To prospectively evaluate the effectiveness of risk-adapted preemptive tocilizumab (PT) administration in preventing severe cytokine release syndrome (CRS) after CTL019, a CD19 chimeric antigen ...receptor T-cell therapy.
Children and young adults with CD19-positive relapsed or refractory B-cell acute lymphoblastic leukemia were assigned to high- (≥ 40%) or low- (< 40%) tumor burden cohorts (HTBC or LTBC) based on a bone marrow aspirate or biopsy before infusion. HTBC patients received a single dose of tocilizumab (8-12 mg/kg) after development of high, persistent fevers. LTBC patients received standard CRS management. The primary end point was the frequency of grade 4 CRS (Penn scale), with an observed rate of ≤ 5 of 15 patients in the HTBC pre-defined as clinically meaningful. In post hoc analyses, the HTBC was compared with a historical cohort of high-tumor burden patients from the initial phase I CTL019 trial.
The primary end point was met. Seventy patients were infused with CTL019, 15 in the HTBC and 55 in the LTBC. All HTBC patients received the PT intervention. The incidence of grade 4 CRS was 27% (95% CI, 8 to 55) in the HTBC and 3.6% (95% CI, 0.4 to 13) in the LTBC. The best overall response rate was 87% in the HTBC and 100% in the LTBC. Initial CTL019 expansion was greater in the HTBC than the LTBC (
< .001), but persistence was not different (
= .73). Event-free and overall survival were worse in the HTBC (
= .004,
< .001, respectively). In the post hoc analysis, grade 4 CRS was observed in 27% versus 50% of patients in the PT and prior phase I cohorts, respectively (
= .18).
Risk-adapted PT administration resulted in a decrease in the expected incidence of grade 4 CRS, meeting the study end point, without adversely impacting the antitumor efficacy or safety of CTL019.
CNS relapse of acute lymphocytic leukaemia is difficult to treat. Durable remissions of relapsed or refractory B-cell acute lymphocytic leukaemia have been observed following treatment with ...CD19-directed chimeric antigen receptor (CAR) T cells; however, most trials have excluded patients with active CNS disease. We aimed to assess the safety and activity of CAR T-cell therapy in patients with a history of CNS relapsed or refractory B-cell acute lymphocytic leukaemia.
In this post-hoc analysis, we included 195 patients (aged 1-29 years; 110 56% male and 85 44% female) with relapsed or refractory CD19-positive acute lymphocytic leukaemia or lymphocytic lymphoma from five clinical trials (Pedi CART19, 13BT022, ENSIGN, ELIANA, and 16CT022) done at the Children's Hospital of Philadelphia (Philadelphia, PA, USA), in which participants received CD19-directed CAR T-cell therapy between April 17, 2012, and April 16, 2019. The trials required control of CNS disease at enrolment and infusion and excluded treatment in the setting of acute neurological toxic effects (>grade 1 in severity) or parenchymal lesions deemed to increase the risk of neurotoxicity. 154 patients from Pedi CART19, ELIANA, ENSIGN, and 16CT022 received tisagenlecleucel and 41 patients from the 13BT022 trial received the humanised CD19-directed CAR, huCART19. We categorised patients into two strata on the basis of CNS status at relapse or within the 12 months preceding CAR T-cell infusion-either CNS-positive or CNS-negative disease. Patients with CNS-positive disease were further divided on the basis of morphological bone marrow involvement-either combined bone marrow and CNS involvement, or isolated CNS involvement. Endpoints were the proportion of patients with complete response at 28 days after infusion, Kaplan-Meier analysis of relapse-free survival and overall survival, and the incidence of cytokine release syndrome and neurotoxicity.
Of all 195 patients, 66 (34%) were categorised as having CNS-positive disease and 129 (66%) as having CNS-negative disease, and 43 (22%) were categorised as having isolated CNS involvement. The median length of follow-up was 39 months (IQR 25-49) in the CNS-positive stratum and 36 months (18-49) in the CNS-negative stratum. The proportion of patients in the CNS-positive stratum with a complete response at 28 days after infusion was similar to that in the CNS-negative stratum (64 97% of 66 vs 121 94% of 129; p=0·74), with no significant difference in relapse-free survival (60% 95% CI 49-74 vs 60% 51-71; p=0·50) or overall survival (83% 75-93 vs 71% 64-79; p=0·39) at 2 years between the two groups. Overall survival at 2 years was significantly higher in patients with isolated CNS involvement compared with those with bone marrow involvement (91% 82-100 vs 71% 64-78; p=0·046). The incidence and severity of neurotoxicity (any grade, 53 41% vs 38 58%; grade 1, 24 19% vs 20 30%; grade 2, 14 11% vs 10 15%; grade 3, 12 9% vs 6 9%, and grade 4, 3 2% vs 2 3%; p=0·20) and cytokine release syndrome (any grade, 110 85% vs 53 80%; grade 1, 12 9% vs 2 3%; grade 2, 61 47% vs 38 58%; grade 3, 18 14% vs 7 11% and grade 4, 19 15% vs 6 9%; p=0·26) did not differ between the CNS-negative and the CNS-positive disease strata.
Tisagenlecleucel and huCART19 are active at clearing CNS disease and maintaining durable remissions in children and young adults with CNS relapsed or refractory B-cell acute lymphocytic leukaemia or lymphocytic lymphoma, without increasing the risk of severe neurotoxicity; although care should be taken in the timing of therapy and disease control to mitigate this risk. These preliminary findings support the use of these CAR T-cell therapies for patients with CNS relapsed or refractory B-cell acute lymphocytic leukaemia.
Children's Hospital of Philadelphia Frontier Program.
We identified Bub1b as an essential element for the growth and survival of rhabdomyosarcoma (RMS) cells using a bar-coded, tetracycline-inducible short hairpin RNA (shRNA) library screen. Knockdown ...of Bub1b resulted in suppression of tumor growth in vivo, including the regression of established tumors. The mechanism by which this occurs is via postmitotic endoreduplication checkpoint and mitotic catastrophe. Furthermore, using a chromatin immunoprecipitation assay, we found that Bub1b is a direct transcriptional target of Forkhead Box M1 (FoxM1). Suppression of FoxM1 either by shRNA or the inhibitor siomycin A resulted in reduction of Bub1b expression and inhibition of cell growth and survival. These results show the important role of the Bub1b/FoxM1 pathway in RMS and provide potential therapeutic targets.
Roots and shoots of plant bodies develop from meristems—cell populations that self-renew and produce cells that undergo differentiation—located at the apices of axes 1.The oldest preserved root ...apices in which cellular anatomy can be imaged are found in nodules of permineralized fossil soils called coal balls 2, which formed in the Carboniferous coal swamp forests over 300 million years ago 3–9. However, no fossil root apices described to date were actively growing at the time of preservation 3–10. Because the cellular organization of meristems changes when root growth stops, it has been impossible to compare cellular dynamics as stem cells transition to differentiated cells in extinct and extant taxa 11. We predicted that meristems of actively growing roots would be preserved in coal balls. Here we report the discovery of the first fossilized remains of an actively growing root meristem from permineralized Carboniferous soil with detail of the stem cells and differentiating cells preserved. The cellular organization of the meristem is unique. The position of the Körper-Kappe boundary, discrete root cap, and presence of many anticlinal cell divisions within a broad promeristem distinguish it from all other known root meristems. This discovery is important because it demonstrates that the same general cellular dynamics are conserved between the oldest extinct and extant root meristems. However, its unique cellular organization demonstrates that extant root meristem organization and development represents only a subset of the diversity that has existed since roots first evolved.
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•The oldest fossilized root meristem is described from >300-million-year-old soil•The discovery allows the first description of a fossilized root stem cell niche•The cellular organization and therefore development of the meristem is unique•The discovery reveals previously unknown diversity in plant meristem types
Hetherington et al. report the discovery of the oldest fossilized remains of an actively growing root meristem from Carboniferous (>300-million-year-old) soil. The cellular organization of stem cells and differentiating cells is unique. This discovery reveals new but now extinct meristem diversity in Carboniferous plants.
The autoinflammatory disorder, Neonatal-onset Multisystem Inflammatory Disease (NOMID) is the most severe phenotype of disorders caused by mutations in CIAS1 that result in increased production and ...secretion of active IL-1β. NOMID patients present with systemic and organ-specific inflammation of the skin, central nervous system and bone, and respond dramatically to treatment with IL-1 blocking agents. We compared the cellular infiltrates and transcriptome of skin biopsies from patients with NOMID (n = 14) before treatment (lesional (LS) and non-lesional (pre-NL) skin) and after treatment (post-NL) with the IL-1 blocker anakinra (recombinant IL-1 receptor antagonist, Kineret®, Swedish Orphan Biovitrum AB, SOBI), to normal skin (n = 5) to assess tissue responses in the context of untreated and treated disease. Abundant neutrophils distinguish LS skin from pre-NL and post-NL skin. CD11c(+) dermal dendritic cells and CD163(+) macrophages expressed activated caspase-1 and are a likely source of cutaneous IL-1 production. Treatment with anakinra led to the disappearance of neutrophils, but CD3(+) T cells and HLA-DR(+) cells remained elevated. Among the upregulated genes IL-6, IL-8, TNF, IL-17A, CCL20, and the neutrophil defensins DEFA1 and DEFA3 were differentially regulated in LS tissues (compared to normal skin). Important significantly downregulated pathways in LS skin included IL-1R/TLR signaling, type I and II cytokine receptor signaling, mitochondrial dysfunction, and antigen presentation. The differential expression and regulation of microRNAs and pathways involved in post-transcriptional modification were suggestive of epigenetic modification in the chronically inflamed tissue. Overall, the dysregulated genes and pathways suggest extensive "adaptive" mechanisms to control inflammation and maintain tissue homeostasis, likely triggered by chronic IL-1 release in the skin of patients with NOMID.
In this report, we describe a novel T437N STAT1 mutation found in a mother and 3 of her 4 children which we demonstrate yields gain-of-function. All of the four patients with the T437N STAT1 mutation ...experienced lymphadenopathy. However, two of the children developed Nodular Lymphocyte Predominant Hodgkin Lymphoma (NHLPL) and have responded to chemotherapeutic regimens. The fourth sibling had neither the STAT1 variant nor lymphadenopathy or malignancy. To our knowledge this is the first description of a potential association between STAT1 GOF mutations and lymphoma development.
Leakage at an anastomosis is a major and often catastrophic complication of gastrointestinal (GI) surgery. Staple-line reinforcement with one of the several materials commercially available has been ...utilized to reduce the incidence of this complication. The bioprosthetic material, small intestinal submucosa (SIS, Surgisis((R)); Cook, Inc., Bloomington, IN) has found widespread applications in surgery. However, its ability to improve the durability of staple-lines in GI surgery in terms of burst pressure has not been documented. We hypothesized that SIS reinforcement of staple-lines in healthy living GI tissue would increase durability, as determined by leak rates at increased intraluminal pressures, compared to unreinforced staple-lines.
Two healthy Yorkshire-Cross pigs were subjected to midline laparotomy and underwent small intestinal division (n=28) with GIA stapling devices. Half of the staple-lines were reinforced with SIS. The staple-lines were then exposed to increased intraluminal pressures by means of a constant-rate dye solution infusion, until staple-lines exhibited visible leakage of the dye solution. The intraluminal pressure was recorded at the time of visible leakage.
Staple-lines reinforced with SIS had significantly better durability as determined by analysis of variance and Kaplan-Meier survival calculations, with respect to leak rate as a function of intraluminal pressure (P<0.003). The mean burst pressure of the unreinforced staple-lines was 53 mmHg, while those staple-lines reinforced with SIS had a mean burst pressure of 83 mmHg.
Reinforcement of stapled GI anastomoses with SIS significantly increases anastomotic burst pressure. These findings suggest a role for this material in GI surgery.
The response of the Antarctic ice sheets to future warming is uncertain. The IPCC are predicting minimal melt from Antarctica while others suggest increased meltwater contributions are possible. The ...Pliocene period (5.333 Ma to 2.58 Ma) may provide insights into future ice sheet response, because atmospheric CO2 concentrations were similar to today (350-450 ppmv) and the earth surface was between 2°C and 4°C warmer than the preindustrial conditions. Geological records indicate that Antarctica's ice sheets were smaller and more dynamic at this time and many sea-level estimates require meltwater input from the Greenland, West (WAIS) and East Antarctic Ice sheets (EAIS). However, only a few records exist proximal to the Antarctic ice sheet which allow for reconstruction of the Pliocene climate state. We present a multiproxy climate reconstruction from a sedimentary succession that was deposited in an ancient fjord within the Transantarctic Mountains, covering discrete intervals between the early Pliocene and the late Pleistocene. In contrast to modern frigid conditions, our records indicate sea surface temperatures of about 5.6°C at c. 4.1 Ma, the presence of a plant community at the fjord margins and evidence of soil formation. Simulations of potential vegetation cover in the Pliocene indicate our reconstruction is most compatible with a complete collapse of the WAIS and a large scale retreat of the EAIS from the subglacial basins with atmospheric CO2 levels of less than 450 ppmv. Our study indicates that under present day atmospheric CO2 conditions, in the early Pliocene, the Antarctic ice sheets retreated significantly. Understanding the mechanisms driving this large-scale ice sheet retreat would enable us to assess whether current atmospheric CO2 concentrations will lead to the same ice sheet configuration once the Earth system has come to a new equilibrium state.
•DVDP-11 is a record of Pliocene to modern transition of an ancient Antarctic fjord.•Biomarkers indicate warm surface waters (5.6°C) and a terrestrial plant community on land.•Numerical models indicate a collapse of the WAIS, a large EAIS draw down, and collapse of Taylor Dome.
Though 85% of children and young adults with acute lymphoblastic leukemia (ALL) are cured, until recently, the prognosis of relapsed or refractory disease has been dismal. The advent of chimeric ...antigen receptor (CAR) T-cell therapy has transformed the treatment of relapsed/refractory ALL. The most well-studied, successful CARs are autologous, murine-based anti-CD19 CARs, but new constructs are currently under clinical investigation.
This review describes the history and design of CAR T cells, clinical trial outcomes of anti-CD19 and newer CARs, treatment-related toxicities including cytokine release syndrome and neurotoxicity, and issues with resistance and relapse. A search of PubMed and clinicaltrials.gov spanning from 2012-present was used to select original reports investigating the use of CAR T in pediatric patients.
CD19-targeted CARs have demonstrated remarkable response rates and produced durable remissions in very high-risk pediatric patient populations. The therapies, however, are limited by unique treatment-related toxicities and considerable rates of antigen-positive and antigen-negative relapses. Current research efforts focused on elucidating mechanisms of resistance/relapse and on developing strategies to prevent and treat relapse are critical to optimizing the use of CAR-T. In addition, ongoing trials testing CARs earlier in therapy and for new indications are key to informing their widespread usage.
Objective
Blocking interleukin‐1 with anakinra in patients with the autoinflammatory syndrome neonatal‐onset multisystem inflammatory disease (NOMID) reduces systemic and organ‐specific inflammation. ...However, the impact of long‐term treatment has not been established. This study was undertaken to evaluate the long‐term effect of anakinra on clinical and laboratory outcomes and safety in patients with NOMID.
Methods
We conducted a cohort study of 26 NOMID patients ages 0.80–42.17 years who were followed up at the NIH and treated with anakinra 1–5 mg/kg/day for at least 36 months. Disease activity was assessed using daily diaries, questionnaires, and C‐reactive protein level. Central nervous system (CNS) inflammation, hearing, vision, and safety were evaluated.
Results
Sustained improvements in diary scores, parent's/patient's and physician's global scores of disease activity, parent's/patient's pain scores, and inflammatory markers were observed (all P < 0.001 at 36 and 60 months). At 36 and 60 months, CNS inflammation was suppressed, with decreased cerebrospinal fluid white blood cell counts (P = 0.0026 and P = 0.0076, respectively), albumin levels, and opening pressures (P = 0.0012 and P < 0.001, respectively). Most patients showed stable or improved hearing. Cochlear enhancement on magnetic resonance imaging correlated with continued hearing loss. Visual acuity and peripheral vision were stable. Low optic nerve size correlated with poor visual field. Bony lesions progressed. Adverse events other than viral infections were rare, and all patients continued to receive the medication.
Conclusion
These findings indicate that anakinra provides sustained efficacy in the treatment of NOMID for up to 5 years, with the requirement of dose escalation. Damage progression in the CNS, ear, and eye, but not bone, is preventable. Anakinra is well tolerated overall.
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