Immunotherapy of B-cell malignancies with bispecific antibodies is an emerging treatment option. However, not all patients benefit from these therapies, presumably due to pretreatment regimens. Therefore, we determined the effect of different treatment lines on the activity of T cells and their responsiveness to AFM11. AFM11 is a tetravalent, bispecific CD19/CD3 immunoengager based on Affimed’s ROCK platform, currently being investigated in phase I clinical trials for non-Hodgkin lymphoma and acute lymphoblastic leukemia. T cells from B-cell lymphoma patients treated with either rituximab+bendamustine (R-Benda), rituximab+CHOP (R-CHOP), or with high-dose BEAM chemotherapy (HD-BEAM) and autologous HSCT were compared with T cells from healthy donors. Overall, in these patients, T-cell numbers were significantly reduced. To determine whether distinct chemotherapy affects AFM11 efficacy, functional T-cell assays were performed. It is interesting to note that, only in assays that combine target cell lysis, cytokine production and proliferation over 4 days at an effector to target ratio of up to 1:25 significant differences could be detected between the different treatment groups: T cells after R-CHOP showed only modest decrease in their functionality when compared with healthy controls, whereas R-Benda and HD-BEAM had a profound effect on AFM11-induced T-cell cytotoxicity. In conclusion, T cells from lymphoma patients are reduced in number and have functional defects following treatment with certain chemotherapy regimens, also reducing AFM11 efficacy. Importantly, AFM11 was still able to trigger B-cell-directed T-cell immunity in all treatment groups.
Background: MLL rearrangements (MLLr) are a common cause of aggressive, incurable acute lymphoblastic leukaemias (ALL) in infants and children, most of which originate in utero. The most common MLLr produces an MLL-AF4 fusion protein. MLL-AF4 is thought to promote leukaemogenesis by activating key target genes, mainly by altering the epigenetic profile of the cell through recruitment of DOT1L and increasing histone H3 lysine 79 methylation (H3K79me2/3). One of these key genes is PROM1 which encodes the cell surface protein CD133 (Prominin-1; Mak2016). CD133 has previously been shown to be expressed on ALL blasts and is of potential therapeutic interest. However, the mechanism by which MLL-AF4 dysregulates PROM1 expression and the impact of PROM1 expression on leukaemia cell survival remains unclear. Aims: To determine the mechanism by which MLL-AF4 causes aberrant expression of PROM1 in leukaemia. Methods: We characterised normal fetal haematopoietic stem and progenitor cells (HSPC), blasts from patient leukaemia samples, and SEM cells (a MLL-AF4+ cell line) by immunophenotyping and transcriptome analysis. ChIP-Seq and Capture C (a high resolution chromosome conformation capture technique) was used to elucidate enhancer-promoter structure at the PROM1 locus. Results: We find that the MLL-AF4 complex aberrantly upregulates PROM1 transcription by controlling enhancer promoter-interactions.
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