Facts and Challenges in Immunotherapy for T-Cell Acute Lymphoblastic Leukemia

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.

Keywords: T-cell acute lymphoblastic leukemia; chimeric antigen receptor; immunotherapy; leukemia-initiating cells; monoclonal antibodies; relapse.

Figure 1

Human intrathymic T-cell developmental stages and corresponding T-ALL phenotypic subtypes. (a) Early thymic precursors (ETP) that have entered the human thymus differentiate through sequential developmental stages: pro-T, pre-T, immature CD4 single positive (CD4ISP), pre-T-cell receptor (pre-TCR), double positive CD4⁺ CD8⁺ (DP) and single posive (SP), which can be identified by the expression of different cell surface markers and the sequential acquisition of the pre-TCR and the TCRαβ receptors. (b) T-ALL subtypes (ETP-ALL, Pro-T, Pre-T, Cortical and Mature) are based on the 1995 EGIL classification of acute leukemias and the 2017 WHO classification of Tumours of Haematopoietic and Lymphoid Tissues, which included ETP-ALL as a new provisional entity. This classification was established by immunophenotyping based on surface molecules expressed at sequential intrathymic stages of human T-cell development. cCD3 (cytoplasmic CD3); sCD3 (surface CD3); TdT (terminal deoxynucleotidyl transferase). Presence or absence of the indicated molecule is represented by (+) and (−), respectively.

Figure 2

Recent immunotherapeutic interventions for T-ALL. Different strategies targeting the indicated cell surface molecules expressed on leukemic cells have been designed for T-ALL treatment. Monoclonal antibodies have been tested in the clinic against relapsed and/or refractory T-ALL (upper right); chimeric antigen receptors were assayed either in preclinical or in clinical settings (lower right); and new molecules have revealed their potential as promising targets in preclinical models (left). Identifiers [The National Clinical Trial (NCT) number] of clinical trials in progress including T-ALL patients are shown [52].

Figure 3

Schematic representation of the different CAR generations. CARs are conformed by an extracellular antigen recognition domain derived from the VH and VL antibody regions, a transmembrane domain (TM) and an intracellular signaling domain. First-generation CARs contain a single intracellular signaling domain derived from the CD3ζ chain of the TCR complex (CD3ζ), whereas second- and third-generation CARs incorporate additional costimulatory molecules (Costim.1 or Costim.2), derived from signaling molecules such as CD28 or 4-1BB. Fourth-generation CAR T cells co-express the CAR together with an immune system stimulatory cytokine, which is expressed either constitutively or after activation of a downstream transcription factor following antigen engagement. Fifth-generation CAR T cells express a second-generation CAR, and are genetically engineered to no longer express endogenous TCR and/or MHC molecules.