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Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/214440
Enhancing CAR-T Cell Therapy for Hematological Malignancies through Dual Targeting and Combination with NK Cells
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[eng] CAR-T therapy has represented a milestone for the treatment of hematological patients in relapse or refractory to conventional treatments, leading to the approval by regulatory agencies of four CAR-T products against CD19 for the treatment of patients with acute lymphoblastic leukemia (ALL) or non-Hodgkin lymphoma (NHL), and two CAR-T products against BCMA for the treatment of multiple myeloma (MM). Despite promising response rates, some patients have been observed to relapse after CAR- therapy
T. The main escape mechanisms vary depending on the disease. In NHL, most patients relapse with loss of antigenic target or decreased antigen levels, while in MM, it is mainly due to the lack of persistence of CAR-T cells.
The main objective of this thesis is to prevent these mechanisms of resistance to CAR-T therapy through two projects, one focused on NHL and the other on MM. On the one hand, we hypothesized that the generation of dual CAR-T cells, directed against CD19 and BCMA antigens, could decrease selective pressure on a single antigen and improve CAR-T therapy in NHL. On the other hand, we hypothesize that the combination of CAR-T cells against BCMA with other immune cells such as NK cells derived from umbilical cord blood, could improve their antitumor efficacy synergistically. As CAR constructs, we used ARI0001 (CAR-CD19) and ARI0002h (CAR-BCMA), both academically developed at the Hospital Clínic de Barcelona.
In the first part, different dual CAR-T strategies are developed: 1) co-transduction with two lentiviral vectors, 2) Mixture of monospecific CAR-T cells, 3) bicistronic lentiviral vector that codes for both CARs,
4) a single CAR receptor with dual specificity with two extracellular domains in tandem or loop conformation. For in vitro models, different tumor lines representative of the hematological diseases of interest are used.
For in vivo models, immunosuppressed mice (NSG) are used in which a systemic model of disease is developed through intravenous injection of tumor cells for subsequent treatment.
First, it was found that co-transduction (ARI0003) is the dual strategy that allows us to have CAR-T cells with better expression of membrane CAR receptors compared to the bicistronic, tandem and loop strategy. In addition, co-transduced cells are especially effective in models with low CD19 antigen expression, both in vitro and in vivo. This set of preclinical results has been submitted to the Spanish Agency for Medicines and Medical Devices to request approval for a clinical trial to test ARI0003 in patients with NHL, including those who relapsed after receiving a CD19-directed CAR-T.
In a second part, we demonstrated that the combination between CAR-T BCMA and cord NK cells increased antitumor efficacy in MM models, achieving synergistic activity between both immune cells, especially at early times. In the presence of NK cells, CAR-T cells migrated more rapidly to tumor cells forming attack clusters earlier, thus eliminating tumor cells more efficiently. In addition, we observed a lower expression of markers of depletion in the presence of NK cells, suggesting that the combination of CAR-T cells with NK could reduce the depletion of CAR-T cells.
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BACHILLER GARCÍA, Mireia. Enhancing CAR-T Cell Therapy for Hematological Malignancies through Dual Targeting and Combination with NK Cells. [consulta: 7 de desembre de 2025]. [Disponible a: https://hdl.handle.net/2445/214440]