Publications by authors named "Sebastian J Schober"

4 Publications

  • Page 1 of 1

Sarcoma treatment in the era of molecular medicine.

EMBO Mol Med 2020 11 13;12(11):e11131. Epub 2020 Oct 13.

Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK.

Sarcomas are heterogeneous and clinically challenging soft tissue and bone cancers. Although constituting only 1% of all human malignancies, sarcomas represent the second most common type of solid tumors in children and adolescents and comprise an important group of secondary malignancies. More than 100 histological subtypes have been characterized to date, and many more are being discovered due to molecular profiling. Owing to their mostly aggressive biological behavior, relative rarity, and occurrence at virtually every anatomical site, many sarcoma subtypes are in particular difficult-to-treat categories. Current multimodal treatment concepts combine surgery, polychemotherapy (with/without local hyperthermia), irradiation, immunotherapy, and/or targeted therapeutics. Recent scientific advancements have enabled a more precise molecular characterization of sarcoma subtypes and revealed novel therapeutic targets and prognostic/predictive biomarkers. This review aims at providing a comprehensive overview of the latest advances in the molecular biology of sarcomas and their effects on clinical oncology; it is meant for a broad readership ranging from novices to experts in the field of sarcoma.
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http://dx.doi.org/10.15252/emmm.201911131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645378PMC
November 2020

MHC Class I-Restricted TCR-Transgenic CD4 T Cells Against STEAP1 Mediate Local Tumor Control of Ewing Sarcoma In Vivo.

Cells 2020 06 29;9(7). Epub 2020 Jun 29.

Department of Pediatrics, Children's Cancer Research Center, Kinderklinik München Schwabing, School of Medicine, Technical University of Munich, 80804 Munich, Germany.

In this study we report the functional comparison of T cell receptor (TCR)-engineered major histocompatibility complex (MHC) class I-restricted CD4 versus CD8 T cells targeting a peptide from (STEAP1) in the context of HLA-A*02:01. STEAP1 is a tumor-associated antigen, which is overexpressed in many cancers, including Ewing sarcoma (EwS). Based on previous observations, we postulated strong antitumor potential of tumor-redirected CD4 T cells transduced with an HLA class I-restricted TCR against a STEAP1-derived peptide. We compared CD4 T cell populations to their CD8 counterparts in vitro using impedance-based xCELLigence and cytokine/granzyme release assays. We further compared antitumor activity of STEAP-TCR transgenic (tg) CD4 versus CD8 T cells in tumor-bearing xenografted Rag2gc mice. TCR tgCD4 T cells showed increased cytotoxic features over time with similar functional avidity compared to tgCD8 cells after 5-6 weeks of culture. In vivo, local tumor control was equal. Assessing metastatic organotropism of intraveniously (i.v.) injected tumors, only tgCD8 cells were associated with reduced metastases. In this analysis, EwS-redirected tgCD4 T cells contribute to local tumor control, but fail to control metastatic outgrowth in a model of xenografted EwS.
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http://dx.doi.org/10.3390/cells9071581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408051PMC
June 2020

Donor lymphocyte infusions in adolescents and young adults for control of advanced pediatric sarcoma.

Oncotarget 2018 Apr 27;9(32):22741-22748. Epub 2018 Apr 27.

Department of Pediatrics and Children's Cancer Research Center, TUM School of Medicine, Technical University of Munich, Kinderklinik München Schwabing, 80804 Munich, Germany.

Background: Allogeneic stem cell transplantation (allo-SCT) and donor lymphocyte infusions (DLI) may induce a graft-versus-tumor effect in pediatric sarcoma patients. Here, we describe general feasibility, toxicity and efficacy of DLI after allo-SCT.

Results: 4 of 8 patients responded. ES#4 had stable disease (SD) for 9 months after DLI and RMS#4 partial response for 8 months with combined hyperthermia/chemotherapy. In ES#4, DLI led to SD for 6 months and reverted residual disease before allo-SCT into complete remission. After DLI, ES#4 and RMS#4 developed acute GvHD (°III-°IV), ES#4 also developed chronic GvHD. 5 patients including ES#4 lived longer than expected. Median survival after allo-SCT was 2.3 years, post-relapse survival (PRS) was 13 months. Off note, HLA-mismatched DLI were associated with a trend towards increased survival after allo-SCT and increased PRS compared to HLA-matched DLI (23 versus 3 months).

Materials And Methods: We studied eight adolescents and young adults (AYAs) with advanced Ewing sarcoma (ES#1-4) and rhabdomyosarcoma (RMS#1-4) who received DLI. Escalating doses ranged from 2.5 × 10 to 1 × 10 CD3 cells/kg body weight. AYAs were evaluated for response to DLI, graft-versus-host disease (GvHD) and survival.

Conclusions: DLI after allo-SCT may control advanced pediatric sarcoma in AYAs with controllable toxicity.
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http://dx.doi.org/10.18632/oncotarget.25228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5978262PMC
April 2018

Ewing sarcoma partial regression without GvHD by chondromodulin-I/HLA-A*02:01-specific allorestricted T cell receptor transgenic T cells.

Oncoimmunology 2017;6(5):e1312239. Epub 2017 Apr 12.

Department of Pediatrics and Children's Cancer Research Center, Kinderklinik München Schwabing, Technische Universität München, Munich, Germany.

: Chondromodulin-I (CHM1) sustains malignancy in Ewing sarcoma (ES). Refractory ES carries a dismal prognosis and patients with bone marrow (BM) metastases do not survive irrespective of therapy. We assessed HLA-A*02:01/CHM1-specific allorestricted T cell receptor (TCR) wild-type and transgenic cytotoxic (CD8) T cells against ES. : Three refractory HLA-A2 ES patients were treated with HLA-A*02:01/peptide-specific allorepertoire-derived (i.e., allorestricted) CD8 T cells. Patient #1 received up to 4.8 × 10/kg body weight HLA-A*02:01 allorestricted donor-derived wild-type CD8 T cells. Patient #2 received up to 8.2 × 10/kg HLA-A*02:01 donor-derived and patient #3 up to 6 × 10/kg autologous allorestricted TCR transgenic CD8 T cells. All patients were treated with the same TCR complementary determining region 3 allorecognition sequence for CHM1 peptide 319 (CHM1). : HLA-A*02:01/CHM1-specific allorestricted CD8 T cells showed specific lysis of all patient-derived ES cell lines. Therapy was well tolerated and did not cause graft versus host disease (GvHD). Patients #1 and #3 showed slow progression, whereas patient #2, while having BM involvement, showed partial metastatic regression associated with T cell homing to involved lesions. CHM1 TCR transgenic T cells could be tracked in his BM for weeks. : CHM1-TCR transgenic T cells home to affected BM and may cause partial disease regression. HLA-A*02:01/antigen-specific allorestricted T cells proliferate without causing GvHD.
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http://dx.doi.org/10.1080/2162402X.2017.1312239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5467994PMC
April 2017