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Innovative CAR T-cell based immunotherapy for the treatment of Relapsed/Refractory Acute Leukemias

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Universitat de Barcelona. Facultat de Medicina i Ciències de la Salut

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[eng] Resistance to standard therapy and relapses are observed in several cases of both myeloid and lymphoid cell malignancies. Such phenomenon poses unquestionable limits to the utility of current therapeutic approaches, and remains a critical endeavor for the clinical management of patients with advanced cancers. To counteract resistance and to prevent relapse, the deployment of a wide portfolio of agents was put into action, providing at times only marginal benefits with large trade off in toxicity and tolerability. With the advent of immunotherapy huge improvements in patients’ management and overall survival was achieved, particularly in the field of CAR T-cells. Engineering T-cells to redirect them against a tumor antigen have granted impressive responses in the treatment of B-cell malignancies. On the other hand, the clinical implementation of CARTs for other blood cancers is lagging behind. Major reasons lay within the biology, expression and localization of the antigen to be targeted, as it can play vital roles in cell regulation and development in healthy tissues. The present work have provided extensive contribution to the field of CAR T-cells in two different manners: i) by elucidating with robust in vitro and in vivo comparative experiments whether CD123 selective targeting qualifies as myeloablative or not ii) by validating CD1a as a feasible therapeutic antigen for T-ALL and by creating a novel anti CD1a CAR, which showed robust antileukemic activity while preserving safety towards healthy T-cells and T-cells precursors. The development of innovative therapeutic tools that permit to tackle refractory-relapsed cancer with otherwise no further therapeutic options, opens the doors for important advances that will enable society to win the battle against blood cancers.

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Tesis Doctorals - Facultat - Medicina i Ciències de la Salut

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Innovative CAR T-cell based immunotherapy for the treatment of Relapsed/Refractory Acute Leukemias