scholarly journals Development of the T-ALLiPSC-based Therapeutic Cancer Vaccines for T-cell acute Lymphoblastic Leukemia

2021 ◽  
Author(s):  
Zhu Li ◽  
Xuemei Chen ◽  
Luning Liu ◽  
Meiling Zhou ◽  
Guangqian Zhou ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Tumor Cells ◽  
Cytotoxic T Lymphocyte ◽  
Lymphoblastic Leukemia ◽  
Therapeutic Vaccines ◽  
Therapeutic Cancer Vaccine ◽  
Whole Cell Lysate ◽  
Cell Acute Lymphoblastic Leukemia

Abstract PurposeThe T-cell acute lymphoblastic leukemia (T-ALL) is a kind of hematological malignancy in children. Despite the significant improvement in the cure rate of T-ALL upon treatment with chemotherapy regimens, steroids, and allotransplantation there are relapses. This study focuses on the tumor-specific therapeutic vaccines derived from the induced pluripotent stem cells (iPSC) to address the issue of T-ALL recurrence.MethodsPatient-derived tumor cells were reprogrammed into the iPSCs and the RNA-seq data of the T-ALL-iPSCs and H-iPSCs were analyzed. In vitro, the whole cell lysate antigens of iPSCs were prepared to induce the dendritic cells (DC) maturation, which in turn stimulated the tumor-specific T cells to kill the T-ALL tumor cells (Jurkat, CCRF-CEM, MOLT-4).ResultsBoth T-ALL-iPSCs and H-iPSCs were highly related to the tumor-related genes. The transcriptome analysis showed the T-ALL-iPSCs to be similar to the T-ALL tumor cells. The cytotoxic T lymphocyte (CTL) stimulated by the DC-loaded T-ALL-iPSC-derived antigens showed specific cytotoxicity against the T-ALL cells in vitro.ConclusionsThe T-ALL-iPSC-based therapeutic cancer vaccine can elicit a specific anti-tumor effect on T-ALL.

scholarly journals Phloridzin Docosahexaenoate (PZ-DHA) : A Novel Naturally Derived Drug Active in T-Cell Acute Lymphoblastic Leukemia (T-ALL)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5197-5197
Author(s):  
Niroshaathevi Arumuggam ◽  
Nicole Melong ◽  
Catherine K.L. Too ◽  
Jason N. Berman ◽  
H.P. Vasantha Rupasinghe
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Xenograft Model ◽  
Jurkat Cells ◽  
Interferon Α ◽  
Omega 3 ◽  
Cell Acute Lymphoblastic Leukemia

Abstract T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignant disease that accounts for about 15% of pediatric and 25% of adult ALL. Although risk stratification has provided more tailored therapy and improved the overall survival of T-ALL patients, clinical challenges such as suboptimal drug responses, morbidity from drug toxicities, and drug resistance still exist. Plant polyphenols have therapeutic efficacy as pharmacological adjuvants to help overcome these challenges. They can be acylated with fatty acids to overcome issues concerning bioavailability, such as poor intestinal absorption and low metabolic stability. Phloridzin (PZ), a flavonoid found in apple peels, was acylated with an omega-3 fatty acid, docosahexaenoic acid (DHA), to generate a novel ester called phloridzin docosahexaenoate (PZ-DHA). The cytotoxic effect of PZ-DHA was studied in the human Jurkat T-ALL cell line. PZ-DHA significantly reduced the viability and cellular ATP levels of treated cells. PZ-DHA was found to selectively induce apoptosis in Jurkat cells, while sparing normal murine T-cells. Apoptosis was further confirmed by demonstrating the ability of PZ-DHA to induce morphological alterations, DNA fragmentation, caspase activation, and the release of intracellular lactate dehydrogenase. PZ-DHA also significantly inhibited cell division in Jurkat cells. Furthermore, interferon-α-induced phosphorylation of the transcription factor, STAT3, was downregulated following PZ-DHA treatment. The in vitro efficacy of PZ-DHA was recapitulated in vivo in an established zebrafish xenograft model, where the proliferation of transplanted Jurkat cells was inhibited when PZ-DHA was added to the embryo water. Overall, these findings provide evidence for PZ-DHA as a novel therapeutic agent with activity in T-ALL. Studies examining the effect of PZ-DHA on patient-derived ALL cells engrafted in zebrafish are currently underway. Disclosures No relevant conflicts of interest to declare.

scholarly journals miR-22-3p Negatively Affects Tumor Progression in T-Cell Acute Lymphoblastic Leukemia

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1726
Author(s):  
Valentina Saccomani ◽  
Angela Grassi ◽  
Erich Piovan ◽  
Deborah Bongiovanni ◽  
Ludovica Di Martino ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Target Genes ◽  
Cell Transformation ◽  
Lymphoblastic Leukemia ◽  
T Cell Development ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Notch1 Signaling Pathway

T-cell acute lymphoblastic leukemia (T-ALL) is a rare, aggressive disease arising from T-cell precursors. NOTCH1 plays an important role both in T-cell development and leukemia progression, and more than 60% of human T-ALLs harbor mutations in components of the NOTCH1 signaling pathway, leading to deregulated cell growth and contributing to cell transformation. Besides multiple NOTCH1 target genes, microRNAs have also been shown to regulate T-ALL initiation and progression. Using an established mouse model of T-ALL induced by NOTCH1 activation, we identified several microRNAs downstream of NOTCH1 activation. In particular, we found that NOTCH1 inhibition can induce miR-22-3p in NOTCH1-dependent tumors and that this regulation is also conserved in human samples. Importantly, miR-22-3p overexpression in T-ALL cells can inhibit colony formation in vitro and leukemia progression in vivo. In addition, miR-22-3p was found to be downregulated in T-ALL specimens, both T-ALL cell lines and primary samples, relative to immature T-cells. Our results suggest that miR-22-3p is a functionally relevant microRNA in T-ALL whose modulation can be exploited for therapeutic purposes to inhibit T-ALL progression.

scholarly journals Fratricide-resistant CD1a-specific CAR T cells for the treatment of cortical T-cell acute lymphoblastic leukemia

Blood ◽  
2019 ◽  
Vol 133 (21) ◽  
pp. 2291-2304 ◽  
Author(s):  
Diego Sánchez-Martínez ◽  
Matteo L. Baroni ◽  
Francisco Gutierrez-Agüera ◽  
Heleia Roca-Ho ◽  
Oscar Blanch-Lombarte ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Antileukemic Activity ◽  
Car T Cells ◽  
Car T ◽  
Cell Acute Lymphoblastic Leukemia

Abstract Relapsed/refractory T-cell acute lymphoblastic leukemia (T-ALL) has a dismal outcome, and no effective targeted immunotherapies for T-ALL exist. The extension of chimeric antigen receptor (CAR) T cells (CARTs) to T-ALL remains challenging because the shared expression of target antigens between CARTs and T-ALL blasts leads to CART fratricide. CD1a is exclusively expressed in cortical T-ALL (coT-ALL), a major subset of T-ALL, and retained at relapse. This article reports that the expression of CD1a is mainly restricted to developing cortical thymocytes, and neither CD34+ progenitors nor T cells express CD1a during ontogeny, confining the risk of on-target/off-tumor toxicity. We thus developed and preclinically validated a CD1a-specific CAR with robust and specific cytotoxicity in vitro and antileukemic activity in vivo in xenograft models of coT-ALL, using both cell lines and coT-ALL patient–derived primary blasts. CD1a-CARTs are fratricide resistant, persist long term in vivo (retaining antileukemic activity in re-challenge experiments), and respond to viral antigens. Our data support the therapeutic and safe use of fratricide-resistant CD1a-CARTs for relapsed/refractory coT-ALL.

Inhibition of in vitro spontaneous apoptosis by IL-7 correlates with Bcl-2 up-regulation, cortical/mature immunophenotype, and better early cytoreduction of childhood T-cell acute lymphoblastic leukemia

Blood ◽  
2000 ◽  
Vol 96 (1) ◽  
pp. 297-306 ◽  
Author(s):  
Leonid Karawajew ◽  
Velia Ruppert ◽  
Christian Wuchter ◽  
Annett Kösser ◽  
Martin Schrappe ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Expression Profiles ◽  
Lymphoblastic Leukemia ◽  
Receptor Expression ◽  
Spontaneous Apoptosis ◽  
Expression Levels ◽  
Apoptosis Inhibition ◽  
Cell Acute Lymphoblastic Leukemia

Abstract In normal T-cell development, IL-7 plays a nonredundant role as an antiapoptic factor by regulating Bcl-2 expression in pro-T cells. In the current study, we addressed the roles of IL-7 and related cytokines as apoptosis-modulating factors in precursor T-cell acute lymphoblastic leukemia (T-ALL). To this end, leukemic blasts from pediatric patients with T-ALL were prospectively investigated as to their responsiveness to IL-7, IL-4, and IL-2 (in terms of modulation of spontaneous apoptosis, assessed by flow cytometry), cytokine receptor expression profiles, and expression levels of Bcl-2 and Bax proteins. IL-7, in contrast to IL-4 and IL-2, was highly efficient in apoptosis inhibition , and this effect correlated with the expression levels of IL-7R chain and with the up-regulation of Bcl-2 protein expression (P< .0001). Subclassification of T-ALL samples (n = 130) according to their in vitro IL-7 responses revealed that IL-7 refractory samples were more frequently positive for CD34 (P< .0001) and the myeloid-associated antigen CD33 (P= .01), whereas IL-7 responsiveness was associated with an expression of more mature differentiation-associated T-cell antigens (CD1a, surface CD3, CD4/8; P < .05). Furthermore, the extent of apoptosis inhibition by IL-7 in vitro quantitatively correlated with early cytoreduction as determined by the prednisone peripheral blood response on day 8 and cytoreduction in the marrow on day 15 (n = 87;P < .05). Multivariate analysis of the apoptosis-related parameters investigated, including spontaneous apoptosis, its inhibition by IL-7, and expression levels of Bcl-2 and Bax, showed that only IL-7 responsiveness has an independent impact on early cytoreduction (P < .05), thus indicating a potential prognostic relevance of IL-7 sensitivity in T-ALL.

Efficacy of the CDK inhibitor dinaciclib in vitro and in vivo in T-cell acute lymphoblastic leukemia

2017 ◽  
Vol 405 ◽  
pp. 73-78 ◽  
Author(s):  
Sausan A. Moharram ◽  
Kinjal Shah ◽  
Fatima Khanum ◽  
Alissa Marhäll ◽  
Mohiuddin Gazi ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Cdk Inhibitor ◽  
Cell Acute Lymphoblastic Leukemia

Targeting Oncogenic Interleukein-7 Receptor Signaling With N-Acetylcysteine In T-Cell Acute Lymphoblastic Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2535-2535
Author(s):  
Marc R. Mansour ◽  
Casie Reed ◽  
Amy Eisenberg ◽  
Jen-Chieh Tseng ◽  
Akinori Yoda ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Disulfide Bond ◽  
Transmembrane Domain ◽  
Lymphoblastic Leukemia ◽  
Bond Formation ◽  
Disulfide Bond Formation ◽  
Acetaminophen Overdose ◽  
Cell Acute Lymphoblastic Leukemia

Abstract Activating mutations of the interleukin-7 receptor (IL7R) occur in approximately 10% of patients with T-cell acute lymphoblastic leukemia. Most mutations generate a cysteine at the transmembrane domain leading to receptor homodimerization through disulfide bond formation and ligand-independent activation of STAT5. We hypothesized that the reducing agent N-acetylcysteine (NAC), a well-tolerated drug used widely in clinical practice to treat acetaminophen overdose, would disrupt disulfide bond formation, and inhibit mutant IL7R-mediated oncogenic signaling. To first identify a suitable cell model to study mutant IL7R signaling, we sequenced exon 6 of IL7R in 21 T-ALL cell lines. We identified a 4-amino-acid insertion (p.L242_L243insLSRC) in DND-41 cells which is predicted to form IL7R homodimers through disulfide bond formation with the unpaired cysteine of neighboring mutant IL7Rs. We found that treatment with NAC at clinically achievable concentrations disrupted IL7R homodimerization in IL7R-mutant DND-41 cells in vitro (IC50 approximately 150 micromolar) and led to STAT5 dephosphorylation and cell apoptosis. These effects could be rescued in part by a constitutively active allele of STAT5, indicating the mechanism of NAC is mediated predominantly through disruption of IL7R-STAT5 signaling in these cells. In a murine xenograft model of T-ALL, intraperitoneal NAC treatment led to significant inhibition of tumor progression, indicating NAC has activity in vivo. Previous studies of NAC pharmacokinetics in humans have shown steady state plasma levels range from 200 to 900 micromolar when given on standard treatment regimens for acetaminophen overdose, well within the therapeutic range required to kill DND-41 cells in vitro. Targeting leukemogenic IL7R homodimerization with NAC offers a potentially effective, cheap and feasible therapeutic strategy that warrants testing in clinical trials. Disclosures: Rodig: Daiichi-Sankyo/Arqule Inc., Ventana/Roche Inc., Shape Pharmaceuticals Inc.: Consultancy; Ventana/Roche Inc.: Research Funding.

scholarly journals Efficacy of JAK1/2 and BCL2 inhibition on human T cell acute lymphoblastic leukemia in vitro and in vivo

2019 ◽  
Author(s):  
Kirsti L. Walker ◽  
Sabrina A. Kabakov ◽  
Fen Zhu ◽  
Myriam N. Bouchlaka ◽  
Sydney L Olson ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Combination Treatment ◽  
Lymphoblastic Leukemia ◽  
Jurkat Cells ◽  
Human T Cell ◽  
Liquid Chromatography Tandem Mass ◽  
Cell Acute Lymphoblastic Leukemia

AbstractRelapsed/refractory T cell acute lymphoblastic leukemia (T-ALL) is difficult to salvage especially in heavily pretreated patients, thus novel targeted agents are sorely needed. Hyperactivated JAK/STAT and BCL2 overexpression promote increased T-ALL proliferation and survival, and targeting these pathways with ruxolitinib and venetoclax may provide an alternative approach to achieve clinical remissions. Ruxolitinib and venetoclax show a dose-dependent effect individually, but combination treatment synergistically reduces survival and proliferation of Jurkat and Loucy cells in vitro. Using a xenograft CXCR4+ Jurkat model, the combination treatment fails to improve survival, with death from hind limb paralysis. Despite on-target inhibition by the drugs, histopathology demonstrates increased leukemic infiltration into the central nervous system (CNS), which expresses CXCL12, as compared to liver or bone marrow. Liquid chromatography-tandem mass spectroscopy shows that neither ruxolitinib nor venetoclax can effectively cross the blood-brain barrier, limiting efficacy against CNS T-ALL. Deletion of CXCR4 on Jurkat cells by CRISPR/Cas9 results in prolonged survival and a reduction in overall and neurologic clinical scores. While combination therapy with ruxolitinib and venetoclax shows promise for treating T-ALL, additional inhibition of the CXCR4-CXCL12 axis will be needed to eliminate both systemic and CNS T-ALL burden and maximize the possibility of complete remission.

scholarly journals Integrin signaling is critical for myeloid-mediated support of T-cell acute lymphoblastic leukemia

2022 ◽  
Author(s):  
Aram Lyu ◽  
Seo Hee Nam ◽  
Ryan S Humphrey ◽  
Tyler A Durham ◽  
Zicheng Hu ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Close Contact ◽  
Lymphoblastic Leukemia ◽  
Myeloid Cells ◽  
In Vitro Assays ◽  
Pathway Gene ◽  
Cell Acute Lymphoblastic Leukemia

We previously found that T-cell acute lymphoblastic leukemia (T-ALL) requires support from tumor-associated myeloid cells, which activate IGF1R signaling in the leukemic blasts. However, IGF1 is not sufficient to sustain T-ALL survival in vitro, implicating additional myeloid-mediated signals in T-ALL progression. Here, we find that T-ALL cells require close contact with myeloid cells to survive. Transcriptional profiling and in vitro assays demonstrate that integrin-mediated cell adhesion and activation of the downstream FAK/PYK2 kinases are required for myeloid-mediated support of T-ALL cells and promote IGF1R activation. Consistent with these findings, inhibition of integrins or FAK/PYK2 signaling diminishes leukemia burden in multiple organs and confers a survival advantage in a mouse model of T-ALL. Inhibiting integrin mediated cell adhesion or FAK/PYK2 also diminishes survival of primary patient T-ALL cells co-cultured with myeloid cells. Furthermore, elevated integrin pathway gene signatures correlate significantly with myeloid enrichment and an inferior prognosis in pediatric T-ALL patients.

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