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

Adoptive cell therapy with engineered lymphocytes has advanced to a distinguished and rapidly evolving translational research field in modern medicine, and the CRC TRR LETSimmun has been initiated to become a hot spot and catalyst for cutting-edge basic and translation research in lymphocyte engineering in Germany. Pioneering work, with participation of LETSimmun-PIs, on the adoptive transfer of pathogen- and tumor-specific T cells provided important evidence regarding the clinical potency and efficacy of this approach. However, the field was most crucially boosted by the implementation of genetic engineering technologies to introduce target-specific T cell receptors (TCRs) or chimeric antigen receptors (CARs) that determine and redirect the specificity of lymphocytes. In particular, the rapid clinical development and approval of CD19 and BCMA CAR-T cell therapy has allowed patients with B cell neoplasia already now to benefit from engineered lymphocyte therapy. The successful recent transfer of CD19 CAR-T cell therapy to autoimmune diseases and first treatments of infectious diseases with TCR-engineered T cells indicates the broad applicability of these therapies for many different disease entities. However, the field of lymphocyte engineering for clinical therapy is still in an early stage, and there are many challenges and hurdles that need to be addressed. The essential mechanisms responsible for success of cell therapy still require clarification and engineering tools need to be optimized, in order to enable intentional control of cellular fate and function in vivo. For example, progress is needed for advanced non-viral vector and targeted genetic engineering, improved in vivo persistence, migration and functionality to increase response rates and counteract immune escape, identification of optimal targets, receptors and receptor combinations, resistance to suppressive factors from microenvironments, as well as translational development, including high-throughput techniques allowing for patient-individualized cell product generation. The ambition of the scientists and clinicians engaged in LETSimmun is to join forces from different scientific fields and backgrounds to develop novel approaches and strategies for improved future immunotherapies with genetically engineered lymphocytes as a medically desirable (safe and effective), scientifically advanced (continuous innovation), broadly accessible and sustainable (available for all patients in need) treatment that can be applied in different fields of medicine, including hematology/oncology, infectious and autoimmune diseases and degenerative disorders. The investigators are supported by an ‘ATMP development team’, a core unit in ‘biomathematics/bioinformatics’, and a dedicated management and governance team. In order to foster the education and collaboration of young scientists and clinicians, the LETSimmun Early Career Scientist (ECS) Training Program has been established.

• 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 Heads Hudecek, Michael ;  Weber, Wolfgang A. )
• 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 )
• A07 - Developing polyclonal TCR-T cell therapies using CRISPR base and prime editing (Project Heads D' Ippolito, Ph.D., Elvira ;  Petri, Karl )
• A08 - AI-Powered Chimeric Receptors to Overcome Therapeutic Resistance in Myeloma (Project Head Schmidts, Andrea )
• 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 ;  Künkele-Langer, Annette )
• 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 Bräunlein, Ph.D., Eva ;  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 Heads Heissmeyer, Vigo ;  Milles, Lukas )
• 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 ;  Luu, Maik ;  Schumann, Ph.D., Kathrin )
• C05 - Metabolic reprogramming to optimize the cellular fitness and function of engineered T cells (Project Heads Theurich, Sebastian ;  Vaeth, 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 ;  Lindemann, Anja ;  Marckmann, Georg ;  Priesner, Christoph )
• Z03 - Integrative analysis of single cell genomics and immunoprofiling (Project Heads Canzar, Stefan ;  Klughammer, Ph.D., Johanna ;  Theis, Fabian )

Completed projects

• A03 - Targeting neoantigens in multiple myeloma by TCR-transgenic T cells (Project Head Krackhardt, Angela )
• A06 - Engineering CAR-T cells against neuroblastoma with synthetic notch receptors to increase tumor-specificity and endogenous immune activation (Project Head Künkele-Langer, Annette )

• Applicant Institution: Technische Universität München
• Co-Applicant Institution: Julius-Maximilians-Universität Würzburg; Ludwig-Maximilians-Universität München
• Participating Institution: Charité - Universitätsmedizin Berlin
• Participating University: Universitätsklinikum Freiburg der Albert-Ludwigs-Universität Freiburg
• Spokesperson: Professor Dr. Dirk Busch