DEVELOPMENT OF UNIVERSAL T CELLULAS FOR USE IN LEUKEMIA IMMUNOTHERAPY PROTOCOLS (Q3167751): Difference between revisions
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(Created claim: summary (P836): T-cell transplantation expressing chimeric antigen receptors (CARs) is a potent treatment that has shown very encouraging results in refractory leukemias, lymphomas and myelomas. The success of the clinical application of CAR-Ts and their reproducibility depend largely on the quality of the T-cells used and the method used for gene transfer. In this type of therapies, the expression of CARs is usually carried out by transduction of autologous T-...) |
(Changed label, description and/or aliases in en: translated_label) |
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DEVELOPMENT OF UNIVERSAL T CELLULAS FOR USE IN LEUKEMIA IMMUNOTHERAPY PROTOCOLS | |||
Revision as of 16:22, 12 October 2021
Project Q3167751 in Spain
| Language | Label | Description | Also known as |
|---|---|---|---|
| English | DEVELOPMENT OF UNIVERSAL T CELLULAS FOR USE IN LEUKEMIA IMMUNOTHERAPY PROTOCOLS |
Project Q3167751 in Spain |
Statements
81,600.0 Euro
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102,000.0 Euro
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80.0 percent
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1 January 2019
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31 March 2022
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FUNDACION PUBLICA ANDALUZA PROGRESO Y SALUD
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37°10'24.60"N, 3°35'58.31"W
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18087
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El trasplante de linfocitos T expresando receptores de antígeno quiméricos (CARs) es un potente tratamiento que ha mostrado resultados muy esperanzadores en leucemias, linfomas y mielomas refractarios. El éxito de la aplicación clínica de los CAR-T y su reproducibilidad dependen en gran parte de la calidad de los linfocitos T utilizados y el método usado para la trasferencia génica. En este tipo de terapias, la expresión de los CARs se lleva a cabo generalmente mediante la transducción de linfocitos T autólogos con vectores retrovirales. La expresión alta y continuada de CARs provoca la activación incontrolada de los linfocitos T-CARs produciendo efectos secundarios severos como el síndrome de liberación de citoquinas (CRS) y la hipogammaglobulinemia debida a la depleción de células B (BCD), en el caso de CAR-anti CD19. Esto repercute negativamente en el fenotipo de los linfocitos T-CARs disminuyendo su eficacia y persistencia in vivo. Por otro lado la escases y baja calidad de los linfocitos T autólogos, compromete significativamente las estrategias basada en CAR-T. En este proyecto, coordinado, pretendemos mejorar la eficacia de la inmunoterapia basada en CAR-antiCD19 mediante la generación de linfocitos T universales, que expresen de una manera controlada niveles de CAR antiCD19. Para ello desarrollaremos estrategias de edición génica que nos permitan por un lado generar linfocitos T universales deficientes para el TCR y/o HLA-I y permitiendo por otro lado la expresión de los CARs de manera inducible por el propio promotor del TCR. Estos objetivos estarán coordinados con el sub-proyecto 2 con la finalidad de generar células T universales a partir de la sub-población con mejor capacidad de lisis tumoral y de persistencia in vivo. Finalmente trasladaremos los resultados de la investigación a condiciones GLP como fase preclínica de un futuro ensayo clínico fase I. (Spanish)
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T-cell transplantation expressing chimeric antigen receptors (CARs) is a potent treatment that has shown very encouraging results in refractory leukemias, lymphomas and myelomas. The success of the clinical application of CAR-Ts and their reproducibility depend largely on the quality of the T-cells used and the method used for gene transfer. In this type of therapies, the expression of CARs is usually carried out by transduction of autologous T-lymphocytes with retroviral vectors. High and continuous expression of CARs causes uncontrolled activation of T-CARs lymphocytes producing severe side effects such as cytokine release syndrome (CRS) and hypogammaglobulinemia due to B cell depletion (BCD) in the case of CAR-anti CD19. This negatively affects the phenotype of T-CARs lymphocytes, decreasing their efficacy and persistence in vivo. On the other hand, the scarcity and low quality of autologous T-lymphocytes significantly compromises the strategies based on CAR-T. In this coordinated project, we aim to improve the effectiveness of the immunotherapy based on CAR-antiCD19 through the generation of universal T lymphocytes, which express in a controlled way levels of CAR antiCD19. For this we will develop gene editing strategies that allow us on the one hand to generate universal T lymphocytes deficient for TCR or HLA-I and on the other hand allow the expression of the CARs in an inducible way by the promoter of TCR himself. These objectives will be coordinated with sub-project 2 with the aim of generating universal T cells from the sub-population with better capacity for tumor lysis and in vivo persistence. Finally, we will transfer the results of the research to LPG conditions as a preclinical phase of a future phase I clinical trial. (English)
12 October 2021
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Granada
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Identifiers
PI18_00330
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