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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

Abstract

T-cell acute lymphoblastic leukemia (T-ALL) is a rare, aggressive, hematological disease arising duringT-lymphocyte development, representing 10-15% of pediatric ALLs. T-ALL is still characterized by high relapse rates and ineffective options for refractory disease, resulting in poor clinical outcomes. Consequently, development of novel and more effective therapeutic strategies is an urgent unmet need. The development of T-cells expressing a Chimeric Antigen Receptor (CAR) to specifically recognize and attack the patient’s tumoral cells has revolutionized B-cell leukemia treatment. However, the sharing of cell-surface molecules by normal and tumoral T-cells posed a challenge to develop CAR T-cell therapies for this disease. We here propose to circumvent current limitations by implementing an innovative CAR T-cell therapy targeting a molecule specifically expressed in T-ALL cells but absent in normal T cells. Our preliminary results supported the hypothesis that pre-TCR, a molecular complex expressed in developing immature T cells may be a suitable T-ALL-specific target for CAR-T therapy.

Based on this hypothesis, we approached the following specific aims:

1. Defining the functional relevance of pre-TCR as a T-ALL biomarker.
2. Developing pre-TCR-CAR-engineered T cells and validating their function in vitro.
3. Preclinically validating in vivo T-ALL-targeted immunotherapy using pre-TCR-specific CAR-T cells.

The results obtained are as follows:

1. We have demonstrated that pre-TCR is a biomarker of T-ALL leukemia initiating cells, which is required for leukemia generation, maintenance and progression, supporting that pre-TCR is an optimal T-ALL therapeutic target.
2. We have produced pre-TCR-specific 2nd-generation (4-1BB, CD3z) primary human CAR-T cells that have been functionally validated against pre-TCR+ T-ALLs in vitro.
3. We showed that in vivo administration of pre-TCR-CAR-T cells hampers T-ALL progression and increases overall mouse survival in preclinical T-ALL models, providing formal proof of the therapeutic efficacy of pre-TCR-specific CAR-T cells as a novel immunotherapy to improve life expectancy of T-ALL patients.