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Novel immunotherapeutic strategies against T-ALL, a rare pediatric disease

19th national competition for scientific and technical research

Rare diseases

Senior Researcher : María Luisa Toribio García

Research Centre or Institution : Centro de Biología Molecular "Severo Ochoa". CSIC-Universidad Autónoma de Madrid


Preliminary results from our lab support the hypothesis that a protein complex termed preTCR, which is transiently expressed during the development of T lymphocytes, may be an optimal target for the development of a safe, specific, and efficacious immunotherapy based on CAR-T cells against T-cell acute lymphoblastic leukemia (T-ALL), a rare disease mostly affecting children. To confirm this hypothesis, our project has approached the following specific aims: 1) to define the functional relevance of pre-TCR as a T-ALL biomarker; 2) to develop anti-preTCR CAR-engineered T cells confirming their function in vitro, and 3) to validate a T-ALLtargeted immunotherapy based on pre-TCR-specific CAR-T cells in preclinical in vivo assays.

Based on molecular biology strategies, functional in vitro approaches and patientderivedT-ALL xenotransplantation (PDX) mouse models, we have confirmed our initial hypothesis and showed that:

1) Pre-TCR is a biomarker of cells with leukemia-initiating potential in >50% of TALL patients.
2) Pre-TCR targeting with a specific anti-preTCR (anti-pTa) monoclonal antibody (mAb) has therapeutic impact in PDX models in vivo, hampering T-ALL progression and increasing overall mouse survival.
3) The scFv fragment derived from the anti-pTa mAb allowed to generate a preTCRspecific 2nd-generation CAR (CD8α-4-1BB-CD3ζ) that is properly expressed on the surface of transduced primary human T cells.
4) Anti-pre-TCR specificity of our engineered CAR-T cells has been confirmed in functional activation and antibody blocking assays in vitro.
5) We have validated the cytolytic function of anti-preTCR CAR-engineered T cells in functional assays in vitro.
6) In vivo PDX preclinical assays have validated the efficacy of the proposed preTCR-specific CAR-T immunotherapy showing an increased overall survival of treated mice.

In conclusion, results derived from this project provide direct evidence that preTCRspecific CAR-T immunotherapy may be an efficient strategy for treatment of a high proportion of T-ALL patients.


Scientific Production
Magazine Articles 3
Communications at national conferences 4
Communications at international conferences 5


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