Summary
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.
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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| Web resources: | https://cordis.europa.eu/project/id/795833 |
| Start date: | 01-04-2018 |
| End date: | 31-03-2020 |
| Total budget - Public funding: | 158 121,60 Euro - 158 121,00 Euro |
Cordis data
Original description
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.
Status
CLOSEDCall topic
MSCA-IF-2017Update Date
28-04-2024
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