The Role of T-cell Epigenetic Plasticity and Scarring in T-cell Engaging Bispecific Antibody (BsAb) Therapy

• Applicant: Nora Philipp, Ph.D.
• Subject Area: Immunology ; Hematology, Oncology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 563094953

T cell-engaging bispecific antibodies (BsAbs) have greatly advanced the treatment of B-cell neoplasia. The CD3xCD19 BsAb blinatumomab (blina) was the first BsAb approved in 2014 for treatment of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) and strongly improved survival of these patients compared to standard chemotherapy. Its clinical success fueled the development and approval of several other BsAbs since 2022. Despite encouraging response rates, a fraction of patients remains refractory or relapses after BsAb therapy. T-cell exhaustion has been identified as one major resistance mechanism to T cell-based immunotherapy. Exhaustion arises upon chronic antigen stimulation and manifests in hierarchical loss of effector function as well as in the development of distinct transcriptional and epigenetic patterns. These epigenetic patterns are tightly linked to T-cell function and are – to some extend – reversible. It is thus highly relevant, in order to improve BsAb therapy, to understand the kinetics of reversible epigenetic patterns and identify a “point-of-no-return” beyond which T cells are rendered epigenetically scarred and dysfunctional. While studies on T-cell epigenetic states are mainly conducted in chronic viral infections and tumor-infiltrating lymphocytes, the nature and kinetics of epigenetic patterns arising during BsAb therapy remain elusive. We therefore aim to study developing epigenetic patterns associated with T-cell function and exhaustion during BsAb therapy and to identify the “point-of-no-return” in an in vitro long-term culture system for primary human T cells (Philipp 2022, Blood). We have previously shown that intermittent resting rather than continuous BsAb treatment ameliorates T-cell exhaustion. These resting periods can be mimicked by tyrosine kinase inhibitors (TKIs) like the BCR-ABL inhibitor ponatinib (Philipp 2023, Blood). As TKIs are being tested in combination with blina in Philadelphia-chromosome-positive (Ph+) BCP-ALL patients, TKIs could be a tool to rest T cells in vivo. Hence, we will also investigate the effect of intermittent TKI treatment during BsAb therapy on T-cell epigenetic plasticity and identify an optimized BsAb + TKI administration schedule that best preserves T-cell function and epigenetic flexibility over time (Objective I). We will further study whether T cells derived from Ph+ and Ph- BCP-ALL patients pre BsAb therapy preserve higher functionality and epigenetic plasticity if stimulated in vitro with the optimized vs continuous BsAb + TKI schedule (Objective II). Lastly, we will characterize the T-cell functional and epigenetic landscape in Ph+ (blina + TKI) and Ph- (blina only) BCP-ALL patients under blina +/- TKI therapy in vivo (Objective III). These data will help to identify T-cell epigenetic signatures that correlate with function and therapy response. Our study may thus pave the way to improve BsAb therapy, potentially using TKIs to fine-tune T-cell responses in patients.

• DFG Programme: Research Grants
• International Connection: USA
• Cooperation Partners: Professor Dr. Elias Joseph Jabbour; Dr. Andrea Schietinger