IP: Dra. Clara Bueno / Dr. Pablo Menéndez

Resumen 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 MLLr B-ALL patients are refractory to chemotherapy and relapse. Thus, MLLr B-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 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 or phenotypic scape is to modify T cells with one CAR molecule containing two different binding domains in tandem (bispecific CAR). By using in vitro and in vivo approaches, we plan to improve CD19 CAR-T cell therapy for B-ALL by i) developing new bispecific CD19/CD22 CAR and CD19/NG2 CAR, which we expect will reduce single-Ag immune pressure and phenotypic scape, and ii) through the combination of CAR-T cell therapy with PD1/PD-L1 blockade. How to achieve a long-term persistence of CAR-T cells in the host still remains a major challenge, hence understanding the interplay between T cells, ALL blasts and stroma is fundamental to improve the efficiency of this immunotherapy. We will thus address 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.

Entidad financiadora: Programa Horizonte 2020. Ministerio de Ciencia e Innovación