Transforming T-cell suppressive signals in relapsed/refractory B-cell lymphoma with CRISPR knock-in switch receptor CAR T-cells

• Applicant: Dr. Hyatt Balke-Want
• Subject Area: Hematology, Oncology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 555464052

Chimeric antigen receptors (CARs) are the first iteration of clinically applied synthetic immunreceptors and have revolutionized the treatment of B-cell lymphoma (BCL). However, a substantial number of patients will not show a durable response. Switch receptors (SR) are a powerful tool to boost the efficacy of CAR T-cells. Here, the extracellular portion of an inhibitory receptor is combined with the activating domains of a co-stimulatory molecule, thereby enabling transformation of an inhibitory into a stimulatory signal. Our preliminary data indicates that the C-type lectin LGALS9 (Galectin-9) is overexpressed in BCL. Therefore, our goal is to deepen the understanding of the Galectin-9 interaction with the putative T-cell inhibitory receptor TIM-3. Thus, providing a molecular basis to test conventional TIM-3 SR CAR T-cells in BCL and compare them to next-generation TIM-3 SR CAR T-cells with insertion into HAVCR2 via CRISPR knock-in (CKI). The concomitant disruption of the endogenous TIM-3 has the potential to boost CAR T-cell efficacy in BCL. Finally, we will leverage our genome engineering expertise to develop and test CKI TIM-3 SR CAR T-cells generated with a rapid manufacturing protocol (2 days) to improve product stemness and persistence. Our work will provide insights into the T-cell suppressive signals in BCL and measures to overcome them by enhancing both the potency and longevity of CAR T-cells.

• DFG Programme: Research Grants