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Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/215525
Tailored immunotherapies on 3D models of non-Hodgkin lymphoma
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[eng] B-cell non-Hodgkin lymphoma (B-NHL) represent the most frequent group of hematologic tumors. Follicular lymphoma (FL) is usually indolent; however, some patients relapse after standard chemotherapy, increasing risk of transformation to aggressive lymphoma. Mantle cell lymphoma (MCL) is less frequent but very aggressive. In this thesis, we set up 3D models to culture primary cells (named as Patient-Derived Lymphoma Spheroids, PDLS) from B- NHL in vitro by mixing FL/MCL cells with healthy donors’ monocytes and specific cytokine cocktails in ultra-low attachment (ULA) plates. After 7 days, PDLS were highly viable and had an enhanced proliferation. RNA-seq and gene-set enrichment analysis determined PDLS strongly recapitulate the pathological LN as well as pathways involved in lymphoma pathogenesis. Remarkably, MCL-PDLS reproduces in vivo responses to ibrutinib, and its resistance may be overcame by adding anti-PD1 nivolumab. Besides, these models are suitable to test novel immunotherapies, which let us uncover a potential therapeutic benefit of anti-galectin9 antibodies in FL. In parallel, we used Nanostring technology to analyze the transcriptomic immune profile of FL-LN samples. In a cohort of patients at diagnose, homogeneously treated with immunochemotherapy, we discovered CD70 is up-regulated in patients that eventually relapse. Furthermore, we validated this over-expression at protein level and determined, by multiplex immunofluorescence, it is highly expressed in tumor B cells, but also in a subset of T cells from the microenvironment. Our results shoved the generation of a dual CD19-CD27 CAR-T by combining an academic, approved CD19 CAR-T (ARI-0001) and a ligand-based anti-CD70 CAR-T using a truncated CD27 protein.
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ARAUJO AYALA, Ferran. Tailored immunotherapies on 3D models of non-Hodgkin lymphoma. [consulta: 6 de desembre de 2025]. [Disponible a: https://hdl.handle.net/2445/215525]