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InTheMLLrBALL

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Innovative Therapeutic Strategies for Mixed Lineage Leukemia rearranged B cell A...

Innovative Therapeutic Strategies for Mixed Lineage Leukemia rearranged B cell Acute Lymphoblastic Leukemia B-cell acute lymphoblastic leukemia (B-ALL) is the commonest cancer in children and B-ALL with mixed-lineage leukemia rearrangements (MLLr) has a particularly dismal prognosis compared with other B-ALLs. Many MLLrB-ALL patients ar... ver más

31/03/2020

FUNDACIO INSTITUT...

158K€

Presupuesto del proyecto: 158K€

Líder del proyecto

FUNDACIO INSTITUT DE RECERCA CONTRA LA LEUCEM... Actividades de investigación asociacion

TRL 4-5 | 50K€

Fecha límite participación Sin fecha límite de participación.

Financiación concedida El organismo H2020 notifico la concesión del proyecto el día 2020-03-31

MSCA-IF-2017: Individual Fellowships

I+D

Cerrada hace 7 años

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1 Participantes

FUNDACIO INSTITUT DE RECERCA...

158.12K€ | Lider

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Duración del proyecto: 24 meses Fecha Inicio: 2018-03-14
Fecha Fin: 2020-03-31

Líder del proyecto

FUNDACIO INSTITUT DE RECERCA CONTRA LA LEUCEM... Actividades de investigación asociacion

TRL 4-5 | 50K€

Presupuesto del proyecto 158K€

Fecha límite de participación Sin fecha límite de participación.

Descripción del proyecto B-cell acute lymphoblastic leukemia (B-ALL) is the commonest cancer in children and B-ALL with mixed-lineage leukemia rearrangements (MLLr) has a particularly dismal prognosis compared with other B-ALLs. Many MLLrB-ALL patients are refractory to chemotherapy and eventually relapse. Thus, MLLrB-ALL remains clinically challenging. Adoptive transfer of T cells engineered to express artificial chimeric antigen (Ag) receptors (CARs) targeting tumor cell surface-specific Ag is an exciting new approach for cancer immunotherapy. Clinical trials in patients with advanced B-ALL treated with CAR-T cells against CD19 have shown impressive disease remission; however relapse still occurs with loss of CD19. Importantly, the B-ALL patients who have not responded to CD19 CAR-T cells were mainly those carrying MLLr. A strategy to offset tumor Ag-loss relapse is to modify T cells with one CAR molecule containing two different binding domains in tandem (bispecific CAR). By using both in vitro and in vivo approaches, I plan to improve CD19 CAR-T cell therapy for MLLrB-ALL by i)developing a novel bispecific CD19/NG2 CAR, which we expect will reduce single-Ag immune pressure, and ii)through the combination of CD19 CAR-T cell therapy with P-D1/PD-L1 blockade. How to achieve a long-term persistence of CAR-T cells in the host still remains a major challenge in adoptive T cell immunotherapy, and therefore understanding the interplay between T cells, MLLrB-ALL blasts and mesenchymal stromal cells/stroma is fundamental to improve the efficiency of this immunotherapy. We will thus address in vitro and in vivo the contribution of the leukemia microenvironment to CAR-T cell efficacy, as a potential tumor microenvironment (PD1/PD1L)-mediated indirect mechanism of immune escape to CAR T-cells. This cutting-edge proposal will increase my scientific potential and I will be benefited with the complementary/leadership training activities already planned to reach in a near future an independent position.

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