Developing multimodal immune-therapies for the treatment of DLBCL

• Applicant: Professor Dr. Christian Reinhardt
• Subject Area: Hematology, Oncology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 553375105

Diffuse large B cell lymphoma (DLBCL) remains a clinical challenge, as relapsed and refractory disease is difficult to treat. However, recent genomics efforts shed light on the landscape of recurrent aberrations in DLBCL. While this area of investigation is still in flux, there is ample evidence indicating that the C3-EZB-MYC+/DHIThigh and C5 clusters constitute high-risk cases with poor prognosis. A central feature of C5 DLBCL is inappropriate NFkB activation, which is achieved through recurrent mutations within the BCR (CD79B) and/or TLR (MYD88) pathways. A further hallmark of C5 DLBCL are BCL2 copy number gains and recurrent aberrations leading to a block in plasma cell differentiation, such as PRDM1-, SPIB- or TBL1XR1 mutations. High-risk C3 cases on the other hand are dominated by BCL2 structural variants, combined with aberrations in genes encoding for epigenetic modifiers, such as EZH2. Within this cluster, high-risk cases were identified that harbor co-occurring aberrations involving MYC and TP53. One critical obstacle in leveraging these genomic insights for the development of novel therapeutic approaches is the lack of suitable mouse models that mimic the genomic landscape of high-risk DLBCL. Here, we capitalize on our rich in vivo platforms, covering autochthonous C3-EZB-MYC+/DHIThigh and C5 models, in vivo imaging, CRISPR screening and in vivo genome editing, mass cytometry and large-scale murine CAR-T production, to dissect the biology of responses following CAR-T- or bispecific antibody treatment of DLBCL. Our ultimate goal is the identification of molecular entry routes for therapeutic interventions to enhance the depth of therapeutic responses to CAR-T and bispecific antibody treatments. Our systems can further be exploited to accelerate the search for resistance-mediating genes and pathways, once viable targeted treatment approaches have been identified. Based on these considerations, we propose three specific aims: Aim 1: Deploy loss of function screens to identify and characterize lymphoma cell intrinsic genes and pathways mediating resistance against CAR-T treatment Aim 2: Perform longitudinal metabolic profiling of lymphoma-engaging T and CAR-T cells Aim 3: Functionally validate biologically rationalized CAR-T combination therapies in vivo These aims test the hypotheses that 1) lymphoma cell-intrinsic genomic aberrations may dictate response and resistance against CAR-T cell treatment 2) CAR-T cells and T cells experiencing forced target engagement through bispecific antibodies have distinct propensities of undergoing T cell exhaustion and that T cell exhaustion is, at least in part governed by potentially actionable metabolic switches and 3) concomitant ibrutinib treatment may enhance response to CAR-T cell or bispecific antibody treatment by reversing or preventing T cell exhaustion. Overall, the proposed experiments will pave the way for the clinical development of enhanced immune therapies against DLBCL.

• DFG Programme: Research Grants