The emerging scenario of immunotherapy for T-cell Acute Lymphoblastic Leukemia: advances, challenges and future perspectives

Abstract

T-cell acute lymphoblastic leukemia (T-ALL) is a challenging pediatric and adult haematologic disease still associated with an unsatisfactory cure rate. Unlike B-ALL, the availability of novel therapeutic options to definitively improve the life expectancy for relapsed/resistant patients is poor. Indeed, the shared expression of surface targets among normal and neoplastic T-cells still limits the efficacy and may induce fratricide effects, hampering the use of innovative immunotherapeutic strategies. However, novel monoclonal antibodies, bispecific T-cell engagers (BTCEs), and chimeric antigen receptors (CAR) T-cells recently showed encouraging results and some of them are in an advanced stage of pre-clinical development or are currently under investigation in clinical trials. Here, we review this exciting scenario focusing on most relevant advances, challenges, and perspectives of the emerging landscape of immunotherapy of T-cell malignancies.

CD99 tumor associated antigen is a potential target for antibody therapy of T-cell acute lymphoblastic leukemia

“…Currently, targeted molecules for antibodies in the treatment of T-ALL are still limited. Most antibodies target on molecules that are found both malignant T cells and normal cells [ 51 ]. The shared expression of surface molecules results in the elimination of both malignant and non-malignant T cells through antibodies, subsequently causing the development of secondary T-cell immunodeficiency [ 10 ].…”

“…Additionally, the anti-CC chemokine receptor 4 (CCR4) antibody KW-0761 is undergoing a phase II clinical trial to assess efficacy, safety, and pharmacokinetic profiles in CCR4-positive adult T-cell leukemia/lymphoma [49]. Furthermore, immune checkpoint inhibitors, such as the anti-programmed cell death-1 (anti-PD-1) mAb nivolumab, are in phase II trial studies for the treatment of patients with human T-cell leukemia virus (HTLV)-associated Tcell leukemia/lymphoma [50]. Consequently, the exploration of candidate antibodies for T-ALL remains a critical aspect of ongoing research.…”

Flow Cytometry in the Diagnostic Laboratory Workup of Acute Lymphoblastic Leukemias

“…MoAbs to CD38 (daratumumab) and CD52 (alemtuzumab) have been tried in T-ALL patients and several new antigens such as CXCR4, IL7R, CD30, CD43, CD44, CD99, and CD194 are investigated as potential new targets for immunotherapy in T-ALL patients. 47,48 These antibodies can be utilized in the diagnostic panel of antibodies if clinical settings for immunotherapies are available.…”

CD7 Nanobody-Based Immuno-Nanotoxin for Targeted Treatment of T-Cell Acute Lymphoblastic Leukemia

“…Unlike B-cell ALL, which has well-validated targets (CD19, CD20, and CD22) and a variety of FDA-approved immunotherapies, including monoclonal antibodies, bispecific antibodies, antibody-drug conjugates (ADCs), and chimeric antigen receptor (CAR)-T cells, the lack of mature and specific targets of T-ALL is a major reason underlying its dismal clinical prognosis. − CD7, a T-lineage-specific antigen, is overexpressed in T-ALL and known to mediate endocytosis, making it an attractive target for treating T-ALL recently. − Several CD7 CAR-T cell therapies are under early clinical evaluation and have shown some response. − However, the development of CD7 CAR-T cells is complicated, costly, and associated with major challenges, such as cytokine release syndrome and fratricide. , …”