Expansion Point Research Articles

A Novel Method for Molecular Enumeration of Circulating Tisa-Cel and Axi-Cel in Lymphoma Patients

Background: Chimeric antigen receptor (CAR) T-cell therapy is an effective treatment in approximately 40% of relapsed/refractory lymphomas. High rates of complete remission (CR) observed in clinical trials, led to fast-track FDA and EMA approval and commercialization of two CD19-directed CAR T-cell products (tisagenlecleucel/Tisa-cel/Kymriah and axicabtagene ciloleucel/Axi-cel/Yescarta) for refractory/relapsed diffuse large B cell lymphoma (DLBCL) and primary mediastinal large B cell lymphoma (PMBCL). In these studies, CAR T-cell engraftment and in vivo expansion have a crucial impact on disease response and toxicity. It is of paramount importance to develop homogeneous standardized approaches for monitoring expansion and persistence of CAR T-cells also in the case of cells not detectable by flow cytometry (FCM) as these data can guide clinical decision making. Aims of this study were: to assess relevant time-points for FCM analysis across the different products to develop a unique quantitative PCR assay to detect both tisa-cel and axi-cel. Methods: We prospectively collected samples from 28 patients (pts) (16 DLBCL, 5 transformed follicular lymphoma and 7 PMBCL) treated with axi-cel (n=15) and tisa-cel (n=13) at the Fondazione IRCCS Istituto Nazionale Tumori between Nov 2019 and July 2020. CAR T-cells were monitored in the peripheral blood (PB) on days 0, 4, 7, 9, 14, 21, 28 and monthly post infusion by FCM. Cells were stained with CD19 CAR Detection Reagent (Miltenyi), Anti-Biotin-PE, CD3-FITC, CD4-VioGreen, CD8-APC-Vio770, CD45-VioBlue, CD14-APC and 7-AAD Staining Solution and analyzed by FCM using the MACSQuant® Analyzer (Miltenyi). To evaluate CAR T-cell persistence, we also generated a unique droplet digital PCR (ddPCR) primer-probe assay to target both tisagen-cel and axi-cel. We obtained a partial cDNA sequence of the two CAR constructs by amplification and direct sequencing of fragments generated with primers designed by educated guess to bind to the anti-CD19 murine single-chain variable fragment (scFV) and to the CD8α or CD28 trans-membrane regions of tisagen-cel and axi-cel vectors respectively. The assay was used to quantify CAR+ cells on genomic DNA extracted from PB cells collected serially after infusion. FCM and molecular data were correlated to outcome. Results: Peak expansion of CAR T-cells by FCM occurred within the first 14 days post-infusion. At the point of maximal expansion, collectively a mean of 17% of circulating CD3+ T cells were CAR+ and CAR+ cells were more abundant among CD3+ cells in pts receiving axi-cel (26% vs 8.5% for tisagen-cel, p<0.05). Patients achieving CR at 1 month from CAR T-cell therapy (n=10) had significantly more CAR+ cells at day 9 than non-CR pts (mean 146 vs 18 CAR+ cells/ul, p<0.05) and their magnitude of expansion in the first 14 days was higher than the one of non-CR pts (mean area under the curve (AUC)= 1110 vs 177; p<0.05). A cut-off value of CAR+ cells at day 9>62/ul was prognostic with sensitivity of 67% and specificity of 76% (Receiver operating characteristic analysis). At subsequent time points the number of CAR T-cells decreased, but continued to be detectable by FCM up to 6 months post infusion although at very low levels (mean 2 CAR+ cell/ul) irrespective of outcome. To evaluate whether these low counts reliably represent CAR T+ cells or are rather signals due to aspecific binding of the antibodies, a ddPCR assay was set up. The assay displayed an excellent separation between positive and negative droplets on both axi-cel and tisagen-cel products, good reproducibility and specificity with max standard deviation of 0.06 and no CAR positive signal in healthy donors. Additionally, the CAR specific signal was detectable up to the 0,01% dilution. FCM and ddPCR data had a good correlation (r=0.93, p<0.001): in accordance with FCM, ddPCR revealed a peak expansion of CAR+ signals at day 9 post infusion, followed by a progressive reduction of the CAR+ signal over time in all pts that becomes undetectable in case of relapse despite the presence of 1-2 cells/ul by FCM that probably represent aspecific findings. Conclusion: The combined use of FCM and the novel molecular assay facilitates the precise enumeration of commercial anti-CD19 CAR T-cells. Higher frequencies of CAR+ T cells at day 9 distinguish responders irrespectively of the product they received in our small prospective series. Updated results will be presented. Disclosures Chiappella: Servier: Honoraria; Roche: Honoraria; Takeda: Honoraria; Iqone: Honoraria; Janssen: Honoraria; Gilead-Kite: Honoraria; Celgene: Honoraria. Corradini:Kite: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Incyte: Consultancy; BMS: Other; Takeda: Consultancy, Honoraria, Other; Servier: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; F. Hoffman-La Roche Ltd: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Travel and accommodations paid by for; KiowaKirin: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Travel and accommodations paid by for; AbbVie: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Gilead: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Daiichi Sankyo: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: Travel and accommodations paid by for.

A Broadband Enhanced Structure-Preserving Reduced-Order Interconnect Macromodeling Method for Large-Scale Equation Sets of Transient Interconnect Circuit Problems

In the transient analysis of an engineering power electronics device, the order of its equivalent circuit model is excessive large. To eliminate this issue, some model order reduction (MOR) methods are proposed in the literature. Compared to other MOR methods, the structure-preserving reduced-order interconnect macromodeling (SPRIM) based on Krylov subspaces will achieve a higher reduction radio and precision for large multi-port Resistor-Capacitor-Inductor (RCL) circuits. However, for very wide band frequency transients, the performance of a Krylov subspace-based MOR method is not satisfactory. Moreover, the selection of the expansion point in this method has not been comprehensively studied in the literature. From this point of view, a broadband enhanced structure-preserving reduced-order interconnect macromodeling (SPRIM) method is proposed to reduce the order of equation sets of a transient interconnect circuit model. In addition, a method is introduced to determine the optimal expansion point at each frequency in the proposed method. The proposed method is validated by the numerical results on a transient problem of an insulated-gate bipolar transistor (IGBT)-based inverter busbar under different exciting conditions.

The common and intrinsic skin electric-double-layer (EDL) and its bonding characteristics of nanostructures

We show that nanocrystals share a common and intrinsic skin electric-double-layer (EDL). The EDL is determined to be 2.14 regular-bond-length thick using differential phonon spectroscopy that distills phonon abundance transiting from the core region to the EDL of the sized crystals. Theoretical reproduction of the size-resolved Raman shift for Si, CeO2, and SnO2 nanocrystals, elasticity of ZnO, and the XPS 2p energy shift, band gap expansion and melting point shift of Si crystals confirmed the universality of the EDL of which bonds are shorter and stronger than those inside the bulk or the particle core interior. The EDL bond contraction and the associated electron entrapment and polarization originate, and the EDL volume quantifies the size dependency of nanostructures while the electron entrapment or polarization entitles the undercoordinated single or edge atoms with properties that a bulk does never show.

Influence of bismuth (Bi) addition on the structure and properties of annealed Sn-9Zn eutectic binary solder alloy

ABSTRACT The Sn-9Zn eutectic alloy has been considered as a potential replacement for toxic lead-based solders for its lower melting point (198 °C) and improved mechanical properties compared to traditional lead-based solder alloys. This paper investigates the influence of bismuth (Bi) addition as a surface-active element on the structural, thermal, mechanical, and electrical properties of eutectic Sn–9Zn alloy. Different amounts of Bi were added (x = 0.5, 1, 2, 3, wt %) to study the characteristics of Sn-9Zn-xBi ternary alloys followed by annealing at 150 °C for 60 minutes. Microstructures and phase constituents of developed alloys were examined and compared using optical microscopy and XRD respectively. The melting point and coefficient of linear thermal expansion were determined by differential thermal analysis and thermo-mechanical analysis. Tensile Properties (ultimate tensile strength, elongation, %), microhardness (HV), and electrical conductivity (% IACS) were measured. The results indicated that the addition of Bi decreased the melting point by about 10 °C, the heat of fusion, coefficient of thermal expansion, electrical conductivity than Sn-9Zn eutectic alloy. Bi addition enhanced the ultimate tensile strength and hardness by about 65% by 50% respectively. SnBi inter-metallic compound (IMC) precipitates were formed and extracted from the β-Sn matrix with a non-uniform microstructure.

On the Discrete Version of the Schwarzschild Problem

We consider a Schwarzschild type solution in the discrete Regge calculus formulation of general relativity quantized within the path integral approach. Earlier, we found a mechanism of a loose fixation of the background scale of Regge lengths. This elementary length scale is defined by the Planck scale and some free parameter of such a quantum extension of the theory. Besides, Regge action was reduced to an expansion over metric variations between the tetrahedra and, in the main approximation, is a finite-difference form of the Hilbert–Einstein action. Using for the Schwarzschild problem a priori general non-spherically symmetrical ansatz, we get finite-difference equations for its discrete version. This defines a solution which at large distances is close to the continuum Schwarzschild geometry, and the metric and effective curvature at the center are cut off at the elementary length scale. Slow rotation can also be taken into account (Lense–Thirring-like metric). Thus, we get a general approach to the classical background in the quantum framework in zero order: it is an optimal starting point for the perturbative expansion of the theory, finite-difference equations are classical, and the elementary length scale has quantum origin. Singularities, if any, are resolved.

Model order reduction for delay systems by iterative interpolation

AbstractAdaptive algorithms for computing the reduced‐order model of time‐delay systems (TDSs) are proposed in this work. The algorithms are based on interpolating the transfer function at multiple expansion points and greedy iterations for selecting the expansion points. The ‐error of the reduced transfer function is used as the criterion for choosing the next new expansion point. One heuristic greedy algorithm and one algorithm based on the error system and adaptive sub‐interval selection are developed. Results on four TDSs with tens of delays from electromagnetic applications are presented and show the efficiency of the proposed algorithms.

Aluminum borophosphate glaze-coated aluminum alloy substrate: Coating properties and coating/substrate coupling

Thermal fatigue can cause irreversible damage in aluminum alloys restricting their use in the automotive industry, despite their excellent mechanical and technological properties. The application of ceramic coating is an alternative to obtain a protective barrier to improve the wear resistance at high temperatures. However, the low melting point and high coefficient of thermal expansion (CTE) of aluminum alloys limit the coating options. Thus, a suitable coupling feature can be obtained between aluminum alloys and a glazed coating. A glazed coating based on the aluminum borophosphate system was developed and applied onto an aluminum-silicon-copper commercial alloy. The coating was characterized by X-ray diffractometry, scanning electron microscopy, hardness tests, and thermal analysis. The coupling between the glazed coating and the aluminum alloy surface was studied employing optical dilatometry and optical fleximetry. A dense, good adhesion coating and presenting adequate dilatometric coupling (effective coupling temperature of 345 °C) related to the investigated aluminum alloy was obtained at 500 °C. The good compatibility of CTE between the layers (24.54 × 10−6 °C-1 for the substrate and 14.56 × 10−6 °C-1 for the coating) led to a crack-free material. For this reason, microhardness increased from 136 (aluminum alloy) to 325 HV (glazed aluminum alloy). The glazed coating can expand the use of this alloy, improving its performance and thermal efficiency. This result suggests an enormous potential of applications in the automotive industry, for instance.

Two-dimensional extreme distribution for estimating mechanism reliability under large variance

The effective estimation of the operational reliability of mechanism is a significant challenge in engineering practices, especially when the variance of uncertain factors becomes large. Addressing this challenge, a novel mechanism reliability method via a two-dimensional extreme distribution is investigated in the paper. The time-variant reliability problem for the mechanism is first transformed to the time-invariant system reliability problem by constructing the two-dimensional extreme distribution. The joint probability density functions (JPDFs), including random expansion points and extreme motion errors, are then obtained by combining the kernel density estimation (KDE) method and the copula function. Finally, a multidimensional integration is performed to calculate the system time-invariant reliability. Two cases are investigated to demonstrate the effectiveness of the presented method.

Oxidative stability of direct-expanded chickpea-sorghum snacks.

In contrast to other pulses, chickpea has a relatively high fat content (3%–10%). This study was designed to investigate direct‐expanded chickpea–sorghum extruded snacks (50:50, 60:40, and 70:30 chickpea:sorghum, w/w) with respect to: their oxidative stability and sensory properties during accelerated (55°C) and room temperature (25°C) storage; correlations between chemical markers (peroxide value and p‐anisidine value) and sensory data during accelerated storage; and the shelf‐life of snacks extruded at the optimal expansion point as determined by a rotatable central composite design. Peroxide values and p‐anisidine values were in the range of 0–2.5 mEq/Kg and 5–30, respectively, for both accelerated and room temperature storage, and increased during storage (p < .05). 70:30 and 60:40 (w/w) chickpea–sorghum snacks had higher peroxide and p‐anisidine values compared to the 50:50 snack during storage at either temperature (p < .05). Rancid aroma and off‐flavor of 60:40 and 70:30 chickpea–sorghum snacks (slightly intense = 6) also were higher than that of the 50:50 snack (moderately weak = 3) (p < .05). Significant correlations (p < .05) were found between chemical markers and sensory attributes (p < .05). The study illustrated that shelf‐life decreased as the percentage of chickpea in the blend increased. Therefore, in terms of shelf‐life, a 50:50 chickpea–sorghum blend is preferable.

Medium-induced cascade in expanding media

Detailed insight into the interplay between parton energy loss and the way deconfined medium created in heavy-ion collisions expands is of great importance for improving the understanding of the jet quenching phenomenon. In this paper we study the impact of the expansion of deconfined medium on the single-gluon emission spectrum, its resummation and the jet suppression factor (QAA) within the BDMPS-Z formalism. We calculate these quantities for three types of expansion scenarios, namely static, exponentially decaying and Bjorken expanding media. The distribution of medium-induced gluons is calculated using an evolution equation with splitting kernels derived from the gluon emission spectra. A universal behavior of splitting kernels is derived in the regime of soft gluon emissions when evaluated at a common effective evolution time τeff. Novel scaling features of the resulting gluon distribution and jet QAA are discussed. For realistic spectra valid beyond the soft-gluon emission limit, where the results are obtained by a numerical solution of the evolution equation, these features are partially replaced by a scaling expected from considering an averaged jet quenching parameter along the trajectory of propagation. Further we show that differences arising from different types of the medium expansion can be to a large extent scaled out by appropriate choice of the quenching parameter. Sizable differences among the values of the quenching parameter for different types of medium expansion point to the importance of the medium expansion for precise modeling of the jet quenching phenomenon.

Beyond the electric-dipole approximation in simulations of x-ray absorption spectroscopy: Lessons from relativistic theory

We present three schemes to go beyond the electric-dipole approximation in x-ray absorption spectroscopy calculations within a four-component relativistic framework. The first is based on the full semi-classical light-matter interaction operator and the two others on a truncated interaction within the Coulomb gauge (velocity representation) and multipolar gauge (length representation). We generalize the derivation of the multipolar gauge to an arbitrary expansion point and show that the potentials corresponding to different expansion points are related by a gauge transformation, provided that the expansion is not truncated. This suggests that the observed gauge-origin dependence in the multipolar gauge is more than just a finite-basis set effect. The simplicity of the relativistic formalism enables arbitrary-order implementations of the truncated interactions, with and without rotational averaging, allowing us to test their convergence behavior numerically by comparison to the full formulation. We confirm the observation that the oscillator strength of the electric-dipole allowed ligand K-edge transition of TiCl4, when calculated to the second order in the wave vector, becomes negative but also show that inclusion of higher-order contributions allows convergence to the result obtained using the full light-matter interaction. However, at higher energies, the slow convergence of such expansions becomes dramatic and renders such approaches at best impractical. When going beyond the electric-dipole approximation, we therefore recommend the use of the full light-matter interaction.

A meshfree collocation method based on moving Taylor polynomial approximation for high order partial differential equations

This paper presents a meshfree collocation method for solving high order partial differential equations (PDEs). The leading numerical difficulty is the approximation of high order derivatives. To make the approximation simple and efficient, a moving Taylor polynomial (MTP) approximation is presented by using movable expansion point for each sub-domain. Derivatives can be derived straightforward from the corresponding Taylor coefficients, which are determined by solving a weighted least squares problem. A distinct feature of the method is its ability to give the derivatives along with the shape function itself without further cost. To ensure the accuracy of high order approximation, stability of the weighted least squares problems for determining the Taylor coefficients is another issue should be addressed. For this purpose, the basis functions are rescaled by the size of window functions, and QR decomposition is adopted to solve the weighted least squares problems. The collocation method based on this MTP approximation does not require any grid or background cell, so it is a truly meshfree method. When solving the linear algebraic system generated by the MTP collocation method, a preconditioned sparse biconjugate gradients stabilized (BICGSTAB) solver is used to accelerate the computation speed. Numerical tests show that the proposed method is much accurate and efficient for high order PDEs.

The novel Leal-polynomials for the multi-expansive approximation of nonlinear differential equations

This work presents the novel Leal-polynomials (LP) for the approximation of nonlinear differential equations of different kind. The main characteristic of LPs is that they satisfy multiple expansion points and its derivatives as a mechanism to replicate behaviour of the nonlinear problem, giving more accuracy within the region of interest. Therefore, the main contribution of this work is that LP satisfies the successive derivatives in some specific points, resulting more accurate polynomials than Taylor expansion does for the same degree of their respective polynomials. Such characteristic makes of LPs a handy and powerful tool to approximate different kind of differential equations including: singular problems, initial condition and boundary-valued problems, equations with discontinuities, coupled differential equations, high-order equations, among others. Additionally, we show how the process to obtain the polynomials is straightforward and simple to implement; generating a compact, and easy to compute, expression. Even more, we present the process to approximate Gelfand's equation, an equation of an isothermal reaction, a model for chronic myelogenous leukemia, Thomas-Fermi equation, and a high order nonlinear differential equations with discontinuities getting, as result, accurate, fast and compact approximate solutions. In addition, we present the computational convergence and error studies for LPs resulting convergent polynomials and error tendency to zero as the order of LPs increases for all study cases. Finally, a study of CPU time shows that LPs require a few nano-seconds to be evaluated, which makes them suitable for intensive computing applications.

Flow boiling CHF experiment with sudden expansion tubes

Abstract Deformed cladding in nuclear power plants can partially block the path of coolant flow and thus alter the heat transfer characteristics between the cladding surface and coolant. In this research, critical heat flux(CHF) in a sudden expansion flow path, was experimentally investigated. Flow boiling CHF experiments were carried out under atmospheric pressure with deionized water for vertical upward flow, with four expansion ratio cases investigated with mass flux ranging from 50 to 250 kg/m2 s. CHF was detected at two different locations. In experiments with either a low expansion ratio(e 1.5) and high mass flux(> 150 kg/m2 s), CHF was detected at the sudden expansion point. Quality at the sudden expansion point was almost zero, which implies that nucleated bubbles under the effect of sudden expansion flow induced CHF at the sudden expansion point. The reason for this transition of CHF location was suggested that local bubble stagnation induced by a balance between drag and buoyancy forces on the bubbles resulted in local flooding in the downward flow.

Dynamics of the scalar shell in higher dimensions

This paper investigates the dynamical evolution of thin-shell developed from a class of d-dimensional black holes. The components of stress–energy tensor of surface matter at thin-shell are evaluated through the Lanczos equations. The corresponding equations of motion and effective potential describe the expansion, collapse and saddle points. It is found that expanding and collapsing characteristics of the shell are enhanced for higher-dimensional spacetimes. We also investigate the dynamics of thin-shell in the presence of massless and massive scalar fields. The evolutionary behavior of massless scalar shell is greatly affected by the black hole parameters. The massive scalar field indicates the oscillation of thin-shell for d=5 with specific values of the parameters. This scalar shell shows collapse for higher-dimensional Schwarzschild–de Sitter and quintessence manifolds while it indicates expansion for higher-dimensional Reissner–Nordström black hole.

AbsTaylor: upper bounding with inner regions in nonlinear continuous global optimization problems

In this paper we propose AbsTaylor, a simple and quick method for extracting inner polytopes, i.e., entirely feasible convex regions in which all points satisfy the constraints. The method performs an inner linearization of the nonlinear constraints by using a Taylor form. Unlike a previous proposal, the expansion point of the Taylor form is not limited to the bounds of the domains, thus producing, in general, a tighter approximation. For testing the approach, AbsTaylor was introduced as an upper bounding method in a state-of-the-art global branch & bound optimizer. Furthermore, we implemented a local search method which extracts feasible inner polytopes for iteratively finding better solutions inside them. In the studied instances, the new method finds in average four times more inner regions and significantly improves the optimizer performance.

Compact Piecewise Linear Model Based Temperature Control of Multicore Systems Considering Leakage Power

Temperature control of the new-generation integrated multicore system is challenging. This is because the leakage power, which is significant in modern systems, is nonlinearly related to temperature, resulting in a complex nonlinear control problem in thermal management. In this article, a new dynamic thermal management (DTM) method with compact piecewise linear (PWL) model based predictive control is proposed to solve the nonlinear control problem. First, a compact PWL thermal model, which takes dynamic power as input, is built by combining multiple local compact linear thermal models expanded at several Taylor expansion points. These local compact linear thermal models are obtained by sampling-based model order reduction with high accuracy. Their Taylor expansion points are selected by a systematic scheme, which exploits the thermal behavior property of the multicore chips. Based on the compact PWL thermal model, a new predictive control method is proposed to compute the future power recommendation for DTM. By approximating the nonlinearity accurately with the compact PWL thermal model and being equipped with predictive control technique, the new DTM achieves an overall high quality temperature management with smooth and accurate temperature tracking. Experimental results show that the new method outperforms the linear model predictive control based method and the echo state network based predictive thermal management method in temperature management quality with lower computing overhead.

Effect of Angle of Attack on Pressure and Lift Coefficient of ONERA OA206 Wing Model Using Computational Fluid Dynamics Method

In this study, we computed the lift force of the aircraft with ONERA OA206 airfoil type. It was positioned at 0%, 25%, 50%, 75%, and 100% of the wingspan for Angle of Attack (AoA) variations of 0o, 4o, 8o, 12o, and 16o. The research was to determine the effect of AoA on pressure, pressure coefficient (Cp), and lift coefficient (CL) on the ONERA OA206 aircraft wing. It shows that the greater AoA on the result of the pressure contour causes the increase in the difference of span at AoA 0o to 16o t these are 0.25%; 0.26%; 0.43%; 0.52%; and 0.53%. Through the graph of the pressure coefficient (Cp) against x/c, it can be seen that the greater AoA, the expansion point, and the stagnation point will shift to the right with the direction of x/c. In addition, the Cp at the lower is greater than the upper of the airfoil. Based on the research results, it was found that CL at the position of 0% to 50% increased when given AoA from 0o to 12o (CL max) and decreased at AoA = 16o (stall). Meanwhile, CL at 75% to 100% increased when given AoA from 0o to 8o (CL max) and decreased at AoA = 12o (stall). With these results, it can be concluded that the maximum AoA that can be applied to the wing of the ONERA OA206 aircraft is 8o. The closer to the end position of the airfoil, the higher the CL measured.

Using historical and political understanding to design for equity in science education

AbstractIn this article we studied how community educators’ designed for equity in an after school science program. Building from discussions of equity in out‐of‐school‐time (OST) science, this case study offers insight into the role of pedagogy in organizing for dignity and belonging in an after school program. This case study focused on the practices of nine Latinx community educators as they supported science practices in an after school program. Grounded in an understanding of place and the specific cultural, political, and historical densities of life in an agricultural town, the study found that educators created a space of affirmation and care that supported alternative paths to deep engagement in science. The findings add dimensionality to current discourses of equity in OST science and engineering education by examining how historical and political understanding of marginalization informed educators’ pedagogical strategies. These strategies include offering: moment‐to‐moment affirmations of young people's ideas, material and cultural generosity in the Studio, connections to political belonging through science, and extensions from community activities into the after school science inquiries. Together educators created a space of belonging that used science and engineering as entry points for creation, political expression, and intellectual expansion.

Therapy of Paediatric B-ALL with a Fast Off Rate CD19 CAR Leads to Enhanced Expansion and Prolonged CAR T Cell Persistence in Patients with Low Bone Marrow Tumour Burden, and Is Associated with a Favourable Toxicity Profile

Introduction: The CARPALL study (NCT02443831) employed a novel CD19CAR (CAT-41BBz CAR) with a faster off rate than the Kymriah FMC63-41BBz CAR (CAT 3.1x10-3s-1, FMC 6.8 x 10-5s-1), with equivalent on-rate (CAT 2.2 x 105, FMC 2.1 x 105). We herein report updated outcomes and CAR T cell persistence with an additional 6 months follow up from a submitted manuscript (Ghorashian et al., Nat Med, submitted) Methods: Patients aged &amp;lt;25 years with high risk, relapsed CD19+ B-ALL were eligible on this multi-centre, open label, non-randomised phase I study of autologous CAT-41BBz CAR T cells. Patients were followed to a data cut-off of 07/18/2019. CAT-41BBz CAR T cells were generated by magnetic bead activation of leucapheresed PBMCs, lentiviral transduction, followed by bioreactor expansion and magnetic bead removal prior to cryopreservation. All patients received lymphodepletion (fludarabine + cyclophosphamide) followed by 1x106/kg CAR T cells. Presence of CAR T cells in the blood and bone marrow (BM) was assessed (flow cytometry and qPCR) monthly for 6 months, then 6 weekly to 1 year and then 3 monthly. BM MRD was assessed (IgH qPCR, flow cytometry) at the same time-points up to 2 years to establish durability of responses as a stand-alone therapy. Primary end-points were incidence of grade 3-5 toxicity and the proportion of patients achieving molecular remission. Results: Of 17 patients recruited, 14 were treated due to manufacturing failure in 3 patients.The median age was 9 years (range 1-19 years). All patients had advanced ALL with a median of 4 prior therapy lines. 10 of 14 patients (71%) had relapsed post allogeneic SCT. Prior to lymphodepletion, 4 patients had &amp;gt;5% BM disease, 6 had disease between 5x10-2and 1x10-5, 4 were BM MRD negative having had recurrent isolated CNS disease. Median transduction efficiency was 31% (range 16.5 to 96.4%). 12/14 treated patients received the anticipated dose of 1x106CAR T cells/kg (2 received 0.9x106/kg). Considering all evaluable patients, (n=14 for CAR T cell persistence by qPCR, n=13 by flow) the geometric mean of Cmax was 128 912/µg DNA and of the area under the curve between D0 and D28 was 1,721,355 copies/ µg DNA (Table 1). At the point of maximal expansion, a median of 35% of circulating T cells were CAR+. Median half-life was 34 days (range 3-102). CAR T cells continued to be detectable by qPCR in 11 of 14 (79%) patients at last assessment and by flow cytometry up to 30 months post infusion in 8 of 13(61%). Median duration of CAR T persistence by flow was 261 days (range 7-917). 3 patients failed to have persistence of CAR T cells beyond 1 month. T cell mediated anti-CAR specific cytotoxic activity was detected in 2/2 evaluable patients. Updated persistence data will be presented at the meeting Cytokine release syndrome (CRS) occurred in 13 (93%, grade 1 n=9, grade 2 n=4). None developed ≥grade 3 CRS, had CRS-related ICU admission, or received Tocilizumab. CRS was associated with modest elevations of IL-6, IFN-γand IL-10. Grade 2 neurotoxicity was observed in 3 patients and resolved spontaneously. One patient had grade 4 leucoencephalopathy presumed due to chemotherapy as well as grade 5 sepsis. Ten patients (71%) had grade 3-4 cytopenia persisting beyond day 28 or recurring afterthis. 12/14 (86%) patients achieved molecular complete or continuing complete remission at a median of 30 days post infusion (range 30-90 days, Table 2). At a median follow-up of 20.3 months, 4/14 (29%) evaluable patients remain MRD negative. 5 relapsed with CD19-disease, 1 with CD19+ disease. The median duration of EFS (based on death or morphological relapse) has not been reached, 12 month EFS = 52%, OS = 70% (Figures 1, 2 and Table 3). Conclusion: We noted excellent CAR T cell expansion and persistence in a ALL cohort treated with the fast off-rate CAT-41BBz CAR despite their lower BM disease at treatment compared to other studies. The kinetics documented for all evaluable patients showed a 5-fold greater CAR T cell expansion and 2-fold longer half-life than responders in published series utilising tisagenlecleucel in a similar ALL cohort (Mueller et al., Blood 2017). Patients had a favourable toxicity profile with no severe (grade 3-4) CRS and equivalent disease outcomes to the ELIANA study despite having similarly advanced disease (Maude et al., NEJM 2018292). These data suggest long lived CAR T cell persistence supports stand-alone therapy for ALL with durable responses. Disclosures Ghorashian: Celgene: Honoraria; novartis: Honoraria; UCLB: Patents &amp; Royalties: UCLB. Kramer:UCLB: Patents &amp; Royalties. Ciocarlie:Servier: Other: Financial Support. Farzaneh:Autolus Ltd: Equity Ownership, Research Funding. Pule:Autolus: Employment, Equity Ownership, Patents &amp; Royalties. Amrolia:UCLB: Patents &amp; Royalties.