyzed for surface expression of HMGB1 using flow cytometry. Expression was quantified and correlated with clinically and prognostically relevant markers.

Results: Expression profiling of HMGB1 in blasts of AML and ALL subtypes did not show differences between primary vs. secondary disease development and gender related differences. In ALL pts. however, age groups at initial diagnosis between ≥20 vs. <20 years were compared and showed significant differences (≥20 vs. <20 years; 89% vs. 49%, p  <0.05) with higher expression in higher age. In AML and CLL these differences were not visible. To evaluate the prognostic significance of HMGB1 expression, expression quantity was correlated with established and prognostic classification systems (in AML ELN, in ALL GMALL) and probability to relapse. No significant correlation was seen in these entities. However, when AML pts. were analyzed for remission rates after first anthracycline based induction therapy, in those who did not experience a complete remission significantly enhanced HMGB1 surface expression was seen (98 vs. 94%; p < 0.05; n = 20). Furthermore, for CLL it was shown that higher HMGB1 expression was found in pretreated patients with relapsed or/and refractory disease (1 vs. more relapses; 94 vs. 98%; p  <0.05; n = 9).

Conclusion: HMGB1 is frequently expressed in hematologic malignancies. In this study it was shown that HMGB1 surface expression on AML blasts can be used as predictors for treatment response. In CLL it may be a marker for advanced disease. In order to implement this marker in FACS routine it could be a useful and practical tool for prognostic assessment and treatment planning.
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http://dx.doi.org/10.1016/j.imbio.2020.152048DOI Listing
January 2021

Pediatric ALL relapses after allo-SCT show high individuality, clonal dynamics, selective pressure, and druggable targets.

Blood Adv 2019 10;3(20):3143-3156

Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children's Hospital, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany.

Survival of patients with pediatric acute lymphoblastic leukemia (ALL) after allogeneic hematopoietic stem cell transplantation (allo-SCT) is mainly compromised by leukemia relapse, carrying dismal prognosis. As novel individualized therapeutic approaches are urgently needed, we performed whole-exome sequencing of leukemic blasts of 10 children with post-allo-SCT relapses with the aim of thoroughly characterizing the mutational landscape and identifying druggable mutations. We found that post-allo-SCT ALL relapses display highly diverse and mostly patient-individual genetic lesions. Moreover, mutational cluster analysis showed substantial clonal dynamics during leukemia progression from initial diagnosis to relapse after allo-SCT. Only very few alterations stayed constant over time. This dynamic clonality was exemplified by the detection of thiopurine resistance-mediating mutations in the nucleotidase NT5C2 in 3 patients' first relapses, which disappeared in the post-allo-SCT relapses on relief of selective pressure of maintenance chemotherapy. Moreover, we identified TP53 mutations in 4 of 10 patients after allo-SCT, reflecting acquired chemoresistance associated with selective pressure of prior antineoplastic treatment. Finally, in 9 of 10 children's post-allo-SCT relapse, we found alterations in genes for which targeted therapies with novel agents are readily available. We could show efficient targeting of leukemic blasts by APR-246 in 2 patients carrying TP53 mutations. Our findings shed light on the genetic basis of post-allo-SCT relapse and may pave the way for unraveling novel therapeutic strategies in this challenging situation.
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http://dx.doi.org/10.1182/bloodadvances.2019000051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6849953PMC
October 2019

Presence of centromeric but absence of telomeric group B KIR haplotypes in stem cell donors improve leukaemia control after HSCT for childhood ALL.

Bone Marrow Transplant 2019 11 14;54(11):1847-1858. Epub 2019 May 14.

Division of Pediatric Stem Cell Therapy, Clinic for Pediatric Oncology, Hematology and Clinical Immunology, Center for Child and Adolescent Health, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany.

Although allogeneic hematopoietic stem-cell transplantation (HSCT) provides high cure rates for children with high-risk acute lymphoblastic leukaemia (ALL), relapses remain the main cause of treatment failure. Whereas donor killer cell immunoglobulin-like receptor (KIR) genotype was shown to impact on relapse incidence in adult myeloid leukaemia similar studies in paediatric ALL are largely missing. Effect of donor KIR genotype on transplant outcome was evaluated in 317 children receiving a first myeloablative HSCT from an HLA-matched unrelated donor or sibling within the prospective ALL-SCT-BFM-2003 trial. Analysis of donor KIR gene polymorphism revealed that centromeric presence and telomeric absence of KIR B haplotypes was associated with reduced relapse risk. A centromeric/telomeric KIR score (ct-KIR score) integrating these observations correlated with relapse risk (hazard ratio (HR) 0.58; P = 0.002) while it had no impact on graft-versus-host disease or non-relapse mortality. In multivariable analyses ct-KIR score was associated with reduced relapse risk (HR 0.58; P = 0.003) and a trend towards improved event-free survival (HR 0.76; P = 0.059). This effect proved independent of MRD level prior to HSCT. Our data suggest that in children with ALL undergoing HSCT after myeloablative conditioning, donor selection based on KIR genotyping holds promise to improve clinical outcome by decreasing relapse risk and prolonged event-free survival.
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http://dx.doi.org/10.1038/s41409-019-0543-zDOI Listing
November 2019

Hematopoietic Stem Cell Transplantation as Treatment for Patients with DOCK8 Deficiency.

J Allergy Clin Immunol Pract 2019 03 2;7(3):848-855. Epub 2018 Nov 2.

Dr von Hauner University Children's Hospital, Ludwig Maximilians Universität, Munich, Germany. Electronic address:

Background: Biallelic variations in the dedicator of cytokinesis 8 (DOCK8) gene cause a combined immunodeficiency with eczema, recurrent bacterial and viral infections, and malignancy. Natural disease outcome is dismal, but allogeneic hematopoietic stem cell transplantation (HSCT) can cure the disease.

Objective: To determine outcome of HSCT for DOCK8 deficiency and define possible outcome variables.

Methods: We performed a retrospective study of the results of HSCT in a large international cohort of DOCK8-deficient patients.

Results: We identified 81 patients from 22 centers transplanted at a median age of 9.7 years (range, 0.7-27.2 years) between 1995 and 2015. After median follow-up of 26 months (range, 3-135 months), 68 (84%) patients are alive. Severe acute (III-IV) or chronic graft versus host disease occurred in 11% and 10%, respectively. Causes of death were infections (n = 5), graft versus host disease (5), multiorgan failure (2), and preexistent lymphoma (1). Survival after matched related (n = 40) or unrelated (35) HSCT was 89% and 81%, respectively. Reduced-toxicity conditioning based on either treosulfan or reduced-dose busulfan resulted in superior survival compared with fully myeloablative busulfan-based regimens (97% vs 78%; P = .049). Ninety-six percent of patients younger than 8 years at HSCT survived, compared with 78% of those 8 years and older (P = .06). Of the 73 patients with chimerism data available, 65 (89%) had more than 90% donor T-cell chimerism at last follow-up. Not all disease manifestations responded equally well to HSCT: eczema, infections, and mollusca resolved quicker than food allergies or failure to thrive.

Conclusions: HSCT is curative in most DOCK8-deficient patients, confirming this approach as the treatment of choice. HSCT using a reduced-toxicity regimen may offer the best chance for survival.
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http://dx.doi.org/10.1016/j.jaip.2018.10.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6771433PMC
March 2019

Clearance of Treatment Refractory Adenoviremia via Adenovirus-specific Donor T-Cell Transfer During Aplasia After αβTCR-CD19-Depleted Stem Cell Transplantation.

Clin Infect Dis 2019 04;68(8):1406-1409

Division of Pediatric Stem Cell Therapy, Clinic for Pediatric Oncology, Hematology and Clinical Immunology, Heinrich Heine University, Medical Faculty, Düsseldorf.

Here, we report the case of severe adenoviremia in a 7-year-old boy with highly-resistant, acute leukemia. A combined approach of αβTCR-CD19-depleted stem cell transplantation, enabling immunosuppression-free post-transplant care, and early transfer of adenovirus-specific donor T cells during aplasia resulted in rapid and complete clearance of the treatment-refractory adenoviremia.
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http://dx.doi.org/10.1093/cid/ciy820DOI Listing
April 2019

Hematopoietic Stem Cell Transplantation in an Infant with Immunodeficiency, Centromeric Instability, and Facial Anomaly Syndrome.

Front Immunol 2017 30;8:773. Epub 2017 Jun 30.

Medical Faculty, Department of Pediatric Oncology, Hematology and Clinical Immunology, University of Düsseldorf, Düsseldorf, Germany.

Immunodeficiency, centromeric instability, and facial anomaly (ICF) syndrome is a rare autosomal recessive genetic condition with severe immunodeficiency, which leads to lethal infections if not recognized and treated in early childhood. Up-to-date treatment regimens consist of prophylactic and supportive treatment of the recurrent infections. Here, we report the case of a 1-year-old boy of Moroccan consanguineous parents, who was diagnosed at 4 months of age with ICF syndrome with a homozygous missense mutation in the gene. He was initially admitted to the hospital with recurrent pulmonary infections from the opportunistic pathogen . Further immunological workup revealed agammaglobulinemia in the presence of B cells. After successful recovery from the PJ pneumonia, he underwent hematopoietic stem cell transplantation (HSCT) from the HLA-matched healthy sister using a chemotherapeutic conditioning regimen consisting of treosulfan, fludarabine, and thiotepa. Other than acute chemotherapy-associated side effects, no serious adverse events occurred. Six months after HSCT immune-reconstitution, he had a stable chimerism with 2.9% autologous portion in the peripheral blood and a normal differential blood cell count, including all immunoglobulin subtypes. This is one of the first cases of successful HSCT in ICF syndrome. Early diagnosis and subsequent HSCT can prevent severe opportunistic infections and cure the immunodeficiency. Centromeric instability and facial anomaly remain unaffected. Although the long-term patient outcome and the neurological development remain to be seen, this curative therapy for immunodeficiency improves life expectancy and quality of life. This case is meant to raise physicians awareness for ICF syndrome and highlight the consideration for HSCT in ICF syndrome early on.
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http://dx.doi.org/10.3389/fimmu.2017.00773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5491950PMC
June 2017

Significance of Frequencies, Compositions, and/or Antileukemic Activity of (DC-stimulated) Invariant NKT, NK and CIK Cells on the Outcome of Patients With AML, ALL and CLL.

J Immunother 2017 Jul/Aug;40(6):224-248

*Department of Hematopoetic Cell Transplantation, Medicine Department 3, University Hospital of Munich, Munich †Department of Hematology and Oncology, University Hospital of Tuebingen, Tuebingen ‡Department of Pediatric Hematology, Oncology and Clinical Immunology, University Hospital of Duesseldorf, Duesseldorf, Germany.

Invariant natural killer T (iNKT)/natural killer (NK)/cytokine-induced killer (CIK) cells are important for immune surveillance. (I) Novel combinations of antibody 6B11 (targeting the Vα24-Jα18-invariant T-cell receptor) with CD4/CD8/CD1d/Vα24 for iNKT subset detection and "T/NK cell-like"-iNKT subsets were defined. Compared with healthy peripheral blood mononuclear cells (MNC) (significantly) lower proportions of iNKT cells (6B11/6B11CD3/6B11CD161), NK cells (CD3CD56/CD3CD161), and CIK cells (CD3CD56/CD3CD161) were found in peripheral blood MNC from acute myeloid (AML)/acute myeloid, lymphoid (ALL)/chronic lymphoid leukemia (CLL) patients in acute disease stages. Subtyping of iNKT cells revealed (significantly) higher proportions of CD3 T cells and CD161 NK cells in AML/ALL/CLL expressing 6B11 compared with healthy MNC. Prognostic evaluations showed higher proportions of iNKT/NK/CIK cells in favorable AML subgroups (younger age, primary, no extramedullary disease, achievement/maintenance of complete remission) or adult ALL and CLL patients. (II) iNKT/NK/CIK cell frequencies increased after (vs. before) mixed lymphocyte cultures of T-cell-enriched immune reactive cells stimulated with MNC/whole blood with or without pretreatment with "cocktails" (dendritic cells generating methods/kits inducing blasts' conversion to leukemia-derived dendritic cells from AML patients). Individual "cocktails" leading to "highest" iNKT cell frequencies could be defined. Antileukemic blast lytic activity correlated significantly with frequencies of iNKT/NK/CIK cells. In summary healthy MNC show significantly more iNKT/NK/CIK cells compared with AML/ALL/CLL MNC, a shift in the iNKT cell composition is seen in healthy versus leukemic samples and iNKT/NK/CIK cell-proportions in AML/ALL/CLL MNC samples correlate with prognosis. "Cocktail"-treated AML blasts lead to higher iNKT/NK/CIK cell frequencies and samples with antileukemic activity show significantly higher frequencies of iNKT/NK/CIK cells. Proportions of iNKT/NK/CIK cells should regularly be evaluated in AML/ALL/CLL diagnosis panels for quantitative/prognostic estimation of individual patients' antileukemic potential and their role in dendritic cells/leukemia-derived dendritic cells triggered immune surveillance.
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http://dx.doi.org/10.1097/CJI.0000000000000171DOI Listing
March 2018

Human RAD52 - a novel player in DNA repair in cancer and immunodeficiency.

Haematologica 2017 02 15;102(2):e69-e72. Epub 2016 Dec 15.

Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Center of Child and Adolescent Health, Heinrich-Heine-University, Düsseldorf, Germany.

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http://dx.doi.org/10.3324/haematol.2016.155838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5286958PMC
February 2017

Cytokine Release Patterns in Mixed Lymphocyte Culture (MLC) of T-Cells with Dendritic Cells (DC) Generated from AML Blasts Contribute to Predict anti-Leukaemic T-Cell Reactions and Patients' Response to Immunotherapy.

Cell Commun Adhes 2015 Apr - Dec;22(2-6):49-65. Epub 2016 Sep 7.

a Department for Haematopoietic Transplantations , University Hospital of Munich , Munich , Germany.

To enlighten interactions between autologous, allogeneic or T-cells from patients after stem cell transplantation with leukaemia-derived-dendritic-cells containing dendritic cells or blast containing mononuclear cells (n = 21, respectively), we determined cytokine-concentrations (interleukin 2, 4, 6, 10, tumor-necrosis-factor-α, interferon-γ) in supernatants of mixed-lymphocyte-culture and in serum (n = 16) of 20 patients with acute myeloid leukaemia and three patients with myelodysplastic syndromes by cytometric-bead-assay. We correlated our data with lytic capabilities of stimulated T-cells in a fluorolysis-assay and clinical data: Dendritic-cell-/mononuclear-cell-stimulation of T-cells resulted in increased cytokine-levels in culture-medium compared to serum. There were no significant differences between cytokine-patterns of cases with/without lytic T-cell-activity, response to immunotherapy (stem cell transplantation/donor-lymphocyte-infusion) or graft-versus-host-disease. However, some predictive cytokine-cut-off-values for antileukaemic T-cell-activity, patients' response to immunotherapy and graft-versus-host-disease could be defined. Cytokine-profiles alone, without functional assays, are no useful tool to predict antileukaemic T-cell-function, although they can indicate lytic T-cell-activity, patients' response to immunotherapy and graft-versus-host-disease.
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http://dx.doi.org/10.1080/15419061.2016.1223634DOI Listing
February 2017

Reduction of Minimal Residual Disease in Pediatric B-lineage Acute Lymphoblastic Leukemia by an Fc-optimized CD19 Antibody.

Mol Ther 2016 09 6;24(9):1634-43. Epub 2016 Jul 6.

Department of General Pediatrics, Hematology/Oncology, University Children's Hospital Tübingen, Tübingen, Germany.

Prognosis of primary refractory and relapsed pediatric B-lineage acute lymphoblastic leukemia (ALL) is very poor. Relapse rates significantly correlate with persistent minimal residual disease (MRD). In MRD, favorable effector-target ratios prevail and thus this situation might be optimally suited for immunotherapy with antibodies recruiting immunological effector cells. We here report on the generation, preclinical characterization and first clinical application in B-lineage ALL of an Fc-optimized CD19 antibody. This third-generation antibody (4G7SDIE) mediated enhanced antibody-dependent cellular cytotoxicity (ADCC) against leukemic blasts with effector cells from healthy volunteers and B-lineage ALL patients. The antibody was produced in a university-owned production unit and was applied on a compassionate use basis to 14 pediatric patients with refractory and relapsed B-lineage ALL at the stage of MRD. In 10/14 patients, MRD was reduced by ≥ 1 log or below the patient-individual detection limit, and 5/14 patients have achieved ongoing complete molecular remission with a median leukemia-free survival of 428 days. Two additional patients died in complete molecular remission due to complications not related to antibody therapy. Besides profound in vivo B-cell depletion, side effects were negligible. A clinical phase 1/2 study to further assess the therapeutic activity of 4G7SDIE is in preparation.
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http://dx.doi.org/10.1038/mt.2016.141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5113107PMC
September 2016

De novo PIK3R1 gain-of-function with recurrent sinopulmonary infections, long-lasting chronic CMV-lymphadenitis and microcephaly.

Clin Immunol 2016 Jan 31;162:27-30. Epub 2015 Oct 31.

University of Duesseldorf, Medical Faculty, Department of Pediatric Oncology, Hematology and Clinical Immunology, Center for Child and Adolescent Health, Duesseldorf, Germany. Electronic address:

PIK3R1 (phosphoinositide-3-kinase, regulatory subunit 1) gain-of-function has recently been described in patients with recurrent sinopulmonary infections, chronic CMV-/EBV-infections, lymphoproliferation, and hypogammaglobulinemia. Here we report a 15-year-old boy with treatment refractory CMV lymphadenitis, severe combined immunodeficiency, microcephaly and a severe developmental defect of Th17 cells. To avoid poor outcome, hematopoietic stem cell transplantation (HSCT) was performed. Subsequently, whole exome sequencing revealed a de novo heterozygous G-to-C mutation (chr5: 5:67,589,663: G>C) at the splice donor site of the PIK3R1 gene. Our data suggest that PIK3R1 gain-of-function leads to developmental defects in helper and regulatory T-cell subsets, the latter expanding the immunological features of PIK3R1 gain-of-function. T-cell subsets play a critical role in the regulation of immune response against infectious agents and of autoimmunity and thus may be particularly accountable for the clinical phenotype of affected patients.
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http://dx.doi.org/10.1016/j.clim.2015.10.008DOI Listing
January 2016

Adoptive T-cell therapy with hexon-specific Th1 cells as a treatment of refractory adenovirus infection after HSCT.

Blood 2015 Mar 23;125(12):1986-94. Epub 2015 Jan 23.

Department of Pediatric Hematology/Oncology, University Children's Hospital Tübingen, Tübingen, Germany; German Center for Infection Research, Ludwig Maximilians University Munich, Munich, Germany.

Hematopoietic stem cell transplantation (HSCT) has improved over the last few decades. However, viral infections are often refractory to pharmacologic treatment and require alternative treatment strategies such as immunotherapy. Adenovirus (AdV) is th predominant disease-causing pathogen in pediatric HSCT. In a clinical trial, we analyzed safety and efficacy of ex vivo adoptive T-cell transfer (ACT) with hexon-specific T cells, predominantly of the T-helper cell 1 (Th1) phenotype, in 30 patients with AdV disease or viremia. ACT was feasible with no acute toxicities or significant onset of graft-versus-host disease. ACT led to in vivo antiviral immunity for up to 6 months with viral control, resulting in complete clearance of viremia in 86% of patients with antigen-specific T-cell responses. After ACT and a follow-up of 6 months, overall survival was markedly increased in responders (mean, 122 days; 15 survivors) compared with nonresponders who all died shortly after ACT (mean, 24 days; no survivors). AdV-related mortality was 100% in nonresponders compared with 9.5% in responders (≥1 log reduction of DNA copies per milliliter after ACT). In summary, ex vivo ACT of AdV-specific Th1 cells was well tolerated and led to successful and sustained restoration of T-cell immunity correlated with virologic response and protection from virus-related mortality. This cellular immunotherapy is a short-term available and broadly applicable treatment. The study is registered at European Union Clinical Trials Register as 2005-001092-35.
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http://dx.doi.org/10.1182/blood-2014-06-573725DOI Listing
March 2015

Immunotherapy with the trifunctional anti-CD20 x anti-CD3 antibody FBTA05 (Lymphomun) in paediatric high-risk patients with recurrent CD20-positive B cell malignancies.

Br J Haematol 2015 Apr 11;169(1):90-102. Epub 2014 Dec 11.

Department of Paediatric Oncology, Haematology and Immunology, University of Duesseldorf, Duesseldorf, Germany.

Children with B cell malignancies refractory to standard therapy are known to have a poor prognosis and very limited treatment options. Here, we report on the treatment and follow-up of ten patients diagnosed with relapsed or refractory mature B-cell Non Hodgkin Lymphoma (B-NHL), Burkitt leukaemia (B-AL) or pre B-acute lymphoblastic leukaemia (pre B-ALL). All children were treated with FBTA05 (now designated Lymphomun), an anti-CD3 x anti-CD20 trifunctional bispecific antibody (trAb) in compassionate use. Within individual treatment schedules, Lymphomun was applied (a) after allogeneic stem cell transplantation (allo-SCT, n = 6) to induce sustained long-term remission, or (b) stand alone prior to subsequent chemotherapy to eradicate residual disease before allo-SCT (n = 4). Nine of ten children displayed a clinical response: three stable diseases (SD), one partial remission (PR) and five induced or sustained complete remissions (CR). Five of these nine responders died during follow-up. The other patients still maintain CR with a current overall survival of 874-1424 days (median: 1150 days). In conclusion, despite the dismal clinical prognosis of children refractory to standard therapy, immunotherapy with Lymphomun resulted in a favourable clinical outcome in this cohort of refractory paediatric patients.
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http://dx.doi.org/10.1111/bjh.13242DOI Listing
April 2015

Lowest numbers of primary CD8(+) T cells can reconstitute protective immunity upon adoptive immunotherapy.

Blood 2014 Jul 22;124(4):628-37. Epub 2014 May 22.

Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München, Munich, Germany; Clinical Cooperation Group "Immune Monitoring," and Clinical Cooperation Group "Antigen-specific Immunotherapy," Helmholtz Center Munich (Neuherberg) and Technische Universität München, Munich, Germany; German Center for Infection Research, Munich, Germany.

Patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) are threatened by potentially lethal viral manifestations like cytomegalovirus (CMV) reactivation. Because the success of today's virostatic treatment is limited by side effects and resistance development, adoptive transfer of virus-specific memory T cells derived from the stem cell donor has been proposed as an alternative therapeutic strategy. In this context, dose minimization of adoptively transferred T cells might be warranted for the avoidance of graft-versus-host disease (GVHD), in particular in prophylactic settings after T-cell-depleting allo-HSCT protocols. To establish a lower limit for successful adoptive T-cell therapy, we conducted low-dose CD8(+) T-cell transfers in the well-established murine Listeria monocytogenes (L.m.) infection model. Major histocompatibility complex-Streptamer-enriched antigen-specific CD62L(hi) but not CD62L(lo) CD8(+) memory T cells proliferated, differentiated, and protected against L.m. infections after prophylactic application. Even progenies derived from a single CD62L(hi) L.m.-specific CD8(+) T cell could be protective against bacterial challenge. In analogy, low-dose transfers of Streptamer-enriched human CMV-specific CD8(+) T cells into allo-HSCT recipients led to strong pathogen-specific T-cell expansion in a compassionate-use setting. In summary, low-dose adoptive T-cell transfer (ACT) could be a promising strategy, particularly for prophylactic treatment of infectious complications after allo-HSCT.
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http://dx.doi.org/10.1182/blood-2013-12-547349DOI Listing
July 2014

Haploidentical stem cell transplantation in DOCK8 deficiency - Successful control of pre-existing severe viremia with a TCRaß/CD19-depleted graft and antiviral treatment.

Clin Immunol 2014 May-Jun;152(1-2):111-4. Epub 2014 Mar 22.

Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Center of Child and Adolescent Health, Heinrich-Heine-University, Duesseldorf, Germany.

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http://dx.doi.org/10.1016/j.clim.2014.03.006DOI Listing
July 2014

CD4(+)and CD8(+)T-cell reactions against leukemia-associated- or minor-histocompatibility-antigens in AML-patients after allogeneic SCT.

Immunobiology 2014 Apr 27;219(4):247-60. Epub 2013 Oct 27.

Helmholtz Center Munich (German Research Center for Environmental Health and Clinical Cooperative Group Hematopoetic Cell-Transplantation), 81377 Munich, Germany; University Hospital of Munich, Department for Hematopoetic Cell Transplantation, Med. Dept. 3, 81377 Munich, Germany. Electronic address:

T-cells play an important role in the remission-maintenance in AML-patients (pts) after SCT, however the role of LAA- (WT1, PR1, PRAME) or minor-histocompatibility (mHag, HA1) antigen-specific CD4(+) and CD8(+)T-cells is not defined. A LAA/HA1-peptide/protein stimulation, cloning and monitoring strategy for specific CD8(+)/CD4(+)T-cells in AML-pts after SCT is given. Our results show that (1) LAA-peptide-specific CD8+T-cells are detectable in every AML-pt after SCT. CD8(+)T-cells, recognizing two different antigens detectable in 5 of 7 cases correlate with long-lasting remissions. Clonal TCR-Vβ-restriction exemplarily proven by spectratyping in PRAME-specific CD8(+)T-cells; high PRAME-peptide-reactivity was CD4(+)-associated, as shown by IFN-γ-release. (2) Two types of antigen-presenting cells (APCs) were tested for presentation of LAA/HA1-proteins to CD4(+)T-cells: miniEBV-transduced lymphoblastoid cells (B-cell-source) and CD4-depleted MNC (source for B-cell/monocyte/DC). We provide a refined cloning-system for proliferating, CD40L(+)CD4(+)T-cells after LAA/HA1-stimulation. CD4(+)T-cells produced cytokines (GM-CSF, IFN-γ) upon exposure to LAA/HA1-stimulation until after at least 7 restimulations and demonstrated cytotoxic activity against naive blasts, but not fibroblasts. Antileukemic activity of unstimulated, stimulated or cloned CD4(+)T-cells correlated with defined T-cell-subtypes and the clinical course of the disease. In conclusion we provide immunological tools to enrich and monitor LAA/HA1-CD4(+)- and CD8(+)T-cells in AML-pts after SCT and generate data with relevant prognostic value. We were able to demonstrate the presence of LAA-peptide-specific CD8(+)T-cell clones in AML-pts after SCT. In addition, we were also able to enrich specific antileukemic reactive CD4(+)T-cells without GvH-reactivity upon repeated LAA/HA1-protein stimulation and limiting dilution cloning.
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http://dx.doi.org/10.1016/j.imbio.2013.10.008DOI Listing
April 2014

Anti-leukaemic activity of a novel haploidentical-transplantation approach employing unmanipulated bone marrow followed by CD6-depleted peripheral blood stem cells in children with refractory/relapsed acute leukaemia.

Br J Haematol 2013 Sep 6;162(6):802-7. Epub 2013 Jul 6.

Clinic of Paediatric Oncology, Haematology and Clinical Immunology, Centre for Child and Adolescent Health, Medical Faculty, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.

The treatment outcome of children with refractory acute leukaemia or relapse post-stem cell transplantation is dismal. We report 10 children (non-remission n = 7) who underwent a new haploidentical transplant approach utilizing unmanipulated bone marrow followed by CD6-depleted peripheral blood stem cells. Nine patients had successful engraftment and no evidence of leukaemia. Acute and chronic graft-versus-host-disease was observed in five and three patients, respectively; two patients died of treatment-related toxicity. Seven patients relapsed after 7 (range 3-34) months, however two patients are alive at 6·5 and 7·0 years. This approach provides anti-leukaemic activity even in heavily pre-treated children but long-term disease control requires further intervention.
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http://dx.doi.org/10.1111/bjh.12455DOI Listing
September 2013

Next-generation-sequencing-spectratyping reveals public T-cell receptor repertoires in pediatric very severe aplastic anemia and identifies a β chain CDR3 sequence associated with hepatitis-induced pathogenesis.

Haematologica 2013 Sep 28;98(9):1388-96. Epub 2013 May 28.

Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children’s Hospital, Medical Faculty, Heinrich Heine University, Duesseldorf, Germany.

Current diagnostic approaches that characterize T-cell deficiency by analyzing diversity of T-cell receptor sequences effectuate limited informational gain about the actual restrictiveness. For deeper insight into T-cell receptor repertoires we developed next-generation-sequencing-spectratyping, which employs high coverage Roche/454 sequencing of T-cell receptor (β)-chain amplicons. For automated analysis of high-throughput-sequencing data, we developed a freely available software, the TCR profiler. Gene usage, length, encoded amino acid sequence and sequence diversity of the complementarity determining region 3 were determined and comprehensively integrated into a novel complexity score. Repertoires of CD8(+) T cells from children with idiopathic or hepatitis-induced very severe aplastic anemia (n=7), children two months after bone marrow transplantation (n=7) and healthy controls (children n=5, adults n=5) were analyzed. Complexity scores clearly distinguished between healthy and diseased, and even between different immune deficiency states. The repertoire of aplastic anemia patients was dominated by public (i.e. present in more than one person) T-cell receptor clonotypes, whereas only 0.2% or 1.9% were public in normal children and adults, respectively. The CDR3 sequence ASSGVGFSGANVLT was highly prevalent in 3 cases of hepatitis-induced anemia (15-32% of all sequences), but was only low expressed in idiopathic aplastic anemia (2-5%, n=4) or healthy controls (<1%). Fifteen high frequent sequences were present exclusively in aplastic anemia patients. Next-generation-sequencing-spectratyping allows in-depth analysis of T-cell receptor repertoires and their restriction in clinical samples. A dominating clonotype was identified in hepatitis-induced anemia that may be associated with disease pathogenesis and several aplastic-anemia-associated, putatively autoreactive clonotypes were sequenced.
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http://dx.doi.org/10.3324/haematol.2012.069708DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3762095PMC
September 2013

In vitro-induced response patterns of antileukemic T cells: characterization by spectratyping and immunophenotyping.

Clin Exp Med 2013 Feb 23;13(1):29-48. Epub 2012 Mar 23.

Faculty of Medical, Department of Paediatric Oncology, Haematology and Immunology, University Dusseldorf, 40225, Dusseldorf, Germany.

Myeloid leukemic cells can be induced to differentiate into leukemia-derived dendritic cells (DCleu) regaining the stimulatory capacity of professional DCs while presenting the leukemic antigen repertoire. But so far, the induced antileukemic T-cell responses are variable both in specificity and in efficacy. In an attempt to elucidate the underlying causes of different T-cell response patterns, T-cell receptor (TR) Vβ chain rearrangements were correlated with the T cells corresponding immunophenotypic profile, as well as their proliferative response and cytolytic capacities. In three different settings, donor T cells, either human leukocyte antigen matched or mismatched (haploidentical), or autologous T cells were repeatedly stimulated with myeloid blasts or leukemia-derived DC/DCleus from the corresponding patients diseased from acute myeloid leukemia (AML). Although no significant differences in T-cell proliferation were observed, the T-cell-mediated cytolytic response pattern varied considerably and even caused blast proliferation in two cases. Spectratyping revealed a remarkable restriction (>75% of normal level) of the CD4+ or CD8+-TR repertoire of blast- or DC/DCleu-stimulated T cells. Although in absolute terms, DC/DCleu stimulation induced the highest grade of restriction in the CD8+ T-cell subset, the CD4+ T-cell compartment seemed to be relatively more affected. But most importantly, in vitro stimulation with DC/DCleu resulted into an identical TR restriction pattern (β chain) that could be identified in vivo in a patient sample 3 months after allo-SCT. Thus, in vitro tests combining functional flow cytometry with spectratyping might provide predictive information about T cellular response patterns in vivo.
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http://dx.doi.org/10.1007/s10238-012-0180-yDOI Listing
February 2013

Fatal outcome despite full lympho-hematopoietic reconstitution after allogeneic stem cell transplantation in atypical ataxia telangiectasia.

J Clin Immunol 2012 Jun 23;32(3):438-40. Epub 2012 Feb 23.

Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich-Heine Universität Düsseldorf, Medical Faculty, 40225, Düsseldorf, Germany.

Allogeneic hematopoietic stem cell transplantation (HSCT) has not been a therapeutic option in ataxia telangiectasia (AT) due to overwhelming toxicity of conditioning in the context of the global DNA repair deficiency. Furthermore HSCT is unable to cure neurological involvement of AT. We report on a Turkish child with a Hyper IgM phenotype disorder, in which clinical aspects of AT were absent and thus, AT not diagnosed. He was transplanted with a reduced toxicity, but full intensity conditioning regimen comprising treosulfan, fludarabine and ATG. The peritransplant period was uneventful and the patient was discharged at day +57. 8 months after HSCT, the patient developed hepatopathy with monoclonal gammopathy of unclear significance and died due to hepatic failure and encephalopathy at the age of 32 months. Post mortem high throughput sequencing revealed a mutation in the ATM gene.
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http://dx.doi.org/10.1007/s10875-012-9654-7DOI Listing
June 2012

CD34+ gene expression profiling of individual children with very severe aplastic anemia indicates a pathogenic role of integrin receptors and the proapoptotic death ligand TRAIL.

Haematologica 2012 Sep 7;97(9):1304-11. Epub 2012 Feb 7.

Department of Pediatric Oncology, Hematology and Clinical Immunology, Center for Child and Adolescent Health, Heinrich Heine University, Moorenstr. 5, 40225 Düsseldorf, Germany.

Unlabelled: BACKGROUND Very severe aplastic anemia is characterized by a hypoplastic bone marrow due to destruction of CD34(+) stem cells by autoreactive T cells. Investigation of the pathomechanism by patient-specific gene expression analysis of the attacked stem cells has previously been impractical because of the scarcity of these cells at diagnosis.

Design And Methods: Employing unbiased RNA amplification, patient-specific gene expression profiling was carried out for CD34(+) cells from patients newly diagnosed with very severe aplastic anemia (n=13), refractory anemia (n=8) and healthy controls (n=10). These data were compared to profiles of myelodysplastic disease (n=55), including refractory anemia (n=18). To identify possible targets of autoimmune attack, presence of autoreactive antibodies was tested in pre-therapeutic sera of patients with very severe aplastic anemia (n=19).

Results: CD34(+) gene expression profiling distinguished between healthy controls, children with aplastic or refractory anemia and clonal disease. Interferon stimulated genes such as the apoptosis inducing death ligand TRAIL were strongly up-regulated in CD34(+) cells of patients with aplastic anemia, in particular in patients responding to immunosuppressive treatment. In contrast, mRNA expression of integrin GPVI and the integrin complexes GPIa/IIa, GPIIb/IIIa, GPIB/GPIX/GPV was significantly down-regulated and corresponding antibodies were detected in 7 of 11 profiled patients and in 11 of 19 aplastic anemia patients. CONCLUSIONS As a potential diagnostic tool, patient-specific gene expression profiling of CD34(+) stem cells made it possible to make the difficult differential diagnosis of most patients with aplastic and refractory anemia. Profiling indicated a prognostic correlation of TRAIL expression and patient benefit from immunosuppressive therapy. Downregulation of integrin expression and concurrent presence of autoreactive anti-integrin-antibodies suggested a previously unrecognized pathological role of integrins in aplastic anemia.
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http://dx.doi.org/10.3324/haematol.2011.056705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3436230PMC
September 2012

Mucormycosis in paediatric patients: demographics, risk factors and outcome of 12 contemporary cases.

Mycoses 2011 Nov 30;54(6):e785-8. Epub 2011 May 30.

Department of Pediatric Hematology/Oncology and Center for Bone Marrow Transplantation, University Hospital of Münster, Münster, Germany.

Mucormycosis is associated with high morbidity and mortality and is perceived as an emerging fungal infection. However, contemporary paediatric data are limited. We present a series of paediatric cases of mucormycosis reported from Germany and Austria collected within a voluntary epidemiological survey through standardised, anonymized case report forms. Twelve cases were reported between January 2004 and December 2008 (six men; mean age: 12.6 years, range: 0.1-17 years). Mucormycosis was proven in nine, and probable in three cases. Isolates included Lichtheimia (syn. Absidia pro parte, Mycocladus) (five), Rhizopus (three) and Mucor (one) species. Infection was limited to soft tissue in three cases, the lung in two cases, and an infected thrombus in one case; rhinocerebral disease was found in three cases, and pulmonary-mediastinal, pulmonary-cerebral and soft tissue-cerebral involvement in one case each. All three patients with isolated soft tissue infection were cured, whereas seven of the remaining patients died (one patient without follow-up). The overall mortality rate was 67%. While these data cannot provide conclusive data on incidence and disease burden of mucormycosis in paediatric patients, they reflect the continuing threat of these infections to immunocompromised patients and the need for improved diagnosis and management.
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http://dx.doi.org/10.1111/j.1439-0507.2011.02025.xDOI Listing
November 2011

Adoptive transfer of pp65-specific T cells for the treatment of chemorefractory cytomegalovirus disease or reactivation after haploidentical and matched unrelated stem cell transplantation.

Blood 2010 Nov 12;116(20):4360-7. Epub 2010 Jul 12.

Department of Pediatric Hematology/Oncology, University Children's Hospital, Tübingen, Germany.

Cytomegalovirus (CMV) disease and infection refractory to antiviral treatment after allogeneic stem cell transplantation (allo-SCT) is associated with a high mortality. Adoptive transfer of CMV-specific T cells could reconstitute viral immunity after SCT and could protect from CMV-related complications. However, logistics of producing virus-specific T-cell grafts limited the clinical application. We treated 18 patients after allo-SCT from human leukocyte antigen-mismatched/haploidentical or human leukocyte antigen-matched unrelated donors with polyclonal CMV-specific T cells generated by ex vivo stimulation with pp65, followed by isolation of interferon-γ-producing cells. Patients with CMV disease or viremia refractory to antiviral chemotherapy or both were eligible for adoptive T-cell transfer and received a mean of 21 × 10³/kg pp65-specific T cells. In 83% of cases CMV infection was cleared or viral burden was significantly reduced, even in cases of CMV encephalitis (n = 2). Viral control was associated with in vivo expansion of CMV-specific T lymphocytes in 12 of 16 evaluable cases, resulting in reconstitution of antiviral T-cell responses, without graft-versus-host disease induction or acute side effects. Our findings indicate that the infusion of low numbers of CMV-specific T cells is safe, feasible, and effective as a treatment on demand for refractory CMV infection and CMV disease after allo-SCT.
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http://dx.doi.org/10.1182/blood-2010-01-262089DOI Listing
November 2010

Adoptive antifungal T cell immunotherapy--into the clinic?

Med Mycol 2011 Apr 30;49 Suppl 1:S164-9. Epub 2010 Jun 30.

Pediatric Hematology and Oncology, Children's Hospital III, Johann Wolfgang Goethe University, Theodor-Stern-Kai 7, Frankfurt, Germany.

The morbidity and mortality rates of invasive fungal infection in allogeneic stem cell recipients are still unacceptably high and have not been significantly improved by alternative antifungal strategies to date. Over the last few years, rapid methods for the clinical-scale generation of functionally active and well characterized antifungal T(H)1 cells have become available. In addition, current data on the use of donor-derived virus-specific T cells in allogeneic stem cell transplantation suggest that the risk of severe adverse events, in particular the risk of graft-versus-host disease, is negligible. Therefore, adoptive antifungal immunotherapeutic strategies should be evaluated in clinical trials. However, one has to recognize that these trials are only meaningful with sufficiently large and homogenous cohorts of patients and if the settings of adoptive antifungal immunotherapy are comparable. Ultimately, the strategy of adoptively transferring antifungal immune responses might improve the outcome in hematopoietic stem cell recipients suffering from invasive fungal infection.
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http://dx.doi.org/10.3109/13693786.2010.497953DOI Listing
April 2011

Improved effector function of leukemia-specific T-lymphocyte clones trained with AML-derived dendritic cells.

Cancer Genomics Proteomics 2008 Sep-Oct;5(5):275-86

Department of Pediatric Oncology, Hematology and Immunology, Heinrich Heine University Medical Center, Dusseldorf, Germany.

Recently it was shown that myeloid leukemic cells can be induced to differentiate into leukemia-derived dendritic cells (DCleu), regaining the stimulatory capacity of professional DCs while presenting the leukemic antigen repertoire. But so far, the induced antileukemic T-cell responses have varied in specificity and efficacy, or have even mediated opposite effects. In an attempt to further characterize the DC/DCleu induced T-cell response pattern, immunoscope spectratyping, a novel and powerful tool to detect T-cell receptor (TCR) rearrangements was used in combination with functional flow cytometry and non-radioactive fluorolysis assays. Human leucocyte antigen (HLA) matched donor T-cells were repeatedly stimulated, either with leukemic blasts (French-American-British, FAB M4eo) or the corresponding blast-derived DCs. Functional comparison revealed no significant difference in their T-cell stimulatory capacity, while the DC/DCleu fraction favored T-cells with a higher lytic activity, comprising a higher proportion of T-memory CD45R0+ cells. Stimulation with blasts and DC/DCleu induced a similar TCR restriction pattern, while stimulation with DC/DCleu favored the CD4 T-cell subset and seemed to cause a higher grade of restriction. In conclusion, a combined strategy using spectratyping with functional tests might not only provide useful information about the specificity and efficacy of the induced T-cell response, but also pave the way to gain effective T-cell clones for therapeutic use.
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February 2009

Graft versus leukemia effect after haploidentical HSCT in a MLL-negative infant AML with HLXB9/ETV6 rearrangement.

Pediatr Blood Cancer 2008 Apr;50(4):921-3

Pediatric Hematology & Oncology, LMU Munich, Dr. von Haunersches Children's Hospital, Munich, Germany.

Recently published data show an extremely poor survival of infants with AML and HLXB9/ETV6 rearrangement which is the fusion, resulting from the translocation t(7;12)(q36;p13). None of the patients reported survived a period of 3 years, including four patients who have received allogeneic hematopoietic stem cell transplantation (HSCT). Herein, we report the clinical course of an 8-month-old patient with acute myeloid leukemia, M2 subtype and with a HLXB9/TEL rearrangement. The patient received a haploidentical HSCT in relapse situation without any prior re-induction. The patient became MRD-negative over a period of 53 days after HSCT. This case reinforces the potential benefit of a graft-versus-leukemia effect in the haploidentical setting even in chemoresistant myeloid leukemias with poor-prognosis molecular features.
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http://dx.doi.org/10.1002/pbc.21376DOI Listing
April 2008

Generation and characterization of anti-Candida T cells as potential immunotherapy in patients with Candida infection after allogeneic hematopoietic stem-cell transplant.

J Infect Dis 2007 Aug 18;196(3):485-92. Epub 2007 Jun 18.

Pediatric Hematology and Oncology, Johann Wolfgang Goethe University, Frankfurt, D-60590, Germany.

Because lymphocytes play a major role in the host response to Candida infection, adoptive transfer of anti-Candida T cells might be a therapeutic option in patients undergoing allogeneic hematopoietic stem-cell transplant (alloHSCT) who have invasive Candida infection. Using the interferon (IFN)- gamma secretion assay, we isolated human anti-Candida T cells after stimulation with a cellular extract of C. albicans. These cells were expanded within 4 weeks to an average number of 2.6x107 T helper 1 type lymphocytes and significantly lost their alloreactive potential, compared with the original cell population. The generated cells were also stimulated by antigens of C. tropicalis but not by antigens of C. glabrata or various molds. In addition, generated anti-Candida T cells were able to induce damage to C. albicans hyphae and significantly increased hyphal damage induced by human neutrophils. Our data suggest that the generation of functionally active anti-Candida T cells is feasible and may be a promising treatment option for patients undergoing alloHSCT.
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http://dx.doi.org/10.1086/519389DOI Listing
August 2007

Safe adoptive transfer of virus-specific T-cell immunity for the treatment of systemic adenovirus infection after allogeneic stem cell transplantation.

Br J Haematol 2006 Jul;134(1):64-76

Department of Paediatric Haematology/Oncology, University Children's Hospital, Eberhard-Karls-University, Tuebingen, Germany.

During periods of immunosuppression, such as postallogeneic stem cell transplantation (SCT), patients are at significant risk for severe viral infections. Human adenovirus (HAdV) infection is a serious complication post-SCT, especially in children. Virus-specific T cells are essential for the clearance of HAdV, as antiviral chemotherapy has revealed limited success. We present feasibility data for a new treatment option using virus-specific donor T cells for adoptive transfer of immunity to patients with HAdV-infection/reactivation. Virus-specific donor T cells were isolated and infused into nine children with systemic HAdV infection after SCT. Isolation was based on gamma-interferon (IFN-gamma) secretion after short in vitro stimulation with viral antigen, resulting in a combination of CD4(+) and CD8(+) T cells. 1.2-50 x 10(3)/kg T cells were infused for adoptive transfer. Isolated cells showed high specificity and markedly reduced alloreactivity in vitro. Adoptive transfer of HAdV-specific immunity was successful in five of six evaluable patients, documented by a dose-independent and sustained in vivo expansion of HAdV-specific T cells, associated with a durable clearance/decrease of viral copies. T-cell infusion was well tolerated in all nine patients, except one case with graft-versus-host disease II of the skin. In conclusion, induction of a specific T-cell response through adoptive transfer was feasible and effective. When performed early in the course of infection, adoptive T-cell transfer may protect from HAdV-related complications.
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http://dx.doi.org/10.1111/j.1365-2141.2006.06108.xDOI Listing
July 2006

Treatment with caspofungin in immunocompromised paediatric patients: a multicentre survey.

J Antimicrob Chemother 2006 Mar 23;57(3):527-35. Epub 2006 Jan 23.

Infectious Disease Research Program, Center for Bone Marrow Transplantation and Department of Paediatric Haematology/Oncology, Children's University Hospital, Muenster, Germany.

Objectives: Although a paediatric dosage has not been established, caspofungin is occasionally used in paediatric patients. We conducted a multicentre retrospective survey to obtain data on immunocompromised paediatric patients considered to require caspofungin therapy.

Methods: The survey identified 64 patients (median age: 11.5 years; 25 females, 39 males) with haematological malignancies (48), marrow failure (9), solid tumours (3), haematological disorders (2) and congenital immunodeficiency (2) who received caspofungin for proven (17), probable (14) and possible (17) invasive fungal infections or empirically (16). Caspofungin was administered until intolerance or maximum efficacy at dosages individually determined by the responsible physician for refractory infection (38), intolerance of other agents (10) or as best therapeutic option (16).

Results: The 64 patients received caspofungin for a median of 37 days (range 3-218) as single agent (20) or in combination (44). The median daily maintenance dosage was 1.07 mg/kg (95% CI 1.09-1.35; range 0.40-2.92) or 34.3 mg/m2 (95% CI 32.3-37.3; range 16.3-57.5). In none of the patients was therapy discontinued due to adverse events (AEs). Clinical AEs were mild to moderate and observed in 34 patients (53.1%). While mean glutamate pyruvate transaminase and glutamate oxalate transaminase values were slightly (P < 0.005) higher at the end of treatment (EOT), serum bilirubin, alkaline phosphatase and creatinine values were not different from baseline. Complete responses, partial responses or stabilization were observed in 5/7/3 of 17 patients with proven, in 3/4/3 of 14 patients with probable and in 7/6/1 of 15 evaluable patients with possible invasive infections. Thirteen of 16 patients on empirical therapy completed without breakthrough infection. Overall survival was 75% at the EOT and 70% at 3 months post-EOT, respectively.

Conclusions: Caspofungin displayed favourable safety and tolerance and may have useful antifungal efficacy in severely immunocompromised paediatric patients.
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http://dx.doi.org/10.1093/jac/dkl009DOI Listing
March 2006