Project Details
Projekt
The CAR T-cell epigenome: Decipher and reprogramme fate decisions of CAR T-cell dysfunction
Applicant
Dr. Viktoria Blumenberg
Subject Area
Hematology, Oncology
Term
since 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 542884574
The adoptive transfer of autologous T cells has revolutionized the treatment of hematological malignancies. Dysfunction of CAR T-cells is recognized as a key pathway of resistance and is associated with inferior patient outcomes. Dysfunctional T cells are characterized by a genome-wide remodeling of their epigenetic state, mediated by exhaustion-specific transcription factors and sequential waves of chromatin remodeling. It remains unknown whether these findings can be generalized to the behavior of approved CAR T-cell products for diffuse large B-cell lymphoma: next-generation genome-wide transcriptional and epigenetic profiling technologies at the single-cell level have not been applied to the CD19-targeted CAR T-cells in clinical use. In addition, epigenetic targets have not been pursued for epigenetic reprogramming of CAR T-cells. I hypothesize that extensive epigenetic remodeling induces fate decisions of CAR T-cell dysfunction. I aim to segregate, for the first time, these lineage trajectories of stepwise-acquired CAR T-cell dysfunction based on the expression signature of immune checkpoints, genes and transcription factors. The first goal will be an in-depth characterization of dysfunctional CAR T-cell lineages including a pipeline of epigenetic targets. Furthermore, I hypothesize that dysfunctional CAR T-cells will insufficiently expand in vivo and will have inferior cytotoxic capacities that translate into clinically insufficient treatment responses. The second goal will be to determine whether there are epigenetic signatures indicative of a dysfunctional state that correlate with the failure of CAR T-cell expansion and inferior therapeutic efficacy. I am to translate these signatures into next-generation biomarker to guide clinical decision-making. Based on this "snapshot" of the CAR T-cell epigenome in clinical use, I hypothesize that these epigenetic correlates of dysfunctional CAR T-cells can be used for rational epigenetic engineering. I aim to epigenetically reprogram CAR T-cells to prevent dysfunction and to provide next-generation CAR T-cell constructs for in vivo testing. Achieving these aims will give a fundamental insight into the network of transcription factors and enhancers governing CAR T-cell dysfunction in clinical use. Tracing the lineage trajectories of CAR T-cell dysfunction throughout the continuum of care will provide a higher resolution of the epigenetic pathways and accelerate the development of personalized immune monitoring applications to guide early therapeutic interventions. Furthermore, these findings will provide the foundation for a new pipeline of highly effective CAR T-cell constructs that can reinvigorate CAR T-cell mediated anti-tumor immunity and facilitate the transition from a one-size-fits-all T-cell-based immunotherapy to tailord treatment modalities for individual patients.
DFG Programme
WBP Fellowship
International Connection
USA
