TRR 338:
LETSIMMUN - Lymphocyte Engineering for Therapeutic Synthetic Immunity
Subject Area
Medicine
Biology
Term
since 2021
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
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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
)
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A04 - Extending and controlling lymphocyte functionalities by engineered cytokines
(Project Head
Feige, Matthias
)
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A05 - Super-resolution microscopy to visualize CAR-T cell receptome and function
(Project Heads
Nerreter, Thomas
;
Sauer, Markus
)
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A06 - Engineering CAR-T cells against neuroblastoma with synthetic notch receptors to increase tumor-specificity and endogenous immune activation
(Project Head
Künkele-Langer, Annette
)
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B01 - Disease specific engineering of CAR T cells utilizing chemokine receptors
(Project Heads
Kobold, Sebastian
;
Subklewe, Marion
)
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B02 - Engineering CAR-T cells to optimize the treatment of cerebral malignancies
(Project Heads
von Baumgarten, Louisa
;
Buchholz, Veit
)
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B03 - Engineering tissue-resident lymphocytes for the modulation of tissue-microenvironments
(Project Head
Gasteiger, Georg
)
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B04 - T cell engineering to overcome immune dysregulation induced by acute leukemia
(Project Head
Feuchtinger, Tobias
)
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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
)
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B06 - Engineering a sustainable and non-exhausting CD8+ T cell response
(Project Head
Kastenmüller, Wolfgang
)
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B07 - Overcoming barriers for T cell therapy of hepatitis B and hepatocellular carcinoma
(Project Head
Protzer, Ulrike
)
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C01 - Exploitation of negative regulators of TCR signaling for therapeutic lymphocyte engineering
(Project Head
Ruland, Jürgen
)
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C02 - Post-transcriptional control of metabolic programs that improve T cell responses against tumors
(Project Head
Heissmeyer, Vigo
)
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C03 - Targeting T cell-intrinsic negative regulators to enhance the therapeutic potential of adoptive T cell therapy
(Project Head
Hornung, Veit
)
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C04 - Dissection and correction of human regulatory T cell dysfunctions by CRISPR engineering
(Project Heads
Kotlarz, Daniel
;
Schumann, Kathrin
)
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C05 - Metabolic reprogramming to optimize the cellular fitness and function of engineered T cells
(Project Heads
Theurich, Sebastian
;
Väth, Ph.D., Martin
)
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Z - Central Tasks of the Collaborative Research Center
(Project Head
Busch, Dirk
)
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Z02 - Bench-to-Bedside Advanced Therapy Medicinal Product (ATMP) Development Platform
(Project Heads
Einsele, Hermann
;
Hildebrandt, Martin
;
Marckmann, Georg
;
Priesner, Christoph
)
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Z03 - Integrative analysis of single cell genomics and immunoprofiling
(Project Heads
Canzar, Stefan
;
Theis, Fabian
)