What is the optimal sequence of T-cell immunotherapies in multiple myeloma? - A comprehensive multi-omic analysis to investigate the roles of the changes in peripheral immune cells and bone marrow microenvironment in T-cell immunotherapy rechallenge

• Applicant: Dr. Xiang Zhou
• Subject Area: Hematology, Oncology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 560922829

The optimal sequence of T-cell immunotherapies (bispecific antibody and CAR T-cell) is still undefined in relapsed/refractory (RR) multiple myeloma (MM). In this project, I will include 80 RRMM patients treated with BCMA targeted CAR T-cell or BCMAxCD3 bispecific antibody. Peripheral blood and bone marrow samples will be collected at baseline, on day+90 after therapy start and at progression. Subsequently, the patients receiving another T-cell immunotherapy as salvage will be further tracked by sampling on day+90 after therapy start and then at the next relapse. ScRNAseq, CITEseq, CyTOF and multiplex immunofluorescence imaging will be performed to determine the immune landscape (in peripheral blood and bone marrow) and its dynamics following T-cell immunotherapy including rechallenge. In turn, the multiomic analysis will be combined with clinical data including pretreatment, bridging therapy before CAR T-cell, response status, overall response rate, adverse events and survival outcomes in the primary therapy and rechallenge for biomarker and drug target identification. In addition, I will perform in vitro functional studies to validate the multiomic data. For instance, the bispecific antibody combination talquetamab (GPRC5DxCD3) and cadonilimab (CTLA4xPD-1) will be investigated in vitro to test the hypothesis if targeting T-cell exhaustion markers can improve the T-cell immunotherapy rechallenge in RRMM. Altogether, this project may provide new perspectives for the MM treatment and may generate new rationales for clinical trials in near future.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Dr. Madhav Dhodapkar