Background LCAR-B38M is a chimeric antigen receptor T cell product with two binding domains targeting B cell maturation antigen. Our previous reports showed a remarkable efficacy of LCAR-B38M in ...patients with relapsed/refractory multiple myeloma (RRMM) at a median follow-up of 2 years. Here, we report long-term safety and efficacy data from a median follow-up of 4 years. Methods LEGEND-2 was a phase 1, single-arm, open-label study conducted in four registered sites in China. Seventy-four participants with RRMM received LCAR-B38M treatment. Lymphodepletion was performed using cyclophosphamide or cyclophosphamide plus fludarabine. LCAR-B38M, at a median dose of 0.513 x 10.sup.6 cells/kg, was intravenously administered either in three split infusions or in a single infusion. The primary objective was the safety of LCAR-B38M, and the secondary objective was efficacy. Results As of May 25, 2021, the median follow-up was 47.8 months. All patients experienced greater than or equal to 1 adverse events (AEs). Grade greater than or equal to 3 AEs were observed in 45/74 (60.8%) patients. Cytokine release syndrome (CRS) occurred in 68/74 (91.9%) cases; 7 (9.5%) had grade greater than or equal to 3 CRS. One patient experienced grade 1 central nervous system toxicity. The overall response rate was 87.8%. Fifty-four out of 74 (73.0%) patients achieved complete response. The median progression-free survival was 18.0 months, and the median overall survival for all patients was not reached. The median duration of response was 23.3 months. Four patients experienced viral infection more than 6 months post-infusion, and four patients developed second primary non-hematological malignancies at a median time of 11.5 months post-CAR-T cell transfer. Conclusions The 4-year follow-up data of LCAR-B38M therapy demonstrated a favorable long-term safety profile and a durable response in patients with RRMM. Trial registration Clinicaltrials.gov NCT03090659 (retrospectively registered on March 27, 2017); ChiCTR-ONH-17012285. Keywords: Multiple myeloma, Chimeric antigen receptor therapy, B cell maturation antigen, Safety, Efficacy
Photothermal therapy (PTT) is one of the most promising approaches to combat multidrug‐resistant bacteria with less potential to induce resistance and systemic toxicity. However, uncontrollable ...distribution of photothermal agents leads to lethal temperatures for normal cells, and failure to offer timely and effective antibacterial stewardship. A pH switchable nanoplatform for persistent luminescence imaging‐guided precise PTT to selectively destroy only pathological cells while protecting nearby normal cells in bacterial infected microenvironment is shown. The PLNP@PANI‐GCS is fabricated by grafting polyaniline (PANI) and glycol chitosan (GCS) onto the surface of persistent luminescence nanoparticles (PLNPs). It takes advantage of the long persistent luminescence of PLNPs to realize autofluorescence‐free imaging, the pH‐dependent light–heat conversion property of PANI to get a stronger photothermal effect at pH 6.5 than pH 7.4, and the pH environment responsive surface charge transition of GCS. Consequently, PLNP@PANI‐GCS enables effective response to bacterial‐infected acid region and electrostatic bonding to bacteria in vivo, ensuring the spatial accuracy of near‐infrared light irradiation and specific heating directly to bacteria. In vivo imaging‐guided PTT to bacterial infection abscess shows effective treatment. PLNP@PANI‐GCS has great potential in treating multidrug‐resistant bacterial infection with low possibility of developing microbial drug resistance and little harm to normal cells.
A pH switchable nanoplatform is developed for in vivo persistent luminescent imaging and precise photothermal therapy of bacterial infections. This nanoplatform exhibits specific photothermal therapy to acidic bacterial‐infected regions but no damage to normal tissues.
As all-
retinoic acid (ATRA) and arsenic trioxide (ATO) are widely accepted in treating acute promyelocytic leukemia (APL), deescalating toxicity becomes a research hotspot. Here, we evaluated ...whether chemotherapy could be replaced or reduced by ATO in APL patients at different risks. After achieving complete remission with ATRA-ATO-based induction therapy, patients were randomized (1:1) into ATO and non-ATO groups for consolidation: ATRA-ATO versus ATRA-anthracycline for low-/intermediate-risk patients, or ATRA-ATO-anthracycline versus ATRA-anthracycline-cytarabine for high-risk patients. The primary end point was to assess disease-free survival (DFS) at 3 y by a noninferiority margin of -5%; 855 patients were enrolled with a median follow-up of 54.9 mo, and 658 of 755 patients could be evaluated at 3 y. In the ATO group, 96.1% (319/332) achieved 3-y DFS, compared to 92.6% (302/326) in the non-ATO group. The difference was 3.45% (95% CI -0.07 to 6.97), confirming noninferiority (
< 0.001). Using the Kaplan-Meier method, the estimated 7-y DFS was 95.7% (95% CI 93.6 to 97.9) in ATO and 92.6% (95% CI 89.8 to 95.4) in non-ATO groups (
= 0.066). Concerning secondary end points, the 7-y cumulative incidence of relapse (CIR) was significantly lower in ATO (2.2% 95% CI 1.1 to 4.2) than in non-ATO group (6.1% 95% CI 3.9 to 9.5,
= 0.011). In addition, grade 3 to 4 hematological toxicities were significantly reduced in the ATO group during consolidation. Hence, ATRA-ATO in both chemotherapy-replacing and -reducing settings in consolidation is not inferior to ATRA-chemotherapy (https://www.clinicaltrials.gov/, NCT01987297).
Despite numerous inherent merits of metal–organic frameworks (MOFs), structural fragility has imposed great restrictions on their wider involvement in many applications, such as in catalysis. Herein, ...a strategy for enhancing stability and enabling functionality in a labile Zr(IV)‐MOF has been proposed by in situ porphyrin substitution. A size‐ and geometry‐matched robust linear porphyrin ligand 4,4′‐(porphyrin‐5,15‐diyl)dibenzolate (DCPP2−) is selected to replace the 4,4′‐(1,3,6,8‐tetraoxobenzolmn3,8phenanthroline‐2,7(1H,3H,6H,8H)‐diyl)dibenzoate (NDIDB2−) ligand in the synthesis of BUT‐109(Zr), affording BUT‐110 with varied porphyrin contents. Compared to BUT‐109(Zr), the chemical stability of BUT‐110 series is greatly improved. Metalloporphyrin incorporation endows BUT‐110 MOFs with high catalytic activity in the photoreduction of CO2, in the absence of photosensitizers. By tuning the metal species and porphyrin contents in BUT‐110, the resulting BUT‐110‐50%‐Co is demonstrated to be a good photocatalyst for selective CO2‐to‐CO reduction, via balancing the chemical stability, photocatalytic efficiency, and synthetic cost. This work highlights the advantages of in situ ligand substitution for MOF modification, by which uniform distribution and high content of the incoming ligand are accessible in the resulting MOFs. More importantly, it provides a promising approach to convert unstable MOFs, which mainly constitute the vast MOF database but have always been neglected, into robust functional materials.
The in situ porphyrin substitution strategy is developed for modifying labile interpenetrated BUT‐109(Zr), affording BUT‐110 with enhanced chemical stability and photocatalytic activity. By tuning the species and contents of metalloporphyrin in BUT‐110, some of the BUT‐110 MOFs may serve as potential photocatalysts for selective CO2‐to‐CO reduction, in the absence of photosensitizer.
Esophageal squamous cell carcinoma (ESCC) is one of the deadliest cancers. We performed exome sequencing on 113 tumor-normal pairs, yielding a mean of 82 non-silent mutations per tumor, and 8 cell ...lines. The mutational profile of ESCC closely resembles those of squamous cell carcinomas of other tissues but differs from that of esophageal adenocarcinoma. Genes involved in cell cycle and apoptosis regulation were mutated in 99% of cases by somatic alterations of TP53 (93%), CCND1 (33%), CDKN2A (20%), NFE2L2 (10%) and RB1 (9%). Histone modifier genes were frequently mutated, including KMT2D (also called MLL2; 19%), KMT2C (MLL3; 6%), KDM6A (7%), EP300 (10%) and CREBBP (6%). EP300 mutations were associated with poor survival. The Hippo and Notch pathways were dysregulated by mutations in FAT1, FAT2, FAT3 or FAT4 (27%) or AJUBA (JUB; 7%) and NOTCH1, NOTCH2 or NOTCH3 (22%) or FBXW7 (5%), respectively. These results define the mutational landscape of ESCC and highlight mutations in epigenetic modulators with prognostic and potentially therapeutic implications.
Persistent luminescent nanoparticles (PLNPs) with intrinsic stimuli‐responsive properties are desirable because of no autofluorescence background and natural responsive luminescence. However, the ...stimuli‐responsive features of pure PLNPs have been unexplored. Here we show a facile one‐pot hydrothermal synthesis of green‐emitting Zn2GeO4:Mn2+,Pr3+ nanoparticles (ZGMP) with regular shape, uniform size and good afterglow luminescent performance. We also report the pH stimuli‐responsive luminescent behavior of ZGMP and its possible mechanism. Taking the intriguing feature of pH responsive persistent luminescence, we explore ZGMP as autofluorescence‐free probes to achieve stimuli‐activated signal switch for biosensing by integrating enzyme catalysis reaction mediated pH modulation. The pH‐responsive persistent luminescence also makes ZGMP promising for high‐level information encryption.
Uniformly torpedo‐shaped green‐emitting Zn2GeO4: Mn2+, Pr3+ nanoparticles with good persistent luminescence performance were synthesized by a simple hydrothermal method. The pH‐responsive persistent luminescence of ZGMP was found and explored for autofluorescence‐free biosensing and high‐level information encryption.
Herein, we present a stable water‐soluble cobalt complex supported by a dianionic 2,2′‐(2,2′‐bipyridine‐6,6′‐diyl)bis(propan‐2‐ol) ligand scaffold, which is a rare example of a high‐oxidation ...species, as demonstrated by structural, spectroscopic and theoretical data. Electron paramagnetic resonance (EPR) spectroscopy and magnetic susceptibility measurements revealed that the CoIV center of the mononuclear complex in the solid state resides in the high spin state (sextet, S=5/2). The complex can effectively catalyze water oxidation via a single‐site water nucleophilic attack pathway with an overpotential of only 360 mV in a phosphate buffer with a pH of 6. The key intermediate toward water oxidation was speculated based on theoretical calculations and was identified by in situ spectroelectrochemical experiments. The results are important regarding the accessibility of high‐oxidation state metal species in synthetic models for achieving robust and reactive oxidation catalysis.
A stable water‐soluble cobalt(IV) complex supported by a dianionic 2,2′‐(2,2′‐bipyridine‐6,6′‐diyl)bis(propan‐2‐ol) ligand scaffold is very active in the catalysis of water oxidation at an overpotential of only 360 mV at pH=6.
Chimeric antigen receptor (CAR) T cell therapy has demonstrated proven efficacy in some hematologic cancers. We evaluated the safety and efficacy of LCAR-B38M, a dual epitope-binding CAR T cell ...therapy directed against 2 distinct B cell maturation antigen epitopes, in patients with relapsed/refractory (R/R) multiple myeloma (MM).
This ongoing phase 1, single-arm, open-label, multicenter study enrolled patients (18 to 80 years) with R/R MM. Lymphodepletion was performed using cyclophosphamide 300 mg/m
. LCAR-B38M CAR T cells (median CAR+ T cells, 0.5 × 10
cells/kg range, 0.07 to 2.1 × 10
) were infused in 3 separate infusions. The primary objective is to evaluate the safety of LCAR-B38M CAR T cells; the secondary objective is to evaluate the antimyeloma response of the treatment based on the general guidelines of the International Myeloma Working Group.
At data cutoff, 57 patients had received LCAR-B38M CAR T cells. All patients experienced ≥ 1 adverse events (AEs). Grade ≥ 3 AEs were reported in 37/57 patients (65%); most common were leukopenia (17/57; 30%), thrombocytopenia (13/57; 23%), and aspartate aminotransferase increased (12/57; 21%). Cytokine release syndrome occurred in 51/57 patients (90%); 4/57 (7%) had grade ≥ 3 cases. One patient reported neurotoxicity of grade 1 aphasia, agitation, and seizure-like activity. The overall response rate was 88% (95% confidence interval CI, 76 to 95); 39/57 patients (68%) achieved a complete response, 3/57 (5%) achieved a very good partial response, and 8/57 (14%) achieved a partial response. Minimal residual disease was negative for 36/57 (63%) patients. The median time to response was 1 month (range, 0.4 to 3.5). At a median follow-up of 8 months, median progression-free survival was 15 months (95% CI, 11 to not estimable). Median overall survival for all patients was not reached.
LCAR-B38M CAR T cell therapy displayed a manageable safety profile and demonstrated deep and durable responses in patients with R/R MM.
ClinicalTrials.gov , NCT03090659 ; Registered on March 27, 2017, retrospectively registered.
Hardware implementation of artificial synaptic devices that emulate the functions of biological synapses is inspired by the biological neuromorphic system and has drawn considerable interest. Here, a ...three‐terminal ferrite synaptic device based on a topotactic phase transition between crystalline phases is presented. The electrolyte‐gating‐controlled topotactic phase transformation between brownmillerite SrFeO2.5 and perovskite SrFeO3−δ is confirmed from the examination of the crystal and electronic structure. A synaptic transistor with electrolyte‐gated ferrite films by harnessing gate‐controllable multilevel conduction states, which originate from many distinct oxygen‐deficient perovskite structures of SrFeOx induced by topotactic phase transformation, is successfully constructed. This three‐terminal artificial synapse can mimic important synaptic functions, such as synaptic plasticity and spike‐timing‐dependent plasticity. Simulations of a neural network consisting of ferrite synaptic transistors indicate that the system offers high classification accuracy. These results provide insight into the potential application of advanced topotactic phase transformation materials for designing artificial synapses with high performance.
A ferrite synaptic transistor with topotactic transformation is presented. The electrolyte‐gating‐controlled topotactic phase transformation between the brownmillerite SrFeO2.5 and perovskite SrFeO3−δ is confirmed by the crystal and electronic structure measurements. This ferrite synaptic transistor can mimic important synaptic functions such as synaptic plasticity and spike‐timing‐dependent plasticity.
Solid/liquid interfaces are ubiquitous in nature and knowledge of their atomic-level structure is essential in elucidating many phenomena in chemistry, physics, materials science and Earth science
. ...In electrochemistry, in particular, the detailed structure of interfacial water, such as the orientation and hydrogen-bonding network in electric double layers under bias potentials, has a significant impact on the electrochemical performances of electrode materials
. To elucidate the structures of electric double layers at electrochemical interfaces, we combine in situ Raman spectroscopy and ab initio molecular dynamics and distinguish two structural transitions of interfacial water at electrified Au single-crystal electrode surfaces. Towards negative potentials, the interfacial water molecules evolve from structurally 'parallel' to 'one-H-down' and then to 'two-H-down'. Concurrently, the number of hydrogen bonds in the interfacial water also undergoes two transitions. Our findings shed light on the fundamental understanding of electric double layers and electrochemical processes at the interfaces.
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