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

2020 ◽  
Vol 21 (20) ◽  
pp. 7685
Author(s):  
Fátima Bayón-Calderón ◽  
María L. Toribio ◽  
Sara González-García
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Malignant Disease ◽  
Lymphoblastic Leukemia ◽  
Antigen Receptors ◽  
Challenges And Opportunities ◽  
Life Threatening ◽  
Cell Acute Lymphoblastic Leukemia ◽  
T Cell Immunodeficiency ◽  
T Cell Malignancies

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.

Chromosomal Rearrangements Affecting ABL1 in T-Cell Acute Lymphoblastic Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2894-2894
Author(s):  
Jan Cools ◽  
Carlos Graux ◽  
Marc Boogaerts ◽  
Peter Vandenberghe ◽  
Iwona Wlodarska ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Cell Biology ◽  
Lymphoblastic Leukemia ◽  
Functional Characterization ◽  
Recurrent Event ◽  
Exon 2 ◽  
Male Age ◽  
Cell Acute Lymphoblastic Leukemia ◽  
T Cell Malignancies

Abstract T-cell Acute Lymphoblastic Leukemia (T-ALL) is a heterogeneous entity with several biologically distinct subtypes that differ in clinical outcome. Cytogenetics in T-ALL shows recurrent involvement of TCR a/d (14q11) and TCR b (7q34) rearrangements. The Philadelphia translocation, encoding the BCR-ABL1 (BCR-ABL) fusion gene, is typically found in chronic myeloid leukemia (CML) and precursor B-cell acute lymphoblastic leukemia (B-ALL), but is exceptionally rare in T-ALL. To study the potential involvement of ABL1 gene rearrangements in T-cell malignancies, we screened 90 T-ALL cases by fluorescence in situ hybridization (FISH), using BCR and ABL1 probes. No BCR-ABL1 rearrangements were detected, but 5 patients showed amplification of ABL1 and are described in a separate abstract and 2 patients showed a chromosomal rearrangement affecting ABL1. The first patient (male, age 16, 455x109 WBC/L, 99% blasts, cortical T immunophenotype) showed a cryptic t(9;14)(q34;q32). This was demonstrated in 7/12 metaphases and 60% of nuclei using FISH with the 5′/3′-ABL1 probes RACE-PCR detected a fusion between EML1 at 14q32 and ABL1 at 9q34. The fusion transcript joins exon 1–18 of EML1 to exon 2 of ABL1 and generates an ORF of 4926 nt. The functional characterization of the fusion protein is ongoing. The second patient (male, age 16, 25x109 WBC/L, 35% blasts, mature T-cell immunophenotype) showed a 47, XY, +10[5], idem, inv(9)(p21q34)[2}]/46, XY[9] karyotype. One third of the metaphases are tetraploid with the same distribution of abnormalities. The split signals obtained with the 5′-/3′ABL1 probes in the inv(9) subclone point to an ABL1 rearrangement that is being characterized at the present. These result suggest that ABL1 rearrangements are a rare but recurrent event in T-cell malignancies and support a role of ABL1 in T-cell biology. The therapeutic potential of ABL1 inhibitors for treating this group of T-ALL needs to be explored.

scholarly journals TET2 as a tumor suppressor and therapeutic target in T-cell acute lymphoblastic leukemia

2021 ◽  
Vol 118 (34) ◽  
pp. e2110758118
Author(s):  
Maike Bensberg ◽  
Olof Rundquist ◽  
Aida Selimović ◽  
Cathrine Lagerwall ◽  
Mikael Benson ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Survival Rates ◽  
Endogenous Retroviruses ◽  
Sequencing Data ◽  
Human Endogenous Retroviruses ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Normal Human ◽  
T Cell Malignancies

Pediatric T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy resulting from overproduction of immature T-cells in the thymus and is typified by widespread alterations in DNA methylation. As survival rates for relapsed T-ALL remain dismal (10 to 25%), development of targeted therapies to prevent relapse is key to improving prognosis. Whereas mutations in the DNA demethylating enzyme TET2 are frequent in adult T-cell malignancies, TET2 mutations in T-ALL are rare. Here, we analyzed RNA-sequencing data of 321 primary T-ALLs, 20 T-ALL cell lines, and 25 normal human tissues, revealing that TET2 is transcriptionally repressed or silenced in 71% and 17% of T-ALL, respectively. Furthermore, we show that TET2 silencing is often associated with hypermethylation of the TET2 promoter in primary T-ALL. Importantly, treatment with the DNA demethylating agent, 5-azacytidine (5-aza), was significantly more toxic to TET2-silenced T-ALL cells and resulted in stable re-expression of the TET2 gene. Additionally, 5-aza led to up-regulation of methylated genes and human endogenous retroviruses (HERVs), which was further enhanced by the addition of physiological levels of vitamin C, a potent enhancer of TET activity. Together, our results clearly identify 5-aza as a potential targeted therapy for TET2-silenced T-ALL.

Intravenous Forodesine (BCX-1777), a Novel Purine Nucleoside Phosphorylase (PNP) Inhibitor, Demonstrates Clinical Activity in Phase I/II Studies in Patients with B-Cell Acute Lymphoblastic Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2743-2743 ◽  
Author(s):  
Richard R. Furman ◽  
Varsha V. Gandhi ◽  
J. Claude Bennett ◽  
Shanta Bantia ◽  
J. Michael Kilpatrick
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Phase I ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Clinical Activity ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Pre Treatment ◽  
T Cell Malignancies

Abstract Forodesine is a potent, specific transition-state analog inhibitor of PNP with clinical activity in T-cell malignancies. Pharmacodynamic studies support that this anti-leukemic effect is mediated through the accumulation of plasma 2′-deoxyguanosine (dGuo) and intracellular Dgtp. In vitro studies indicated that B-cell acute lymphoblastic leukemia (B-ALL) cells can also accumulate Dgtp. These preclinical data led to a phase I/II multicenter dose-escalation study to evaluate forodesine in pts with various hematologic malignancies. 15 pts were treated with forodesine, including 6 with B-ALL. Forodesine was given via a 30-min IV infusion followed 24 hrs later by doses every 12 hrs for a total of 9 doses. A second course could be repeated after a 2-week break. Doses were escalated by 50% to pts grouped in cohorts of 3 (starting dose: 40 mg/m2). There was a rapid rise in plasma dGuo and a maximum PNP inhibition was achieved at 40 mg/m2 (Fig 1). 7/15 treated pts (2 T-cell malignancies and 5 B-ALL), including 5/6 treated B-ALL pts, demonstrated a hematologic benefit, defined as a decrease in tumor burden. 3 of the responding B-ALL pts were further treated with 6 courses of forodesine on a compassionate use protocol. One pt treated at 135 mg/m2 demonstrated a complete response with a decrease in bone marrow blast cells from 22% to 5% at the end of therapy. The other 2 pts, treated with 90 mg/m2 and 135 mg/m2 forodesine respectively, showed dramatic improvement in their CBC despite the persistence of bone marrow blasts. The dramatic fall in WBC count was accompanied in each pt by a rise in plasma dGuo (Cmax: 1.9–7.1 μM) and intracellular Dgtp (380–800 pmoles/107 cells vs 25–40 pmoles/107 cells pre-treatment), The response of the pt treated with 90 mg/m2 forodesine is shown in Fig 2. The absolute neutrophil count (ANC) improved from ~0 at pre-treatment to 1800 cells/mm3 at Day 18. To-date forodesine has been safe and well-tolerated at all dose levels tested with no dose-limiting toxicities. Clinical activity has been seen in T- and B-ALL. It is interesting to note the restoration of normal hematopoiesis, indicating the specificity of forodesine for leukemic cell populations and supporting that forodesine represents an important breakthrough in the development of less toxic ALL therapy. This encouraging clinical activity has led to the initiation of a phase II trial in pts with B-ALL. Additional clinical and pharmacodynamic results will be presented.

scholarly journals Inhibition of BCL11B induces downregulation of PTK7 and results in growth retardation and apoptosis in T-cell acute lymphoblastic leukemia

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Kehan Li ◽  
Cunte Chen ◽  
Rili Gao ◽  
Xibao Yu ◽  
Youxue Huang ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Growth Retardation ◽  
Lymphoblastic Leukemia ◽  
Downstream Target ◽  
B Cell Leukemia ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Induced Apoptosis ◽  
Necrosis Factor ◽  
Aggressive Subtype

AbstractT-cell acute lymphoblastic leukemia (T-ALL) is an aggressive subtype of leukemia with poor prognosis, and biomarkers and novel therapeutic targets are urgently needed for this disease. Our previous studies have found that inhibition of the B-cell leukemia/lymphoma 11B (BCL11B) gene could significantly promote the apoptosis and growth retardation of T-ALL cells, but the molecular mechanism underlying this effect remains unclear. This study intends to investigate genes downstream of BCL11B and further explore its function in T-ALL cells. We found that PTK7 was a potential downstream target of BCL11B in T-ALL. Compared with the healthy individuals (HIs), PTK7 was overexpressed in T-ALL cells, and BCL11B expression was positively correlated with PTK7 expression. Importantly, BCL11B knockdown reduced PTK7 expression in T-ALL cells. Similar to the effects of BCL11B silencing, downregulation of PTK7 inhibited cell proliferation and induced apoptosis in Molt-4 cells via up-regulating the expression of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and p27. Altogether, our studies suggest that PTK7 is a potential downstream target of BCL11B, and downregulation of PTK7 expression via inhibition of the BCL11B pathway induces growth retardation and apoptosis in T-ALL cells.

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