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Dive into the research topics where Heiko-Manuel Teltschik is active.

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Featured researches published by Heiko-Manuel Teltschik.


Haematologica | 2014

Pediatric posttransplant relapsed/refractory B-precursor acute lymphoblastic leukemia shows durable remission by therapy with the T-cell engaging bispecific antibody blinatumomab

Patrick Schlegel; Peter Lang; Gerhard Zugmaier; Martin Ebinger; Hermann Kreyenberg; Kai-Erik Witte; Judith Feucht; Matthias Pfeiffer; Heiko-Manuel Teltschik; Christina Kyzirakos; Tobias Feuchtinger; Rupert Handgretinger

We report on posttransplant relapsed pediatric patients with B-precursor acute lymphoblastic leukemia with no further standard of care therapy who were treated with the T-cell engaging CD19/CD3-bispecific single-chain antibody construct blinatumomab on a compassionate use basis. Blast load was assessed prior to, during and after blinatumomab cycle using flow cytometry to detect minimal residual disease, quantitative polymerase chain reaction for rearrangements of the immunoglobulin or T-cell receptor genes, and bcr/abl mutation detection in one patient with Philadelphia chromosome-positive acute lymphoblastic leukemia. Blinatumomab was administered as a 4-week continuous intravenous infusion at a dosage of 5 or 15 μg/m2/day. Nine patients received a total of 18 cycles. Four patients achieved complete remission after the first cycle of treatment; 2 patients showed a complete remission from the second cycle after previous reduction of blast load by chemotherapy. Three patients did not respond, of whom one patient proceeded to a second cycle without additional chemotherapy and again did not respond. Four patients were successfully retransplanted in molecular remission from haploidentical donors. After a median follow up of 398 days, the probability of hematologic event-free survival is 30%. Major toxicities were grade 3 seizures in one patient and grade 3 cytokine release syndrome in 2 patients. Blinatumomab can induce molecular remission in pediatric patients with posttransplant relapsed B-precursor acute lymphoblastic leukemia and facilitate subsequent allogeneic hematopoietic stem cell transplantation from haploidentical donor with subsequent long-term leukemia-free survival.


Bone Marrow Transplantation | 2015

Improved immune recovery after transplantation of TCRαβ/CD19-depleted allografts from haploidentical donors in pediatric patients

Peter J. Lang; Tobias Feuchtinger; Heiko-Manuel Teltschik; Wolfgang Schwinger; Paul-Gerhardt Schlegel; Matthias Pfeiffer; Michael Schumm; Lang Am; Lang B; Carl-Philipp Schwarze; Martin Ebinger; Christian Urban; Rupert Handgretinger

Immune recovery was retrospectively analyzed in a cohort of 41 patients with acute leukemia, myelodysplastic syndrome and nonmalignant diseases, who received αβ T- and B-cell-depleted allografts from haploidentical family donors. Conditioning regimens consisted of fludarabine or clofarabine, thiotepa, melphalan and serotherapy with OKT3 or ATG-Fresenius. Graft manipulation was carried out with anti-TCRαβ and anti-CD19 Abs and immunomagnetic microbeads. The γδ T cells and natural killer cells remained in the grafts. Primary engraftment occurred in 88%, acute GvHD (aGvHD) grades II and III–IV occurred in 10% and 15%, respectively. Immune recovery data were available in 26 patients and comparable after OKT3 (n=7) or ATG-F (n=19). Median time to reach >100 CD3+ cells/μL, >200 CD19+ cells/μL and >200 CD56+ cells/μL for the whole group was 13, 127 and 12.5 days, respectively. Compared with a historical control group of patients with CD34+ selected grafts, significantly higher cell numbers were found for CD3+ at days +30 and +90 (267 vs 27 and 397 vs 163 cells/μL), for CD3+4+ at day +30 (58 vs 11 cells/μL) and for CD56+ at day +14 (622 vs 27 cells/μL). The clinical impact of this accelerated immune recovery will be evaluated in an ongoing prospective multicenter trial.


Haematologica | 2010

Reconstitution of natural killer cell receptors influences natural killer activity and relapse rate after haploidentical transplantation of T- and B-cell depleted grafts in children.

Matthias Pfeiffer; Tobias Feuchtinger; Heiko-Manuel Teltschik; Michael Schumm; Ingo Müller; Rupert Handgretinger; Peter Lang

Background Natural killer cells have been demonstrated to exert remarkable graft-versus-leukemia effects after haploidentical transplantation. Acquisition of both, inhibiting and activating, receptors on developing natural killer cells is an important step in their functional maturation. Here, we report on the reconstitution of natural killer receptors after haploidentical transplantation of T-and B-cell (CD3/CD19) depleted grafts with co-transfusion of natural killer cells in children and its influence on natural killer cell activity and clinical outcome. Design and Methods We analyzed reconstitution patterns of natural killer receptors at different time intervals after haploidentical transplantation by multi-color flow cytometry. Natural killer cell activity and antibody-dependent cellular cytotoxicity was tested against cell lines and leukemic blasts in vitro. Survival was analyzed using Kaplan-Meier estimates. Results Recovery of CD56+/CD16+ cells was fast with high cytolytic activity against K562 and strong antibody-dependent cellular cytotoxicity activity against neuroblastoma and leukemic blasts as early as day 14 posttransplant. KIR reconstitution showed a predominance of KIR negative natural killer cells early after transplantation and an early reconstitution of CD158b compared to CD158a and CD158e. These differences were independent of presence or absence of the corresponding KIR ligands in donors or recipients. This reconstitution pattern was associated with a higher relapse probability of patients homozygous for HLA-C1-alleles compared to patients homozygous or even heterozygous for HLA-C2-alleles. Conclusions Our results indicate a fast recovery of functional and alloreactive natural killer cells with a constant KIR pattern after haploidentical transplantation with T- and B-cell depleted grafts. Moreover, these natural killer cells can mediate antibody-dependent cellular cytotoxicity and therefore may allow for an early use of antibodies against residual malignant cells.


British Journal of Haematology | 2014

Transplantation of CD3/CD19 depleted allografts from haploidentical family donors in paediatric leukaemia

Peter Lang; Heiko-Manuel Teltschik; Tobias Feuchtinger; Ingo Müller; Matthias Pfeiffer; Michael Schumm; Martin Ebinger; Carl Philipp Schwarze; Bernd Gruhn; André Schrauder; Michael H. Albert; Johann Greil; Christian Urban; Rupert Handgretinger

Transplantation of T‐ and B‐cell depleted allografts from haploidentical family donors was evaluated within a prospective phase II trial in children with acute lymphoblastic leukaemia, acute myeloid leukaemia and advanced myelodysplastic syndrome (n = 46). 20 patients had active disease; 19 patients received a second or third stem cell transplantation (SCT). Toxicity‐reduced conditioning regimens consisted of fludarabine or clofarabine (in active disease only), thiotepa, melphalan and serotherapy. Graft manipulation was carried out with immunomagnetic microbeads. Primary engraftment occurred in 88%, with a median time to reach >1·0 × 109/l leucocytes, >20 × 109/l platelets and >0·1 × 109/l T‐cells of 10, 11 and 50 days, respectively. After retransplantation, engraftment occurred in 100%. Acute graft‐versus‐host disease (GvHD) grade II and III‐IV occurred in 20% and 7%, chronic GvHD occurred in 21%. Both conditioning regimens had comparable toxicity. Transplant‐related mortality (TRM) was 8% at one year and 20% at 5 years. Event‐free survival at 3 years was: 25% (whole group), 46% (first, second or third complete remission [CR], first SCT) vs. 8% (active disease, first SCT) and 20% (second or third SCT, any disease status). This approach allows first or subsequent haploidentical SCTs to be performed with low TRM. Patients in CR may benefit from SCT, whereas the results in patients with active disease were poor.


Annals of the New York Academy of Sciences | 2012

Immune reconstitution and strategies for rebuilding the immune system after haploidentical stem cell transplantation

Lena Oevermann; Peter J. Lang; Tobias Feuchtinger; Michael Schumm; Heiko-Manuel Teltschik; Patrick Schlegel; Rupert Handgretinger

Haploidentical hematopoietic stem cell transplantation is a curative alternative option for patients without an otherwise suitable stem cell donor. In order to prevent graft‐versus‐host disease (GvHD), different in vitro and in vivo T cell–depletion strategies have been developed. A delayed immune reconstitution is common to all these strategies, and an impaired immune function after haploidentical transplantation with subsequent infections is a major cause of deaths in these patients. In addition to in vitro and in vivo T cell–depletion methods, posttransplant strategies to rapidly rebuild the immune system have been introduced in order to improve the outcome. Advances in in vitro and in vivo T cell–depletion methods, and adoptive transfer of immune cells of the innate and specific immune system, will contribute to reduce the risk of GvHD, lethal infections, and the risk of relapse of the underlying malignant disease.


Bone Marrow Transplantation | 2009

Cytolytic activity of NK cell clones against acute childhood precursor-B-cell leukaemia is influenced by HLA class I expression on blasts and the differential KIR phenotype of NK clones

Tobias Feuchtinger; Matthias Pfeiffer; Pfaffle A; Heiko-Manuel Teltschik; Wernet D; Michael Schumm; Lotfi R; Rupert Handgretinger; Peter J. Lang

Relapse after allo-SCT in patients with acute leukaemia remains a major problem. A beneficial impact of alloreactive natural killer (NK) cells has been reported for myeloid malignancies, but has been questionable for B-lineage ALL. We analysed lysis of primary paediatric precursor-B-ALL blasts by 285 NK cell clones to investigate whether HLA class I expression on the blasts and phenotypic killer cell Ig-like receptor (KIR) expression on NK cells affect the lytic activity against ALL blasts. Precursor-B-ALL blasts with low HLA-I expression were lysed by a majority (79%) of NK cell clones, whereas those with high HLA-I expression showed low susceptibility to NK clones independent of their KIR expression patterns. NK cell activity against susceptible blasts was regulated by differential surface expression of the three major KIRs (CD158a, CD158b, CD158e). NK clones with none of these three KIRs or a single KIR that recognized no ligand, were not inhibited by the targets and exerted higher lysis (P=<0.0005) in comparison to NK clones expressing KIRs with a ligand on the ALL blasts. In conclusion, the quantity of HLA-I expression on precursor-B-ALL blast regulates overall NK cell susceptibility; in case of reduced HLA expression, differential surface expression of KIRs affects NK cell alloreactivity against those blasts.


Best Practice & Research Clinical Haematology | 2011

Long-term IL-2 therapy after transplantation of T cell depleted stem cells from alternative donors in children

Patrick Schlegel; Heiko-Manuel Teltschik; Matthias Pfeiffer; Rupert Handgretinger; Michael Schumm; Ewa Koscielniak; Tobias Feuchtinger; Thomas Klingebiel; Peter Bader; Paul-Gerhard Schlegel; Johann Greil; Peter Lang

The aim of this pilot study was to evaluate the feasibility of long-term subcutaneous application of low-dose IL-2 in children with malignancies at very high risk of relapse who underwent highly T cell and B cell depleted HLA-identical (MUD) or full haplotype mismatched related hematopoetic stem cell transplantation. We studied 11 patients with acute leukemias / myelodysplastic syndrome and juvenile myelomonocytic leukemia (active disease and/or second stem cell transplantation, n = 8; ≥CR 2, n = 2) and relapsed or progressive Ewings sarcoma (n = 2) who received prophylactic IL-2 treatment for a high probability of disease recurrence after allo-HSCT. Toxicities from IL-2 were transient fever, fatigue and local inflammation. In one patient GvHD grade III with no clear association to IL-2 administration occurred. IL-2 administration was started at median day 57 (range 13-154) post-transplant for a mean duration of 28 days (range 15-250). IL-2 administration clearly increased NK cell activity. 3 of 11 patients (ALL, AML, multifocal Ewings sarcoma) survived with a follow-up of ten years. In conclusion, long-term low-dose IL-2 subcutaneous application is feasible in children due to a low side effect profile even after HLA mismatched transplantation and may be a strategy to prevent relapse in pediatric malignancies with extremely high risk of relapse.


Molecular Therapy | 2016

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

Ursula Jördis Eva Seidel; Patrick Schlegel; Ludger Grosse-Hovest; Martin Hofmann; Steffen Aulwurm; Elwira Pyz; Friedhelm R. Schuster; Roland Meisel; Martin Ebinger; Tobias Feuchtinger; Heiko-Manuel Teltschik; Kai-Erik Witte; Carl-Philipp Schwarze; Hans-Georg Rammensee; Rupert Handgretinger; Gundram Jung; Peter Lang

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.


Bone Marrow Transplantation | 2015

Favorable NK cell activity after haploidentical hematopoietic stem cell transplantation in stage IV relapsed Ewing’s sarcoma patients

Ursula Jördis Eva Seidel; A-M Lang; Patrick Schlegel; Tobias Feuchtinger; Catherine Nitschke-Gerard; Christina Kyzirakos; Heiko-Manuel Teltschik; Martin Ebinger; Michael Schumm; Rupert Handgretinger; Peter J. Lang

Natural killer (NK) cell activity has been shown to have potential activity against Ewing’s sarcoma (EWS) especially in tumors with low HLA I expression and high NKG2D expression. Two patients with metastatic relapsed and primary metastatic stage IV EWS who had received two courses of high dose chemotherapy with autologous stem cell rescue were transplanted from a haploidentical parental stem cell donor. Patients are alive in ongoing CR for 10.2 and 3.4 years now. Post transplant local second and first relapses were treated successfully in both patients. In vivo IL-2 stimulation not only increased the number and activity of effector cells in one patient but was also associated with severe GvHD. In vitro studies demonstrated high NK cell activity against K562 and relevant activity against EWS cell line A673 post transplant. NK activity was enhanced by cytokine prestimulation as well as by EWS targeting anti-GD2 Ab. Haploidentical hematopoietic stem cell transplantation (HSCT) might contribute to long-term survival by NK cell-mediated effect exerted by donor-derived NK cells. Local tumor recurrence was manageable in both high-risk patients indicating systemic immune control preventing subsequent metastasizing. The efficacy of haploidentical HSCT, cytokine application and tumor targeting antibodies for the use of Ab-dependent cellular cytotoxicity needs evaluation in clinical trials.


British Journal of Haematology | 2016

Treatment of graft failure with TNI-based reconditioning and haploidentical stem cells in paediatric patients

Heiko-Manuel Teltschik; Frank Heinzelmann; Bernd Gruhn; Tobias Feuchtinger; Patrick Schlegel; Michael Schumm; Bernhard Kremens; Ingo Müller; Martin Ebinger; Carl Philipp Schwarze; Hellmut Ottinger; Daniel Zips; Rupert Handgretinger; Peter J. Lang

Graft failure is a life‐threatening complication after allogeneic haematopoietic stem cell transplantation (HSCT). We report a cohort of 19 consecutive patients (median age: 8·5 years) with acute leukaemias (n = 14) and non‐malignant diseases (n = 5) who experienced graft failure after previous HSCT from matched (n = 3) or haploidentical donors (n = 16) between 2003 and 2012. After total nodal irradiation (TNI)‐based reconditioning combined with fludarabine, thiotepa and anti‐T cell serotherapy, all patients received T cell‐depleted peripheral blood stem cell grafts from a second, haploidentical donor. Median time between graft failure and retransplantation was 14 d (range 7–40). Sustained engraftment (median: 10 d, range 9–32) and complete donor chimerism was observed in all evaluable patients. 5 patients additionally received donor lymphocyte infusions. Graft‐versus‐host disease (GvHD) grade II and III occurred in 1 patient each (22%); no GvHD grade IV was observed. 2 patients had transient chronic GvHD. The regimen was well tolerated with transient interstitial pneumonitis in one patient. Treatment‐related mortality after one year was 11%. Event‐free survival and overall survival 3 years after retransplantation were 63% and 68%. Thus, a TNI‐based reconditioning regimen followed by transplantation of haploidentical stem cells is an option to rescue patients with graft failure within a short time span and with low toxicity.

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Michael Schumm

Boston Children's Hospital

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Peter Lang

Boston Children's Hospital

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Martin Ebinger

Boston Children's Hospital

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Patrick Schlegel

Boston Children's Hospital

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Christian Urban

Medical University of Graz

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