Project Details
Projekt
Engineering resilient CAR-T against resistant cancer cells
Applicant
Dr. Andrea Schmidts
Subject Area
Hematology, Oncology
Term
since 2022
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 494809850
Chimeric antigen receptor T cell (CAR-T) therapy has revolutionized the treatment of hematological cancers. Unprecedented response rates have been achieved in patients with certain aggressive B-cell malignancies and relapsed/refractory multiple myeloma, highlighting the immense potential of this novel class of medicines. However, these exceptional treatment responses are currently of limited duration. Less than half of all patients receiving commercial CD19-targeting CAR-T therapy experience long-term disease control. Moreover, emerging clinical data on BCMA-directed CAR-T therapy indicate that the rate of sustained remissions is even lower in multiple myeloma patients. To achieve a higher rate of durable remissions, there is an urgent need to understand how disease resistance to CAR-T develops, how to anticipate it, and how to counter it with “resilient” CAR-T therapies.Therefore, I aim to (1) model genetic resistance of leukemia, lymphoma and myeloma cells against CAR-T, and (2) to explore novel CAR engineering and pharmacological booster approaches to overcome resistance to CAR-T treatment in multiple myeloma.First, using my expertise in next-generation CRISPR tools (base and prime editing), I will model patient-specific CD19 escape variants to CAR-T therapy. By installing these patient-specific variants, I will determine the threshold for immune escape and investigate the impact of individual variants on CAR-T gene expression, phenotype and effector function.Second, I will use CRISPR tiling screens to perform saturation mutagenesis across the coding and non-coding regions of the gene encoding BCMA in situ. This will be coupled with in vitro selection using BCMA-directed CAR-T to systematically detect escape variants.Third, I will investigate whether the pharmacological modulation of common myeloma resistance pathways can potentiate the anti-tumor efficiency of BCMA-targeting CAR-T therapy.Finally, building on my expertise in engineering anti-myeloma CAR-T treatments, I will use an innovative approach for pooled generation and parallel testing of various CAR designs to identify trispecific CARs with optimal anti-myeloma efficiency.This work will enable the prediction and the early detection of disease resistance, tailored selection of CAR-T products, and build a platform for testing pre-clinical CAR designs for their “resistance profile”. Moreover, it will identify pharmacological and engineering approaches for making CAR-T resilient against disease resistance. Only by understanding resistance to current CAR-T therapies, will we be able to extend their reach to more challenging indications like acute myeloid leukemia and solid tumors in the future.
DFG Programme
Independent Junior Research Groups
International Connection
USA
