International Medical Services
Immunotherapy
Während die zelluläre Tumorimmuntherapie die Krebsbehandlung bei erwachsenen Patienten bereits nachhaltig verändert hat, sind bislang nur wenige Immuntherapien für die Behandlung von Krebs im Kindesalter zugelassen. Das Potenzial immuntherapeutischer Ansätze in der pädiatrischen Population wird jedoch durch den Erfolg von CART-19 bei pädiatrischen B-ALL-Patienten und von monoklonalen Anti-GD2-Antikörpern bei Neuroblastom-Patienten aufgezeigt.
Aktuelle Projekte der wissenschaftlichen Arbeitsgruppen des Kinderonkologischen Zentrums konzentrieren sich daher auf die Anpassung von Immuntherapien an die pädiatrische Population, einschließlich der Aufklärung von Resistenzmechanismen und die Integration dieser Ansätze in die Therapie pädiatrischer Krebserkrankungen.
Project 1. Mechanisms of resistance to CART-19 therapies
Relapsed and chemotherapy-refractory B-cell acute lymphoblastic leukaemias (B-ALL) remain significant causes of cancer-associated morbidity and mortality for children. An emerging immunotherapy uses modified T-cells expressing chimeric antigen receptors (CART) against CD19 (CART-19) to treat children with high-risk B-ALL. In CART-19 therapy, T cells of the patient are engineered to express CARTs that link a single-chain anti-CD19 antibody to the intracellular signalling domain of the T-cell receptor. Upon CD19 recognition, the CARTs activate the cytotoxic T-cells to attack the tumour cells. CART-19 therapy was recently approved for the treatment of paediatric B-ALL in the USA and Europe. Unfortunately, about 10-20% of children relapse under CART-19 therapy. Up to 50% of these therapy-resistant cases were characterised by the loss of detectable CD19 epitope. In this project, we want to identify predictive biomarkers for the escape from CART-19 therapy and to develop strategies to avoid the loss of the CD19 target epitope.
Contact: Dr. rer. nat. Nicole Ziegler, Dr. med. Francesca Alt
Project relevant publications:
Fischer J, Paret C, El Malki K, Alt F, Wingerter A, Neu MA, Kron B, Russo A, Lehmann N, Roth L, Fehr EM, Attig S, Hohberger A, Kindler T, Faber J. CD19 Isoforms Enabling Resistance to CART-19 Immunotherapy Are Expressed in B-ALL Patients at Initial Diagnosis. J Immunother. 2017 Jun;40(5):187-195. doi:
10.1097/CJI.0000000000000169. PMID: 28441264; PMCID: PMC5424577.
Project 2. Gangliosides as targets in pediatric tumors
Gangliosides are sialylated glycosphingolipids composed of ceramide and an oligosaccharide complex and are found in the plasma membrane. Some gangliosides, such as GD2, have a low expression in normal tissues but are overexpressed in several tumor entities. Due to this restricted expression, GD2 has long been recognized as an important target for cancer immunotherapy . However, the anti-GD2 antibodies dinutuximab and naxitamab are released only for the treatment of children with high-risk neuroblastoma so far. We have recently shown that GD2 is expressed also by other pediatric tumor entities and that GD2 is a relevant target not only for immunotherapies but also for targeted therapies. In this project, we will analyse the expression, regulation and druggability of GD2 and other gangliosides in pediatric tumors.
Contact: PD Dr. rer. nat. Claudia Paret, Dr. med. Arthur Wingerter and Dr. med. Khalifa el Malki
Project relevant publications:
Wingerter A, El Malki K, Sandhoff R, Seidmann L, Wagner DC, Lehmann N, Vewinger N, Frauenknecht KBM, Sommer CJ, Traub F, Kindler T, Russo A, Otto H, Lollert A, Staatz G, Roth L, Paret C, Faber J.
Exploiting Gangliosides for the Therapy of Ewing's Sarcoma and H3K27M-Mutant Diffuse Midline Glioma. Cancers
(Basel). 2021 Jan 29;13(3):520. doi: 10.3390/cancers13030520. PMID: 33572900; PMCID: PMC7866294.
Project 3. Relevance of immune checkpoint inhibitors in paediatric tumours
The use of immune checkpoint inhibitors is revolutionizing the oncology field. However, there is limited research focusing on immune checkpoint proteins and inhibitors in pediatric solid tumors. Only few expression data are available and there is a lack of information concerning their relevance as therapeutic target. The aim of this study is to describe the expression pattern of checkpoint proteins in different pediatric tumor entities and to identify potential checkpoint proteins as targets in combination therapies. For this, we are developing in vitro models to analyse the interaction between tumor cells and the immune system.
Contact: Dr. med. Khalifa El Malki, TransMed Fellowship
Project 4. Non conventional T cells as new players in cancer immunotherapy
While the majority of cancer immunotherapies focus on harnessing the anti-tumor CD8+ cytotoxic T cell response, latest research suggests that tumor cells can be recognized and eliminated also by nonconventional T cells, such as iNKT and γδ T cells. Unlike conventional αβ T cells, antigen recognition is independent of HLA haplotype in iNKT and γδ T cells and offers new options for pan-population cancer immunotherapies. iNKT and Vδ1 T cells recognize lipids via CD1d molecules, but so far, the nature of those lipids is largely unknown. In this project we aim for the analysis the infiltration of nonconventional and conventional T cells and the identification of endogenous lipid ligands in pediatric tumors. Our project is expected to provide new insights into the therapeutic utility of unconventional T cell therapy and it helps to get new information about the tumor immunology of pediatric tumors.
Contact: Dr. rer. nat. Nadine Lehmann
Project relevant publications:
Lehmann N, Paret C, El Malki K, Russo A, Neu MA, Wingerter A, Seidmann L,
Foersch S, Ziegler N, Roth L, Backes N, Sandhoff R, Faber J. Tumor Lipids of
Pediatric Papillary Renal Cell Carcinoma Stimulate Unconventional T Cells. Front Immunol. 2020 Aug 20;11:1819. doi: 10.3389/fimmu.2020.01819. PMID: 32973759; PMCID: PMC7468390.
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