Relapsed/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 dosedependent 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 ontarget 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.
Purpose of reviewTakayasu arteritis is a rare chronic granulomatous large vessel vasculitis that predominantly affects the aorta and its branches. The purpose of this review is to unite the current knowledge regarding the pathophysiology, cause, and epidemiology as well as diagnosis, prognosis, and treatment of this condition in children. Recent findingsAlthough the etiopathogenesis is not fully understood, studies suggest an autoimmune basis for the disease as well as a genetic predisposition. It is a disease primarily affecting young women with up to a third of cases with onset in childhood. There are distinct features of childhood-onset Takayasu arteritis (cTA) that merit this separate review. Diagnostic criteria and clinical manifestations are unique in pediatric patients with renovascular hypertension being the most prevalent presentation. Traditional treatments involving highdose corticosteroids and cytotoxic agents are being reconsidered for less toxic contemporary biologic agents. Current algorithms for treatment include early introduction of corticosteroid-sparing agents, such as methotrexate or mycophenolate as well as tumor necrosis factor-alpha (TNF-a) inhibitor (infliximab, adalimumab) and/or interleukin-6 (IL-6) receptor inhibitor (tocilizumab). SummaryEarly diagnosis of cTA with goals to develop effective and well tolerated treatment paradigms are essential to improve the long-term prognosis of this rare and devastating disease.
Relapsed/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 dosedependent 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 ontarget 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.
T cell Acute Lymphoblastic Leukemia (T-ALL) is an aggressive hematologic malignancy comprising 15% of pediatric and 25% of adult cases of ALL. With current treatment options, T-ALL survival rates have reached 50-60% in adults and 85% in children. Despite great strides in the treatment of this subset of ALL, T-ALL still shows resistance to first-line therapies in over 50% of adults and 25% of children, and relapse is often chemorefractory. Mutations in the Janus Activating Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) pathways and overexpression of the B cell lymphoma-2 (Bcl-2) protein are highly linked to the progression of T-ALL, and to the resistance of a number of available treatments for lymphoid malignancies. JAK/STAT is one of the main cytokine signaling pathways involved in hematopoietic cell growth and development. Indeed, the JAK/STAT pathway is often constitutively activated by T-ALL. The Bcl-2 pathway also plays an important role in cell survival. Overexpression of Bcl-2, an anti-apoptotic member of the Bcl-2 family, promotes cell survival by binding and neutralizing pro-apoptotic members. Inhibition of key proteins in both of these pathways has been greatly explored individually, but little is known about their combined effects on T-ALL. It is hypothesized that T-ALL manipulates both of these pathways as a means of escaping individual inhibition of either JAK/STAT or Bcl-2. Our hypothesis is that inhibiting both the JAK/STAT and Bcl-2 pathways with two small molecule inhibitors; Ruxolitinib (JAK 1/2 inhibitor) and Venetoclax (BH3 mimetic targeting Bcl-2), will inhibit T-ALL growth and survival. Proliferation of T-ALL was assessed by MTT assay and viability was measured by trypan blue and flow cytometry at 24, 48 and 72-hour time points post-treatment. Single-drug dose responses were conducted for both inhibitors. Six doses of both Ruxolitinib and Venetoclax were tested from a range of 0.156uM-5uM for Ruxolitinib and 1.56nM-50nM of Venetoclax. A response was seen for the three highest doses of both inhibitors (1.25uM, 2.5uM, and 5uM for Ruxolitinib and 12.5nM, 25nM, 50nM for Venetoclax). However, a synergistic effect was only achieved when combining 1.25uM Ruxolitinib with 25nM Venetoclax or 2.5uM Ruxolitinib with 12.5nM or 25nM Venetoclax. The combination dose of 1.25uM Ruxolitinib and 25nM Venetoclax demonstrated the greatest combined synergistic effect (CI<1) for all three assays at both 48 hours and 72 hours post-treatment. This optimal in vitro dose of 1.25uM Ruxolitinib and 25nM Venetoclax significantly lowered proliferation and viability of jurkat cells compared to no treatment (P<0.0001), vehicle control (P<0.0001) and the single-drug dose control groups (P<0.0001). Targeting both the JAK/STAT and Bcl-2 pathway with orally available FDA approved small molecule inhibitors could provide a novel alternative treatment for patients who relapse, fail or are resistant to first-line chemotherapeutic regiments. Disclosures No relevant conflicts of interest to declare.
No abstract
Ex vivo expansion of human NK cells with CD137L and IL-15 is being explored both preclinically and clinically as a means of increasing the number and activation of NK cells for a variety of cancers, but results to date have not shown consistent efficacy. JAK1/2 inhibition impairs NK cell maturation, activation and cytotoxicity. However, the absence or mutation of STAT1/3 molecules which are typically phosphorylated by JAK1/2 enhance NK cytotoxicity. We hypothesize that inhibition of the JAK/STAT pathway in CD137L/IL-15 activated NK cells stimulate NK cell activation and increase more potent effectors if combined with a BCL2 inhibitor. NKs were ex vivo expanded with CD137L/IL-15 for 12 days, then exposed to increasing concentrations of Ruxolitinib (0.313 – 10μM) and/or Venetoclax (6.25 – 200nM) for 24 hours before analysis. Ruxolitinib and Venetoclax enriched a CD56dim cytotoxic subset and decreased a CD56 bright cytokine-producing subset in a dose-dependent manner. Ruxolitinib alone increased CD16 and CD69 expression which indicates NK cell activation. Importantly, both drugs did not induce markers associated with senescence (CD57) or exhaustion (PD-1/Tim-3) or decrease NK cell viability. Treatment of two human T cell acute lymphoblastic leukemia (T-ALL) cell lines with 1.25μM Ruxolitinib and 25nM Venetoclax decreased proliferation and increased apoptosis of T-ALL cells in a synergistic manner (CI<1; p<0.001). Usage of Ruxolitinib and Venetoclax has implications on both the biology of ex vivo activated NK cells and T-ALL, and may be a novel pharmacologic combination for improving adoptive cell therapy of leukemia.
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