TRR 338:  LETSIMMUN - Lymphocyte Engineering for Therapeutic Synthetic Immunity

• Subject Area: Medicine ; Biology
• Term: since 2021
• Website: Homepage
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 452881907

The ambition of scientists and clinicians engaged in the CRC/TRR LETSIMMUN is to establish immunotherapy with engineered lymphocytes as a medically desirable (safe and effective), scientifically advanced (continuous innovation), broadly accessible (available for all patients in need) treatment that can be applied for different clinical fields, including hematology/oncology, infectious and autoimmune diseases. Several challenges and hurdles have to be addressed in order to realize this ambition. In the short-term, issues in manufacturing that lead to batch-to-batch variation of therapeutic cell products have to be solved; the in vivo persistence and performance needs to be improved to provide optimal functionality and to prevent disease recurrence; and proof-of-concept for clinical efficacy with genetically engineered lymphocytes especially in a solid cancer indication ought to be accomplished. In a longer-term perspective, issues related to targets (allowing for true pathogen/tumor selectivity; target thresholds to trigger TCRs & CARs), receptors (with optimal signaling allowing for sustained T cell activity without exhaustion), lymphocyte subpopulations (with optimal intrinsic properties for a particular disease context), cell migration and microenvironment (neutralize negative regulators, amplify positive regulators) as well as translational development (high-throughput techniques allowing for patient-individualized cell products) have been identified as current challenges and will be in the ‘spot light’ of the research program in LETSIMMUN. The team is convinced that with the steadily increasing toolbox of lymphocyte engineering technologies, it will be feasible to manipulate lymphocytes with the highest precision to express targeting receptors in an optimized – and even temporally controllable – fashion, and that lymphocytes can be designed to become resistant to normal counter-regulation through the use or manipulation of physiological, non-physiological and/or artificial regulators that enhance their in vivo functionality and efficacy. This type of synthetic immunity by lymphocyte engineering can be combined with safety mechanisms (e.g. logic gates, reprogrammable receptors, selective in vivo depletion or inactivation) and more universal donor cell sources to provide clinically relevant cell products that are consistent in function and quality, manageable in case of toxicity, and that can be generated efficiently and in modular fashion for different disease entities. The CRC/TRR is structured into three principal research areas (‘Receptor expression and function’, ‘Cell guidance and maintenance’, ‘Signaling and metabolic engineering’) and core units for ‘biomathematics/bioinformatics’ and ‘GMP-compatible cell product generation’. In order to foster the education of young scientists and clinicians, an integrated research training group will be established as a core structure of the CRC/TRR.

• DFG Programme: CRC/Transregios

Current projects

• A01 - Orthotopic T cell receptor replacement by advanced non viral cell engineering (Project Head Busch, Dirk )
• A02 - One CAR – multiple antigens: Universal CAR-T cells that are chemically programmed to recognize tumors (Project Head Hudecek, Michael )
• A03 - Targeting neoantigens in multiple myeloma by TCR-transgenic T cells (Project Head Krackhardt, Angela )
• A04 - Extending and controlling lymphocyte functionalities by engineered cytokines (Project Head Feige, Matthias )
• A05 - Super-resolution microscopy to visualize CAR-T cell receptome and function (Project Heads Nerreter, Thomas ;  Sauer, Markus )
• A06 - Engineering CAR-T cells against neuroblastoma with synthetic notch receptors to increase tumor-specificity and endogenous immune activation (Project Head Künkele-Langer, Annette )
• B01 - Disease specific engineering of CAR T cells utilizing chemokine receptors (Project Heads Kobold, Sebastian ;  Subklewe, Marion )
• B02 - Engineering CAR-T cells to optimize the treatment of cerebral malignancies (Project Heads von Baumgarten, Louisa ;  Buchholz, Veit )
• B03 - Engineering tissue-resident lymphocytes for the modulation of tissue-microenvironments (Project Head Gasteiger, Georg )
• B04 - T cell engineering to overcome immune dysregulation induced by acute leukemia (Project Head Feuchtinger, Tobias )
• B05 - Engineering of CAR-T cells that overcome MYC-dependent immunosuppression in a genetically engineered mouse model of pancreatic cancer (Project Heads Danhof, Sophia ;  Eilers, Martin )
• B06 - Engineering a sustainable and non-exhausting CD8+ T cell response (Project Head Kastenmüller, Wolfgang )
• B07 - Overcoming barriers for T cell therapy of hepatitis B and hepatocellular carcinoma (Project Head Protzer, Ulrike )
• C01 - Exploitation of negative regulators of TCR signaling for therapeutic lymphocyte engineering (Project Head Ruland, Jürgen )
• C02 - Post-transcriptional control of metabolic programs that improve T cell responses against tumors (Project Head Heissmeyer, Vigo )
• C03 - Targeting T cell-intrinsic negative regulators to enhance the therapeutic potential of adoptive T cell therapy (Project Head Hornung, Veit )
• C04 - Dissection and correction of human regulatory T cell dysfunctions by CRISPR engineering (Project Heads Kotlarz, Daniel ;  Schumann, Kathrin )
• C05 - Metabolic reprogramming to optimize the cellular fitness and function of engineered T cells (Project Heads Theurich, Sebastian ;  Väth, Ph.D., Martin )
• Z - Central Tasks of the Collaborative Research Center (Project Head Busch, Dirk )
• Z02 - Bench-to-Bedside Advanced Therapy Medicinal Product (ATMP) Development Platform (Project Heads Einsele, Hermann ;  Hildebrandt, Martin ;  Marckmann, Georg ;  Priesner, Christoph )
• Z03 - Integrative analysis of single cell genomics and immunoprofiling (Project Heads Canzar, Stefan ;  Theis, Fabian )

• Applicant Institution: Technische Universität München (TUM)
• Co-Applicant Institution: Julius-Maximilians-Universität Würzburg; Ludwig-Maximilians-Universität München
• Participating Institution: Charité - Universitätsmedizin Berlin
• Spokesperson: Professor Dr. Dirk Busch