Early Relapse in ALL Is Identified by Time to Leukemia in NOD/SCID Mice and Is Characterized by a Gene Signature Involving Survival Pathways

Meyer, Lüder Hinrich; Eckhoff, Sarah Mirjam; Queudeville, Manon; Kraus, Johann M.; Giordan, Marco; Stursberg, Jana; Zangrando, Andrea; Vendramini, Elena; Möricke, Anja; Zimmermann, Martin; Schrauder, André; Lahr, Georgia; Holzmann, Karlheinz; Schrappe, Martin; Basso, Giuseppe; Stahnke, Karsten; Kestler, Hans A.; Kronnie, Geertruy te; Debatin, Klaus‐Michael

doi:10.1016/j.ccr.2010.11.014

Cited by 79 publications

(99 citation statements)

References 61 publications

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“…Leukemia cell samples obtained at diagnosis from three individual pediatric BCP-ALL patients were expanded using the NOD/SCID/huALL model described above. 36 ALL cells were isolated from ALL-bearing recipients and were cryopreserved. Meanwhile, ALL patients were successfully treated and achieved continuous remission.…”

Section: Treatment Of Bcp-all Cells With Il-4 Cd40l and Cpg Results mentioning

confidence: 99%

Acute lymphoblastic leukemia cells treated with CpG oligodeoxynucleotides, IL-4 and CD40 ligand facilitate enhanced anti-leukemic CTL responses

et al. 2011

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Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. Although the majority of patients initially respond to upfront chemotherapy, relapses with poor prognosis occur in approximately 20% of cases. Thus, novel therapeutic strategies are required to improve long-term survival. B-cell precursor (BCP)-ALL cells express low levels of immunogenic molecules and, therefore, are poorly recognized by the immune system. In the present study, we investigated the effect of various combinations of potent B-cell stimulators including CpG, Interleukin (IL)-2 family cytokines and CD40 ligand (CD40L) on the immunogenicity of primary BCP-ALL cells and a series of BCP-ALL cell lines. The combination of CpG, IL-4 and CD40L was identified as most effective to enhance expression of immunogenic molecules on BCP-ALL cells, resulting in an increased capacity to induce both allogeneic and autologous cytotoxic T lymphocytes (CTL). Importantly, such CTL exhibited significant anti-leukemic cytotoxicity not only towards treated, but also towards untreated BCP-ALL cells. Our results demonstrate that the combination of CpG with other B-cell stimulators is more efficient than CpG alone in generating immunogenic BCP-ALL cells and anti-leukemic CTL. Our results may stimulate the development of novel adoptive T cell transfer approaches for the management of BCP-ALL.

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Section: Treatment Of Bcp-all Cells With Il-4 Cd40l and Cpg Results mentioning

confidence: 99%

Acute lymphoblastic leukemia cells treated with CpG oligodeoxynucleotides, IL-4 and CD40 ligand facilitate enhanced anti-leukemic CTL responses

et al. 2011

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“…[29,135,141,142] Supporting this are recent data demonstrating that early engraftment of pre-B-ALL in immune-deficient mice is associated with the activation of the mTOR pathway and a very high risk of relapse. [143] Experience with chemotherapy for decades, as well as more recent experience with targeted therapies demonstrates that no single agent is likely to be curative. Thus, it is important to study new agents in combination with conventional drugs used to treat ALL.…”

Section: Acute Lymphoblastic Leukemiamentioning

confidence: 99%

Targeting the PI3K/AKT/mTOR Signaling Axis in Children with Hematologic Malignancies

et al. 2012

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The phosphatidylinositiol 3-kinase (PI3K), AKT, mammalian target of rapamycin (mTOR) signaling pathway (PI3K/AKT/mTOR) is frequently dysregulated in disorders of cell growth and survival, including a number of pediatric hematologic malignancies. The pathway can be abnormally activated in childhood acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), and chronic myelogenous leukemia (CML), as well as in some pediatric lymphomas and lymphoproliferative disorders. Most commonly, this abnormal activation occurs as a consequence of constitutive activation of AKT, providing a compelling rationale to target this pathway in many of these conditions. A variety of agents, beginning with the rapamycin analogue (rapalog) sirolimus, have been used successfully to target this pathway in a number of pediatric hematologic malignancies. Rapalogs demonstrate significant preclinical activity against ALL, which has led to a number of clinical trials. Moreover, rapalogs can synergize with a number of conventional cytotoxic agents and overcome pathways of chemotherapeutic resistance for drugs commonly used in ALL treatment, including methotrexate and corticosteroids. Based on preclinical data, rapalogs are also being studied in AML, CML, and non-Hodgkin's lymphoma. Recently, significant progress has been made using rapalogs to treat pre-malignant lymphoproliferative disorders, including the autoimmune lymphoproliferative syndrome (ALPS); complete remissions in children with otherwise therapy-resistant disease have been seen.Rapalogs only block one component of the pathway (mTORC1), and newer agents are under preclinical and clinical development that can target different and often multiple protein kinases in the PI3K/AKT/mTOR pathway. Most of these agents have been tolerated in early-phase clinical trials. A number of PI3K inhibitors are under investigation. Of note, most of these also target other protein kinases. Newer agents are under development that target both mTORC1 and mTORC2, mTORC1 and PI3K, and the triad of PI3K, mTORC1, and mTORC2. Preclinical data suggest these dual-and multi-kinase inhibitors are more potent than rapalogs against many of the aforementioned hematologic malignancies. Two classes of AKT inhibitors are under development, the alkyl-lysophospholipids (APLs) and small molecule AKT inhibitors. Both classes have agents currently in clinical trials. A number of drugs are in development that target other components of the pathway, including eukaryotic translation initiation factor (eIF) 4E (eIF4E) and phosphoinositide-dependent protein kinase 1 (PDK1). Finally, a number of other key signaling pathways interact with PI3K/AKT/mTOR, including Notch, MNK, Syk, MAPK, and aurora kinase. These alternative pathways are being targeted alone and in combination with PI3K/AKT/mTOR inhibitors with promising preclinical results in pediatric hematologic malignancies. This review provides a comprehensive overview of the abnormalities in the PI3K/AKT/mTOR signaling pathway in pediatric hematologic malignanc...

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“…[4][5][6] Primary acute lymphoblastic leukemia (ALL) xenografts in immune-deficient mice accurately represent human disease and gene expression and may have predictive value for clinical variables, such as drug resistance and time to relapse. [7][8][9][10][11] Although this model is a powerful and widely used tool for the ongoing development of new drugs and biologic therapeutics for ALL, [12][13][14][15][16][17][18][19] the kinetics of every primary patient sample are different, some engrafting in 4 weeks and others taking as long as one year, when measured by the appearance of human ALL blasts in peripheral blood. 5,10,20 The endpoints of these studies are typically limited to survival analysis and time to grossly detectable disease.…”

Section: Introductionmentioning

confidence: 99%

Noninvasive bioluminescent imaging of primary patient acute lymphoblastic leukemia: a strategy for preclinical modeling

Barrett

Seif

Carpenito

et al. 2011

Blood

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The efficient engraftment in immunedeficient mice achieved with both acute lymphoblastic leukemia (ALL) cell lines and primary samples has facilitated identification of the antileukemia activity of a wide variety of agents. Despite widespread usage, however, little is known about the early ALL localization and engraftment kinetics in this model, limiting experimental read-outs primarily to survival and endpoint analysis at high disease burden. In this study, we report that bioluminescent imaging can be reproducibly achieved with primary human ALL samples. This approach provides a noninvasive, longitudinal measure of leukemia burden and localization that enhances the sensitivity of treatment response detection and provides greater insight into the mechanism of action of antileukemia agents. In addition, this study reveals significant cell line-and species-related differences in leukemia migration, especially early in expansion, which may confound observations between various leukemia models. Overall, this study demonstrates that the use of bioluminescent primary ALL allows the detection and quantitation of treatment effects at earlier, previously unquantifiable disease burdens and thus provides the means to standardize and expedite the evaluation of anti-ALL activity in preclinical xenograft studies. (Blood. 2011;118(15): e112-e117) IntroductionMurine leukemia models have been useful and versatile tools for identifying and targeting underlying disease mechanisms. 1 However, preclinical studies involving human samples are more immediately applicable when investigating new drugs or therapies. Initial studies with human leukemia in immune-deficient mice, such as the NOD/SCID (NOD.CB17-Prkdc scid /J), were a great step forward and remain valuable for rapid iterations in the study of novel therapies at the preclinical level. 2,3 More recently, use of severely immune-deficient NOD/SCID/␥c Ϫ/Ϫ (NSG; NOD.Cg-Prkdc scid / IL2rg tm1Wjl /SzJ and NOG; NOD.Cg-Prkdc scid /Il2rgt m1Sug /Jic) mice, which lack functional B, T, and NK cells, has allowed for more consistent and reproducible engraftment of normal human cells and primary leukemias. [4][5][6] Primary acute lymphoblastic leukemia (ALL) xenografts in immune-deficient mice accurately represent human disease and gene expression and may have predictive value for clinical variables, such as drug resistance and time to relapse. [7][8][9][10][11] Although this model is a powerful and widely used tool for the ongoing development of new drugs and biologic therapeutics for ALL, [12][13][14][15][16][17][18][19] the kinetics of every primary patient sample are different, some engrafting in 4 weeks and others taking as long as one year, when measured by the appearance of human ALL blasts in peripheral blood. 5,10,20 The endpoints of these studies are typically limited to survival analysis and time to grossly detectable disease. Monitoring the peripheral blood compartment for blasts is the primary method of disease detection, leaving the early engraftment kinetics and localization, t...

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Early Relapse in ALL Is Identified by Time to Leukemia in NOD/SCID Mice and Is Characterized by a Gene Signature Involving Survival Pathways

Cited by 79 publications

References 61 publications

Acute lymphoblastic leukemia cells treated with CpG oligodeoxynucleotides, IL-4 and CD40 ligand facilitate enhanced anti-leukemic CTL responses

Acute lymphoblastic leukemia cells treated with CpG oligodeoxynucleotides, IL-4 and CD40 ligand facilitate enhanced anti-leukemic CTL responses

Targeting the PI3K/AKT/mTOR Signaling Axis in Children with Hematologic Malignancies

Noninvasive bioluminescent imaging of primary patient acute lymphoblastic leukemia: a strategy for preclinical modeling

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