Adoptive T-cell transfer – Virus-specific T cells
Interaction of pediatric leukemia with immune cells
Immunotherapy of acute leukemia – innovative CAR T cells
Advanced T-cell engineering
Prof. Tobias Feuchtinger
Cancer is a life – threatening disease for children. However, survival rates have improved impressively over the last decades due to intensive research. Today more than 70% of children and adolescents suffering from cancer can be successfully treated. The challenge is to treat those children and adolescents without any current treatment options. Better understanding of the disease will lead to novel treatment options or even prevention. In various research projects, medical doctors, biologists and technical staff are working on the transfer of basic knowledge into clinical application, patient-oriented research as well as development of new therapeutic options and clinical studies to improve our patients‘ life.
Hematopoietic stem cell transplantation (HSCT) cures a variety of diseases, such as rare genetic disorders or leukemia, but it exposes patients to a severe transient immune deficiency. Refractory viral infections post HSCT such as Cytomegalovirus (CMV), Epstein-Barr virus (EBV) and Adenovirus (AdV) infections are life-threatening conditions lacking effective treatment options. Protective T-cell immunity could be restored by adoptive transfer of virus-specific T cells: Virus-specific T cells are generated from blood cells of healthy donors and infused into the patients, where they are re-stimulated by the viral infection, expand effectively and induce viral clearance as well as sustained protection. We are working on the translation of advanced T-cell transfer approaches into clinical routine to provide these life-saving treatment options even for highest risk patients.
Overall survival of pediatric B-precursor ALL patients reached 90% in recent years. However, the outcome for refractory or relapsed children still remains very poor. Anti-CD19 chimeric antigen receptor T cells (CD19-CAR) showed significant anti-leukemic activity in relapsed and refractory B-precursor ALL. By genetical engineering of T cells or CAR T cells we aim to improve T cells in terms of persistence, exhaustion and functionality. This includes CRISPR/Cas9 mediated knock-out as well as overexpression of certain genes to obtain a favorable T-cell phenotype for adoptive therapy.
Leukemia continues to be the most common malignant disease for patients under the age of 18. Many patients can be cured through chemotherapy. However, this therapy has serious side effects and some patients still can not be cured. Tissue resident lymphocytes are both, friends and foes, providing protection against malignant cells and mediating tumor-protective micromillieus of immune escape. We investigate the immune system of pediatric patients with leukemia leading to the development of new immune therapies for children with malingancies.
A wide array of immunological and genetic techniques (such as CRISPR/Cas) are established to set up new approaches for future immunotherapy.
Genome-wide off-target analyses of CRISPR/Cas9-mediated T-cell receptor engineering in primary human T cells. Kaeuferle T, Stief TA, Canzar S, Kutlu N, Willier S, Stenger D, Ferrada-Ernst P, Habjan N, Peters A, Busch DH, Feuchtinger T. (2022). Clin. Transl. Immunol. 11:e1372.
Augmenting anti-CD19 and anti-CD22 CAR T-cell function using PD-1-CD28 checkpoint fusion proteins. Blaeschke F, Stenger D, Apfelbeck A, Cadilha BL, Benmebarek MR, Mahdawi J, Ortner E, Lepenies M, Habjan N, Rataj F, Willier S, Kaeuferle T, Majzner RG, Busch DH, Kobold S, Feuchtinger T. (2021). Blood Cancer J. 11(6):108.
Protective T-cell receptor identification for orthotopic reprogramming of immunity in refractory virus infections. Stief TA, Kaeuferle T, Müller TR, Döring M, Jablonowski LM, Schober K, Feucht J, Dennehy KM, Willier S, Blaeschke F, Handgretinger R, Lang P, Busch DH, Feuchtinger T. (2021). Mol Ther. S1525-0016(21)00303-8.
CLEC12A and CD33 co-expression as preferential target on pediatric AML for combinatorial immunotherapy. Willier S, Rothämel P, Hastreiter M, Wilhelm J, Stenger J, Blaeschle F, Rohlfs M, Kaeuferle T, Schmid I, Albert M H, Binder V, Subklewe M, Klein C, Feuchtinger T. (2021). Blood 137(8):1037-1049.
Leukemia escape in immune desert: intraocular relapse of pediatric pro-B-ALL during systemic control by CD19-CAR T cells. Willier S, Raedler J, Blaeschke F, Stenger D, Pazos Escudero M, Jurgeleit F, Grünewald T G P, Binder V, Schmid I, Albert M H, Wolf A, Feuchtinger T. (2020). J Immunother Cancer. 8(2):e001052.
Leukemia-induced dysfunctional TIM-3+CD4+ bone marrow T cells increase risk of relapse in pediatric B-precursor ALL patients. Blaeschke F, Willier S, Stenger D, Lepenies M, Horstmann MA, Escherich G, Zimmermann M, Rojas Ringeling F, Canzar S, Kaeuferle T, Rohlfs M, Binder V, Klein C, Feuchtinger T. (2020). Leukemia 34(10): 2607-2620.
Endogenous TCR promotes in vivo persistence of CD19-CAR-T cells compared to a CRISPR/Cas9-mediated TCR knockout CAR. Stenger D, Stief T A, Kaeuferle T, Willier S, Rataj F, Schober K, Vick B, Lotfi R, Wagner B, Grünwald T G P, Kobold S, Busch D H, Jeremias I, Blaeschke F, Feuchtinger T. (2020). Blood 136(12):1470-1418.
CRISPR-Cas9-Mediated Glucocorticoid Resistance in Virus-Specific T Cells for Adoptive T Cell Therapy Posttransplantation. Kaeuferle T, Deisenberger L, Jablonowski L, Stief TA, Blaeschke F, Willier S, Feuchtinger T. (2020). Mol Ther. 28(9):1965-1973.
Strategies of adoptive T -cell transfer to treat refractory viral infections post allogeneic stem cell transplantation. .
Efficacy, safety and feasibility of fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting in pediatric patients receiving moderately and highly emetogenic chemotherapy - results of a non-interventional observation study. Willier S, Cabanillas Stanchi KM, von Have M, Binder V, Blaeschke F, Feucht J, Feuchtinger T, Döring M. (2019). BMC Cancer. 15(1): 1118.
Low mutational load in pediatric medulloblastoma still translates into neoantigens as targets for specific T-cell immunotherapy. Blaeschke F, Paul MC, Schuhmann MU, Rabsteyn A, Schroeder C, Casadei N, Matthes J, Mohr C, Lotfi R, Wagner B, Kaeuferle T, Feucht J, Willier S, Handgretinger R, Stevanović S, Lang P, Feuchtinger T. (2019). Cytotherapy. 21(9):973-986.
Induction of a central memory and stem cell memory phenotype in functionally active CD4+ and CD8+ CAR T cells produced in an automated good manufacturing practice system for the treatment of CD19+ acute lymphoblastic leukemia.
T-cell responses against CD19+ pediatric acute lymphoblastic leukemia mediated by bispecific T-cell engager (BiTE) are regulated contrarily by PD-L1 and CD80/CD86 on leukemic blasts. Feucht J, Kayser S, Gorodezki D, Hamieh M, Döring M, Blaeschke F, Schlegel P, Bösmüller H, Quintanilla-Fend L, Ebinger M, Lang P, Handgretinger R, Feuchtinger T.
Adoptive T-cell therapy with hexon-specific Th1 cells as a treatment of refractory adenovirus infection after HSCT.
Adoptive transfer of epstein-barr virus (EBV) nuclear antigen 1-specific t cells as treatment for EBV reactivation and lymphoproliferative disorders after allogeneic stem-cell transplantation. 31(1):39-4.
Further publications: Pubmed
Horizon European Union Funding
Dr. Sepp und Hanne Sturm Gedächtnisstiftung
Otto-Hellmeier Kulturhaus Stiftung
Deutsches Zentrum für Infektionsforschung
Gertrud und Hugo Adler-Stiftung
Prof. Dr. med. Tobias Feuchtinger Lab
Kinderklinik und Kinderspital im Dr. von Haunerschen Kinderspital
Klinikum der Universität München, LMU München
Research Building, Lindwurmstraße 2a
Rooms KO.21 and KO.22
Phone: +49 (0)89 4400-52759
Fax: +49 (0)89 4400-54719