The pediatric oncology research group focuses on the following two topics of (1) genetic predisposition in childhood cancer and prevention of acute leukemias and (2) translational cellular immunotherapy and oncolytic virotherapy against pediatric sarcoma.
(1) Acute leukemias: Not long ago, genetic predisposition to childhood cancer was purely believed to be attributed to “chance” or “bad-luck”. Now it has been proven that de-novo or inherited cancer predispositions can cause up to 15% of all pediatric tumors. Nevertheless, the overall impact of genetic predispositions is believed to be much higher, with most yet to be discovered. In this regard, we aim to identify and characterize novel disease-causing germline mutations in children with cancer. We further investigate the interplay of genetic predisposition and environmental challenges, including infection and early immune training, in transgenic murine models. By understanding the underlying genetic basis of cancer in combination with training of the innate and adaptive immune system we subsequently aim for early preventive strategies against childhood leukemia.
(2) Pediatric Sarcoma: Pediatric patients with advanced sarcoma carry a poor prognosis, which is why innovative therapy options for these patients are urgently needed. The success of immunotherapy in the treatment of patients with solid tumours is predominantly restricted to entities showing high numbers of tumour infiltrating T cells e.g. directed against somatic mutation derived neo-antigens such as in malignant melanoma. However, unlike melanoma, pediatric cancers such as Ewing’s sarcoma (EwS) are predominantly less immunogenic, probably due to low somatic mutation rates. As therapeutic options for these patients have reached a plateau, innovative new treatment options are warranted. In this regard, our research goal is the introduction of innovative therapy designs such as T cell based immunotherapeutic approaches to improve survival of children and adolecents with high-risk pediatric sarcoma.
Escudero, A., Takagi, M., Auer, F., Friedrich, U. A., Miyamoto, S., Ogawa, A., Imai, K., Pascual, B., Vela, M., Stepensky, P., Yasin, L., Elitzur, S., Borkhardt, A., Pérez-Martínez, A., & Hauer, J. (2022). Clinical and immunophenotypic characteristics of familial leukemia predisposition caused by PAX5 germline variants. Leukemia, 36(9), 2338–2342.
Schedel A, Friedrich UA, Morcos MNF, et al. Recurrent Germline Variant in RAD21 Predisposes Children to Lymphoblastic Leukemia or Lymphoma. Int J Mol Sci. 2022;23(9):5174.
Hauer J, Fischer U, Borkhardt A. Toward prevention of childhood ALL by early-life immune training. Blood. 2021;138(16):1412-1428.
Bhatia, S., Diedrich, D., Frieg, B., Ahlert, H., Stein, S., Bopp, B., Lang, F., Zang, T., Kröger, T., Ernst, T., Kögler, G., Krieg, A., Lüdeke, S., Kunkel, H., Rodrigues Moita, A. J., Kassack, M. U., Marquardt, V., Opitz, F. V., Oldenburg, M., Remke, M., … Hauer, J. (2018). Targeting HSP90 dimerization via the C terminus is effective in imatinib-resistant CML and lacks the heat shock response. Blood, 132(3), 307–320.
Martín-Lorenzo A, Hauer J, Vicente-Dueñas C, et al. Infection Exposure is a Causal Factor in B-cell Precursor Acute Lymphoblastic Leukemia as a Result of Pax5-Inherited Susceptibility. Cancer Discov. 2015;5(12):1328-1343.
Biele E, Schober SJ, Prexler C, et al. Monocyte Maturation Mediators Upregulate CD83, ICAM-1 and MHC Class 1 Expression on Ewing's Sarcoma, Enhancing T Cell Cytotoxicity. Cells. 2021;10(11):3070.
Thiel U, Schober SJ, Ranft A, et al. No difference in survival after HLA mismatched versus HLA matched allogeneic stem cell transplantation in Ewing sarcoma patients with advanced disease. Bone Marrow Transplant. 2021;56(7):1550-1557.
Schober SJ, Thiede M, Gassmann H, et al. MHC Class I-Restricted TCR-Transgenic CD4+ T Cells Against STEAP1 Mediate Local Tumor Control of Ewing Sarcoma In Vivo. Cells. 2020;9(7):1581.
Thiel U, Schober SJ, Einspieler I, et al. 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.
Kirschner A, Thiede M, Grünewald TG, et al. Pappalysin-1 T cell receptor transgenic allo-restricted T cells kill Ewing sarcoma in vitro and in vivo. Oncoimmunology. 2017;6(2):e1273301.
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