Abstract
T-cell acute lymphoblastic leukemia (T-ALL), a T-cell malignant disease that mainly affects children, is still a medical challenge, especially for refractory patients for whom therapeutic options are scarce. Recent advances in immunotherapy for B-cell malignancies based on increasingly efficacious monoclonal antibodies (mAbs) and chimeric antigen receptors (CARs) have been encouraging for non-responding or relapsing patients suffering from other aggressive cancers like T-ALL. However, secondary life-threatening T-cell immunodeficiency due to shared expression of targeted antigens by healthy and malignant T cells is a main drawback of mAb—or CAR-based immunotherapies for T-ALL and other T-cell malignancies. This review provides a comprehensive update on the different immunotherapeutic strategies that are being currently applied to T-ALL. We highlight recent progress on the identification of new potential targets showing promising preclinical results and discuss current challenges and opportunities for developing novel safe and efficacious immunotherapies for T-ALL.
Highlights
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological disorder that results from the progressive accumulation of genomic alterations in T-cell precursors developing in the thymus
T-ALL is characterized by the infiltration of bone marrow by immature T-cell lymphoblasts, while immature T-cell tumors characterized by a thymic mass and limited bone marrow infiltration are instead diagnosed as T-cell lymphoblastic lymphoma (T-LBL)
In T-ALL, PI3K activation is mandatory for IL-7-mediated p27kip1 down-regulation, Rb hyperphosphorylation, and BCL-2 upregulation, and is required for cell size increase, expression of the glucose transporter Glut1, glucose uptake, and maintenance of mitochondrial integrity [238]. These findings indicate that PI3K is a major effector of IL-7–induced viability, metabolic activation, growth, and proliferation of T-ALL cells, highlighting the importance of developing targeting interventions directed to the interleukin-7 receptor (IL-7R) pathway
Summary
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological disorder that results from the progressive accumulation of genomic alterations in T-cell precursors developing in the thymus. The therapeutic available options for patients experiencing relapse or for those who are refractory to standard chemotherapeutic regimes are very scarce, and since the approval of nelarabine by the US Food and Drug Administration (FDA) in 2005 [44], no new agents have been developed for T-ALL This is certainly not the case for relapsed and/or refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL) patients, whose life expectancy has increased considerably in the last years after the introduction of anti-CD22 antibodies, bi-specific T-cell engagers (BITEs) and, lately, chimeric antigen receptors (CARs). The shared expression of surface markers between normal and leukemic T cells has limited the development of new targeted immunotherapies against T-cell malignancies and against T-ALL This is due to the induction of secondary T-cell immunodeficiency is associated with therapy, which may result in the appearance of opportunistic infections and/or the reactivation of latent infections leading to life-threatening situations. Disease CD4 + T-cell leukemia CD4 + T-cell malignancies CD5 + T-cell malignancies CD7 + NK/T lymphoma; T-LBL; T-ALL CD7 + r/r leukemia or lymphoma CD7 + NK or T-cell malignancies CD7 + T-cell leukemia/lymphoma CD7 + hematological malignancies CD7 + r/r hematological malignancies
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