Risk factors for CAR-T cell manufacturing failure among DLBCL patients: A nationwide survey in Japan

CAR-T細胞製造を成功させるためのレシピ --アフェレーシス前の下ごしらえでの工夫--. 京都大学プレスリリース. 2023-04-27.For successful chimeric antigen receptor T (CAR-T) cell therapy, CAR-T cells must be manufactured without failure caused by suboptimal expansion. In order to determine risk factors for CAR-T cell manufacturing failure, we performed a nationwide cohort study in Japan and analysed patients with diffuse large B-cell lymphoma (DLBCL) who underwent tisagenlecleucel production. We compared clinical factors between 30 cases that failed (7.4%) with those that succeeded (n = 378). Among the failures, the proportion of patients previously treated with bendamustine (43.3% vs. 14.8%; p < 0.001) was significantly higher, and their platelet counts (12.0 vs. 17.0 × 10⁴/μL; p = 0.01) and CD4/CD8 T-cell ratio (0.30 vs. 0.56; p < 0.01) in peripheral blood at apheresis were significantly lower than in the successful group. Multivariate analysis revealed that repeated bendamustine use with short washout periods prior to apheresis (odds ratio [OR], 5.52; p = 0.013 for ≥6 cycles with washout period of 3–24 months; OR, 57.09; p = 0.005 for ≥3 cycles with washout period of <3 months), low platelet counts (OR, 0.495 per 105/μL; p = 0.022) or low CD4/CD8 ratios (<one third) (OR, 3.249; p = 0.011) in peripheral blood at apheresis increased the risk of manufacturing failure. Manufacturing failure remains an obstacle to CAR-T cell therapy for DLBCL patients. Avoiding risk factors, such as repeated bendamustine administration without sufficient washout, and risk-adapted strategies may help to optimize CAR-T cell therapy for DLBCL patients

Energy Confinement Time and Heat Transport in Initial Neutral Beam Heated Plasmas

The confinement characteristics of large net-current-free plasmas heated by neutral-beam injection have been investigated in the Large Helical Device (LHD). A systematic enhancement in energy-confinement times from the scaling derived from the medium-sized heliotron/torsatron experiments have been observed, which is attributed to the edge pedestal. The core confinement is scaled with the Bohm term divided by the square root of the gyro radii. The comparative analysis using a dimensionally similar discharge in the Compact Helical System indicates gyro-Bohm dependence in the core and transport improvement in the edge region of LHD plasmas

Initial physics achievements of large helical device experiments

The Large Helical Device (LHD) experiments [O. Motojima, et al., Proceedings, 16th Conference on Fusion Energy, Montreal, 1996 (International Atomic Energy Agency, Vienna, 1997), Vol. 3, p. 437] have started this year after a successful eight-year construction and test period of the fully superconducting facility. LHD investigates a variety of physics issues on large scale heliotron plasmas (R = 3.9 m, a = 0.6 m), which stimulates efforts to explore currentless and disruption-free steady plasmas under an optimized configuration. A magnetic field mapping has demonstrated the nested and healthy structure of magnetic surfaces, which indicates the successful completion of the physical design and the effectiveness of engineering quality control during the fabrication. Heating by 3 MW of neutral beam injection (NBI) has produced plasmas with a fusion triple product of 8 X 10^18 keV m^3 s at a magnetic field of 1.5 T. An electron temperature of 1.5 keV and an ion temperature of 1.4 keV have been achieved. The maximum stored energy has reached 0.22 MJ, which corresponds to = 0.7%, with neither unexpected confinement deterioration nor visible magnetohydrodynamics (MHD) instabilities. Energy confinement times, reaching 0.17 s at the maximum, have shown a trend similar to the present scaling law derived from the existing medium sized helical devices, but enhanced by 50%. The knowledge on transport, MHD, divertor, and long pulse operation, etc., are now rapidly increasing, which implies the successful progress of physics experiments on helical currentless-toroidal plasmas

Formation of electron internal transport barrier and achievement of high ion temperature in Large Helical Device

An internal transport barrier (ITB) was observed in the electron temperature profile in the Large Helical Device [O. Motojima et al., Phys. Plasmas 6, 1843 (1999)] with a centrally focused intense electron cyclotron resonance microwave heating. Inside the ITB the core electron transport was improved, and a high electron temperature, exceeding 10 keV in a low density, was achieved in a collisionless regime. The formation of the electron-ITB is correlated with the neoclassical electron root with a strong radial electric field determined by the neoclassical ambipolar flux. The direction of the tangentially injected beam-driven current has an influence on the electron-ITB formation. For the counter-injected target plasma, a steeper temperature gradient, than that for the co-injected one, was observed. As for the ion temperature, high-power NBI (neutral beam injection) heating of 9 MW has realized a central ion temperature of 5 keV with neon injection. By introducing neon gas, the NBI absorption power was increased in low-density plasmas and the direct ion heating power was much enhanced with a reduced number of ions, compared with hydrogen plasmas

Impurity emission characteristics of long pulse discharges in Large Helical Device

Line spectra from intrinsic impurity ions have been monitored during the three kinds of long-pulse discharges (ICH, ECH, NBI). Constant emission from the iron impurity shows no preferential accumulation of iron ion during the long-pulse operations. Stable Doppler ion temperature has been also measured from Fe XX, C V and C III spectra

Improved plasma performance on Large Helical Device

Since the start of the Large Helical Device (LHD) experiment, various attempts have been made to achieve improved plasma performance in LHD [A. Iiyoshi et al., Nucl. Fusion 39, 1245 (1999)]. Recently, an inward-shifted configuration with a magnetic axis position R_ax of 3.6 m has been found to exhibit much better plasma performance than the standard configuration with R_ax of 3.75 m. A factor of 1.6 enhancement of energy confinement time was achieved over the International Stellarator Scaling 95. This configuration has been predicted to have unfavorable magnetohydrodynamic (MHD) properties, based on linear theory, even though it has significantly better particle-orbit properties, and hence lower neoclassical transport loss. However, no serious confinement degradation due to the MHD activities was observed, resolving favorably the potential conflict between stability and confinement at least up to the realized volume-averaged beta of 2.4%. An improved radial profile of electron temperature was also achieved in the configuration with magnetic islands, minimized by an external perturbation coil system for the Local Island Divertor (LID). The LID has been proposed for remarkable improvement of plasma confinement like the high (H) mode in tokamaks, and the LID function was suggested in limiter experiments

Compatibility between high energy particle confinement and magnetohydrodynamic stability in the inward-shifted plasmas of the Large Helical Device

The experimentally optimized magnetic field configuration of the Large Helical Device [A. Iiyoshi et al., Nucl. Fusion 39, 1245 (1999)], where the magnetic axis is shifted inward by 15 cm from the early theoretical prediction, reveals 50% better global energy confinement than the prediction of the scaling law. This configuration has been investigated further from the viewpoints of high energy particle confinement and magnetohydrodynamic (MHD) stability. The confinement of high energy ions is improved as expected. The minority heating of ion cyclotron range of frequency was successful and the heating efficiency was improved by the inward shift. The confinement of passing particles by neutral beam injection was also improved under low magnetic field strength, and there could be obtained an almost steady high beta discharge up to 3% in volume average. This was a surprising result because the observed pressure gradient exceeded the Mercier unstable limit. The observed MHD activities became as high as beta but they did not grow enough to deteriorate the confinement of high energy ions or the performance of the bulk plasma, which was still 50% better than the scaling. According to these favorable results, better performance would be expected by increasing the heating power because the neoclassical transport can also be improved there

Reduction of Ion Thermal Diffusivity Associated with the Transition of the Radial Electric Field in Neutral-Beam-Heated Plasmas in the Large Helical Device

Recent large helical device experiments revealed that the transition from ion root to electron root occurred for the first time in neutral-beam-heated discharges, where no nonthermal electrons exist. The measured values of the radial electric field were found to be in qualitative agreement with those estimated by neoclassical theory. A clear reduction of ion thermal diffusivity was observed after the mode transition from ion root to electron root as predicted by neoclassical theory when the neoclassical ion loss is more dominant than the anomalous ion loss

Ion cyclotron range of frequency heating experiments on the large helical device and high energy ion behavior

Ion cyclotron range of frequency (ICRF) heating experiments on the Large Helical Device (LHD) [O. Motojima et al. Fus. Eng. Des. 20, 3 (1993)] achieved significant advances during the third experimental campaign carried out in 1999. They showed significant results in two heating modes; these are modes of the ICH-sustained plasma with large plasma stored energy and the neutral beam injection (NBI) plasma under additional heating. A long-pulse operation of more than 1 minute was achieved at a level of 1 MW. The characteristics of the ICRF heated plasma are the same as those of the NBI heated plasma. The energy confinement time is longer than that of International Stellarator Scaling 95. Three keys to successful ICRF heating are as follows: (1) an increase in the magnetic field strength, (2) the employment of an inward shift of the magnetic axis, (3) the installation of actively cooled graphite plates along the divertor legs. Highly energetic protons accelerated by the ICRF electric field were experimentally observed in the energy range from 30 to 250 keV and the tail temperature depended on the energy balance between the wave heating and the electron drag. The transfer efficiency from the high energy ions to the bulk plasma was deduced from the increase in the energy confinement time due to the high energy ions in the lower density discharge, which agrees fairly well with the result obtained by the Monte Carlo simulation. The transfer efficiency is expected to be 95% at an electron density of more than n_e=5.0×10^19 m^?3 even in the high power heating of 10 MW. The accumulation of impurities, e.g., FeXVI and OV was not observed in high rf power and long pulse operation. The well-defined divertor intrinsic to LHD is believed to be useful in reducing the impurity influx