T cell engineering to overcome immune dysregulation induced by acute leukemi

Research Area

Hematology, Immunology, Oncology


Project Summary

Interaction of acute leukemia (AL) with the immune system is a disease-promoting mechanism and affect immunotherapy approaches. We hypothesize that bone marrow T cells (bmT), representing tumor-infiltrating lymphocytes in AL, control attack/protection of AL through co-stimulation/-inhibition. These mechanisms in bmT that mediate AL immune escape, are ideal target structures for T cell engineering. Transcriptomics revealed candidates and TIM-3 and CD200R will be investigated first as co-inhibitory molecules and cytokine receptors as co-stimulatory molecules, respectively. Combinatorial engineering includes targeted CRISPR/Cas9 mediated homology directed repair (HDR) CAR knock-in together with knock-out of co-inhibitory molecules and overexpression of stimulatory signals. The aim is to improve efficacy of T cell immunotherapy together with an intentional promotor control and improve safety by reduced off-target effects and site-specific DNA-integration into the genome without off-target integration.

Project-Related Publications

Willier, S., Rothämel, P., Hastreiter, M., Wilhelm, J., Stenger, D., Blaeschke, F., Rohlfs, M., Kaeuferle, T., Schmid, I., Albert, MH., Binder, V., Subklewe, M., Klein, C., Feuchtinger T. (2020). CLEC12A and CD33 co-expression as preferential target on pediatric AML for combinatorial immunotherapy. Blood. Epup ahead of print.
Willier, S., Raedler, J., Blaeschke, F., Stenger, D., Pazos Escudero, M., Habjan, N., Grünewald, TGP., Binder, V., Schmid, I., Albert, MH., Wolf, A. and Feuchtinger, T. (2020) Leukemia escape in immune desert: intraocular relapse of pediatric pro-B-ALL during systemic control by CD19-CAR T cells. Journal for ImmunoTherapy of Cancer. Sep;8(2):e001052.
Stenger, D., Stief, T.A., Kauferle, T., Willier, S., Rataj, F., Schober, K., Vick, B., Lotfi, R., Wagner, B., Grunewald, T.G.P., Kobold, S., Busch, D.H., Jeremias, I., Blaeschke, F. and Feuchtinger, T.F. (2020). Endogenous TCR promotes in vivo persistence of CD19-CAR-T cells compared to a CRISPR/Cas9-mediated TCR knockout CAR. Blood. 17;136(12):1407- 1418.
Kaeuferle, T., Deisenberger, L., Jablonowski, L., Stief, T.A., Blaeschke, F., Willier, S. and Feuchtinger, T. (2020). CRISPR-Cas9-Mediated Glucocorticoid Resistance in Virus-Specific T Cells for Adoptive T Cell Therapy Posttransplantation. Mol Ther. Jun 11:S1525-0016(20)30292-6.
Blaeschke, F., Willier, S., Stenger, D., Lepenies, M., Horstmann, M.A., Escherich, G., Zimmermann, M., Rojas Ringeling, F., Canzar, S., Kaeuferle, T., Rohlfs, M., Binder, V., Klein, C. and Feuchtinger, T. (2020). Leukemia-induced dysfunctional TIM-3(+)CD4(+) bone marrow T cells increase risk of relapse in pediatric B-precursor ALL patients. Leukemia. 34(10):2607-2620.
Boekstegers, A.M., Blaeschke, F., Schmid, I., Wiebking, V., Immler, S., Hoffmann, F., Bochmann, K., Muller, S., Grune- wald, T.G.P., Feucht, J. and Feuchtinger, T. (2017). MRD response in a refractory paediatric T-ALL patient through antiprogrammed cell death 1 (PD-1) Ab treatment associated with induction of fatal GvHD. Bone Marrow Transplant 52, 1221- 1224.
Feucht, J., Kayser, S., Gorodezki, D., Hamieh, M., Doring, M., Blaeschke, F., Schlegel, P., Bosmuller, H., Quintanilla-Fend, L., Ebinger, M., Lang, P., Handgretinger, R. and Feuchtinger, T. (2016). 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. Oncotarget 7, 76902-76919.
Feucht, J., Opherk, K., Lang, P., Kayser, S., Hartl, L., Bethge, W., Matthes-Martin, S., Bader, P., Albert, M.H., Maecker- Kolhoff, B., Greil, J., Einsele, H., Schlegel, P.G., Schuster, F.R., Kremens, B., Rossig, C., Gruhn, B., Handgretinger, R. and Feuchtinger, T. (2015). Adoptive T-cell therapy with hexon-specific Th1 cells as a treatment of refractory adenovirus infection after HSCT. Blood 125, 1986-1994.
Icheva, V., Kayser, S., Wolff, D., Tuve, S., Kyzirakos, C., Bethge, W., Greil, J., Albert, M.H., Schwinger, W., Nathrath, M., Schumm, M., Stevanovic, S., Handgretinger, R., Lang, P. and Feuchtinger, T. (2013). 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. J Clin Oncol 31, 39-48.
Feuchtinger, T., Opherk, K., Bethge, W.A., Topp, M.S., Schuster, F.R., Weissinger, E.M., Mohty, M., Or, R., Maschan, M., Schumm, M., Hamprecht, K., Handgretinger, R., Lang, P., and Einsele, H. (2010). Adoptive transfer of pp65-specific T cells for the treatment of chemorefractory cytomegalovirus disease or reactivation after haploidentical and matched unre- lated stem cell transplantation. Blood 116, 4360-4367.