Autologous CD7 CAR T cells generated without T-cell pre-selection in pediatric patients with relapsed/refractory T-ALL: a phase I trial.

Chimeric antigen receptor (CAR) T-cell therapy showed preliminary activity in patients with refractory or relapsed T-cell acute lymphoblastic leukemia (r/r T-ALL). However, many obstacles remain, including manufacturing difficulties and risk of infections. This phase I study (NCT04840875) evaluated autologous CD7 CAR T cells manufactured without pre-selection of healthy T cells in r/r T-ALL. Thirty patients (29 children and one adult) with a median of two lines of prior therapy but without detectable peripheral leukemia were enrolled. Excluding three cases of manufacturing failures, a total of 27 (90%) patients received infusions after products were confirmed free of leukemia contamination, including 16 (59%) meeting planned target doses. Common adverse events within 30 days included grade 3-4 cytopenias (100%), grade 1-2 (70%) and 3-4 (7%; including one dose-limiting toxicity) cytokine release syndrome, grade 1 neurotoxicity (7%), grade 2 infection (4%), and grade 2 graft-versus-host disease (4%). Two patients developed grade 2 infections after day 30. At day 30, 96% responded and 85% achieved CR or CRi. 74% underwent transplantation. Twelve-month progression-free survival with and without censoring transplantation was 22% (95%CI 4-100) and 57% (41-81), respectively. These results support that autologous CD7 CAR T-cell therapy without T-cell pre-selection is feasible in patients with r/r T-ALL.

Fluorescence collection efficiency of atoms in dipole traps.

The fluorescence collection from single atoms and emitters has been extensively utilized in quantum information and quantum optics research. Here, we investigated the collection efficiency of an objective lens by drawing an analogy between the free-space beam (FSB) and a waveguide mode. We explored how efficiency is influenced by their thermal motion within a dipole trap. Furthermore, we introduce an effective energy fraction ratio to quantify potential imperfections in the focusing of the objective lens. Our results provide valuable insights for optimizing the fluorescence collection in single-atom experiments and highlight the importance of considering realistic experimental conditions when estimating achievable efficiencies.

Anti-BCMA/GPRC5D bispecific CAR T cells in patients with relapsed or refractory multiple myeloma: a single-arm, single-centre, phase 1 trial.

BACKGROUND: Some challenges still exist with single-target B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapies due to variable or negative BCMA expression, although they have yielded remarkable efficacy in relapsed or refractory multiple myeloma. We developed anti-BCMA/GPRC5D bispecific CARs to mitigate the limitations and potentiate the functions of CAR T cells. METHODS: This single-arm, phase 1 trial was conducted at the Affiliated Hospital of Xuzhou Medical University (Xuzhou, China). The trial enrolled patients aged 18-75 years with relapsed or refractory multiple myeloma and an Eastern Cooperative Oncology Group performance status of 0-3. Anti-BCMA/GPRC5D bispecific CAR T cells were administered at 0·5 × 106, 1·0 × 106, 2·0 × 106, and 4·0 × 106 CAR T cells per kg in the dose-escalation phase, with additional patients included at the dose selected for the dose-expansion phase. The primary endpoint was safety, which included dose-limiting toxicity and maximum tolerated dose. Activity was also evaluated as a secondary endpoint. The maximum tolerated dose was chosen for the dose-expansion phase. Safety and activity analyses were done in all patients who received anti-BCMA/GPRC5D bispecific CAR T cells as defined in the protocol. This trial is registered with ClinicalTrials.gov (NCT05509530) and is complete. FINDINGS: Between Sept 1, 2022, and Nov 3, 2023, 24 patients were enrolled and underwent apheresis. Three patients were excluded after apheresis (two patients discontinued due to rapid disease progression and one patient was withdrawn because of failed manufacture of CAR T cells), so 21 patients were infused with anti-BCMA/GPRC5D bispecific CAR T cells. Median follow-up was 5·8 months (IQR 5·2-6·7). Median age was 62 years (IQR 56-67). Eight (38%) patients were male, and 13 (62%) female. All patients were Chinese. At the 4·0 × 106 CAR T cells per kg dose, two patients had dose-limiting toxicities, of whom one died of subarachnoid haemorrhage (which was not considered to be related to the study treatment). The maximum tolerated dose was identified as 2·0 × 106 CAR T cells per kg. The most common grade 3 or worse adverse events were haematological toxicities in 19 (90%) patients (except lymphopenia). 15 (71%) patients had cytokine release syndrome, of which all cases were grade 1 or 2. One case of grade 1 immune effector cell-associated neurotoxicity syndrome (ICANS) was observed in a patient who received 4·0 × 106 CAR T cells per kg. No ICANS or grade 3 or worse organ toxicities were observed in patients who received 0·5-2·0 × 106 CAR T cells per kg. The overall response rate was 86% (18 of 21 patients), with 13 (62%) patients having a complete response or better, and 17 (81%) patients having measurable residual disease negativity. Of the 12 patients who received 2·0 × 106 CAR T cells per kg (three in the dose-escalation phase and an addition nine in the dose-expansion phase), the overall response rate was 92% (11 of 12 patients) with nine (75%) patients having a complete response or better. INTERPRETATION: Anti-BCMA/GPRC5D bispecific CAR T cells show a good safety profile and encouraging activity in patients with relapsed or refractory multiple myeloma. FUNDING: National Natural Science Foundation of China. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Carbon coated Na3+xV2-xCux(PO4)3@C cathode for high-performance sodium ion batteries.

Na3V2(PO4)3 is considered as one of the most promising cathodes for sodium ion batteries owing to its fast Na+ diffusion, good structural stability and high working potential. However, its practical application is limited by its low intrinsic electronic conductivity. Herein, a carbon coated Cu2+-doped Na3V2(PO4)3 cathode was prepared. The carbon coating not only improve its apparent conductivity, but also inhibit crystal growth and prevent agglomeration of particles. Moreover, Cu2+ doping contributes to an enhanced intrinsic conductivity and decreased Na+ diffusion energy barrier, remarkably boosting its charge transfer kinetics. Based on the structure characterizations, electrochemical performances tests, charge transfer kinetics analyses and theoretical calculations, it's proved that such an elaborate design ensures the excellent rate performances (116.9 mA h g-1 at 0.1C; 92.6 mA h g-1 at 10C) and distinguished cycling lifespan (95.8 % retention after 300 cycles at 1C; 84.8 % retention after 3300 cycles at 10C). Besides, a two-phase reaction mechanism is also confirmed via in-situ XRD. This research is expected to promote the development of Na3V2(PO4)3-based sodium ion batteries with high energy/power density and excellent cycling lifespan.

Molecular Characterization Analysis and Adaptive Responses of Spodoptera frugiperda (Lepidoptera: Noctuidae) to Nutritional and Enzymatic Variabilities in Various Maize Cultivars.

The fall armyworm, Spodoptera frugiperda Smith (Lepidoptera: Noctuidae), a common agricultural pest known for its extensive migration and wide host ranges, causes considerable harm to maize (Zea mays L.). In this study, we utilized two molecular marker genes, COI and Tpi, to compare the genetic characteristics of the collected original samples. Additionally, through an interactive study between S. frugiperda larvae and six maize varieties aiming to understand the insect's adaptability and resistance mechanisms, our analysis revealed that both the COI and Tpi genes identified S. frugiperda as the corn strain. Further examination of the larvae showed significant differences in nutritional indices, digestive, and detoxification enzyme activities. Special maize varieties were found to offer higher efficiency in nutrient conversion and assimilation compared with common varieties. This study revealed adaptations in S. frugiperda's digestive and detoxification processes in response to the different maize varieties. For instance, larvae reared on common maize exhibited elevated amylase and lipase activities. Interestingly, detoxification enzyme activities exhibited different patterns of variation in different maize varieties. The Pearson correlation analysis between nutritional indices, enzyme activities, and the nutritional content and secondary metabolites of maize leaves provided deeper insights into the pest's adaptability. The results highlighted significant relationships between specific nutritional components in maize and the physiological responses of S. frugiperda. Overall, our findings contribute substantially to the understanding of S. frugiperda's host plant adaptability, offering critical insights for the development of sustainable pest management strategies.

Peripheral blood mononuclear cell low molecular mass protein 7 in acute ischemic stroke: vertical change from admission to discharge and correlation with disability, stroke recurrence, and death.

Objective: Low molecular mass protein 7 (LMP7) aggravates abnormal T cell differentiation and atherosclerosis, but its clinical role in acute ischemic stroke (AIS) is still unclear. This study aimed to investigate the correlation of peripheral blood mononuclear cell (PBMC) LMP7 with T cell subsets, disease severity, and prognosis in AIS patients. Methods: A total of 162 AIS patients were enrolled for detecting PBMC LMP7 and T helper (Th) 1, Th2, and Th17 cells via reverse transcriptase-polymerase chain reaction and flow cytometry, respectively. In addition, PBMC LMP7 at discharge was also quantified. Results: Increased LMP7 at admission was associated with decreased Th2 cells (P=0.014), elevated Th17 cells (P<0.001), C-reactive protein (P=0.005), National Institutes of Health Stroke Scale (NIHSS) score (P=0.007), and disease severity (defined by NIHSS score) (P=0.010). LMP7 at admission reflected a high risk of stroke recurrence (area under curve (AUC): 0.748, 95% confidence interval (CI): 0.564-0.932), but not mRS score at month 3 (M3) >2 (AUC: 0.585, 95%CI: 0.479-0.691), or death (AUC: 0.723, 95%CI: 0.338-1.000). LMP7 at discharge was reduced compared to that at admission (P<0.001). LMP7 at discharge was positively correlated with the risk of stroke recurrence (AUC: 0.849, 95%CI: 0.735-0.963) and death (AUC: 0.919, 95%CI: 0.836-1.000), but had a weak capacity to reflect mRS score at M3 >2 (AUC: 0.671, 95%CI: 0.578-0.765). Conclusion: PBMC LMP7 positively correlates with Th17 cells, inflammation, and disease severity in AIS patients, meanwhile, its level at discharge shows a good ability to reflect the risks of stroke recurrence and death.

Magnetic-free polarization rotation in an atomic vapor cell.

Magnetic-free nonreciprocal optical devices have attracted great attention in recent years. Here, we investigated the magnetic-free polarization rotation of light in an atom vapor cell. Two mechanisms of magnetic-free nonreciprocity have been realized in ensembles of hot atoms, including electromagnetically induced transparency and optically-induced magnetization. For a linearly polarized input probe light, a rotation angle up to 86.4° has been realized with external control and pump laser powers of 10 mW and is mainly attributed to the optically-induced magnetization effect. Our demonstration offers a new approach to realize nonreciprocal devices, which can be applied to solid-state atom ensembles and may be useful in photonic integrated circuits.

Achieving High Initial Coulombic Efficiency and Capacity in a Surface Chemical Grafting Layer of Plateau-type Sodium Titanate.

The plateau-type sodium titanate with suitable sodiation potential is a promising anode candidate for high safe and high energy density of sodium-ion batteries (SIBs). However, the poor initial Coulombic efficiency (ICE) and cyclic instability of sodium titanate are attributed to the unstable interfacial structure along with the decomposition of electrolytes, resulting in the continuous formation of solid electrolyte interface (SEI) film. To address this issue, a chemical grafting method is developed to fabricate a highly stable interface layer of inert Al2O3 on the sodium titanate anode, rendering the high ICE and excellent cycling stability. Based on theoretical calculations, NaPF6 are more likely adsorption on the Al2O3 surface and produce sodium fluoride. The formation of a thin and dense SEI film with rich sodium fluoride achieves the low interfacial resistances and charge-transfer resistances. Benefitting from our design, the obtained sodium titanate exhibits a high ICE from 67.7 % to 79.4 % and an enhanced reversible capacity from 151 mAh g-1 to 181 mAh g-1 at 20 mA g-1, along with an increase in capacity retention from 56.5 % to 80.6 % after 500 cycles. This work heralds a promising paradigm for rational regulation of interfacial stability to achieve high-performance anodes for SIBs.

Cost-effectiveness of edaravone dexborneol versus human urinary kallidinogenase for acute ischemic stroke in China.

BACKGROUND: Clinical trials have demonstrated the efficacy of edaravone dexborneol in the treatment of acute ischemic stroke. This study aims to determine the cost-effectiveness of edaravone dexborneol compared with human urinary kallidinogenase from China's healthcare system perspective. METHODS: A combination of the decision tree and Markov model was constructed to evaluate the cost-effectiveness of edaravone dexborneol versus human urinary kallidinogenase in the treatment of acute ischemic stroke over a lifetime horizon. Efficacy data were derived from pivotal clinical trials of edaravone dexborneol and human urinary kallidinogenase (TASTE trial and RESK trial, respectively) and adjusted using matching-adjusted indirect comparison. Cost and health utility inputs were extracted from published literature and open databases. One-way deterministic sensitivity and probabilistic sensitivity analyses were performed to examine the robustness of the results. RESULTS: Compared with human urinary kallidinogenase, edaravone dexborneol generated 0.153 incremental quality-adjusted life years (QALYs) with an incremental cost of ¥856, yielding an incremental cost-effectiveness ratio of ¥5,608 per QALY gained under the willingness-to-pay threshold (one-time gross domestic product per capita). Both one-way deterministic sensitivity analysis and probabilistic sensitivity analysis demonstrated the robustness of the base case results. CONCLUSIONS: Edaravone dexborneol is a cost-effective treatment choice for acute ischemic stroke patients compared with human urinary kallidinogenase in China.

Macrophage polarization in osteoarthritis progression: a promising therapeutic target.

Osteoarthritis (OA) is one of the leading causes of pain and disability in the elderly. Synovitis, cartilage destruction and osteophyte formation histologically manifest OA. Unfortunately, there is currently no effective therapy to delay its progression and the underlying mechanisms of OA require further exploration. Macrophage is a main cellular component of joint synovium. It is highly plastic and can be stimulated to polarize to different phenotypes, namely, the pro-inflammatory phenotype (M1) and the anti-inflammatory/tissue-repairing phenotype (M2). Ample evidence has demonstrated the vital roles of macrophages in the progression of OA. Imbalanced M1/M2 ratio is significantly related to OA severity indicating macrophage polarization might be a promising therapeutic target for OA. In this review, we summarized the involvements of polarized macrophages in synovitis, cartilage degradation, osteophyte formation and OA-related chronic pain. Promising therapies targeting macrophage polarization including the intra-articular cell/derivates-based therapy and the alternative non-invasive intervention such as photobiomodulation therapy were reviewed as well.

Current advances of photobiomodulation therapy in treating knee osteoarthritis.

Knee osteoarthritis (KOA) is manifested by low-grade joint inflammation, irreversible cartilage degeneration, subchondral bone remodeling and osteophyte formation. It is one of the most prevalent degenerative diseases in the elderly. KOA usually results in chronic joint pain, physical impairment even disability bringing a huge socioeconomic burden. Unfortunately, there is so far no effective interventions to delay the progression and development of KOA. There is a pressing need for explorations and developments of new effective interventions. Photobiomodulation therapy (PBMT), also known as low-level light therapy (LLLT), has attracted widespread attention in treating KOA because it is drug-free, non-invasive, safe and useful with rarely reported side effects. It provides the biological stimulatory effects primarily by enhancing the activity of mitochondrial cytochrome c oxidase. This stimulation, in turn, fosters cell proliferation and tissue regeneration. In addition to this, the paper provides a concise overview of the light parameters and the effectiveness of PBMT when applied in the treatment of KOA patients in clinical settings. It also delves into the experimental evidence supporting the modulatory effects of PBMT and its potential underlying mechanisms in addressing synovitis, cartilage degeneration, and pain resolution.

First insights into 6PPD-quinone formation from 6PPD photodegradation in water environment.

p-Phenylenediamines (PPDs), an important type of rubber antioxidants, have received little study on their environmental fate, particularly for their vital photodegradation process in water environment. Accordingly, N-(1,3-dimethylbutyl)-N'-phenyl-1,4-phenylenediamine (6PPD), as a representative of PPDs, was investigated experimentally and theoretically for its photodegradation in water. Rapid photodegradation occurred when 6PPD was exposed to illumination especially UV region irradiation. Under acidic conditions, the photodegradation of 6PPD accelerated mainly due to the increased absorption of long wavelength irradiation by ionized 6PPD. Nine photodegradation products (e.g., 6PPD-quinone (6PPDQ)) of 6PPD were identified by an ultra-performance liquid chromatography QTOF mass spectrometry. Molar yields of photoproducts such as 6PPDQ, aniline, 4-aminodiphenylamine, and 4-hydroxydiphenylamine were 0.03 ± 0.00, 0.10 ± 0.01, 0.03 ± 0.02, and 0.08 ± 0.01, respectively. Mechanisms involved in 6PPD photodegradation include photoexcitation, direct photolysis, self-sensitized photodegradation, and 1O2 oxidation, as demonstrated by electron paramagnetic resonance (EPR) analysis, scavenging experiments, and the time-dependent density functional theory (TD-DFT). Notably, the toxicity of the reaction solution formed during the photodegradation of 6PPD was increased by the formation of highly toxic products (e.g., 6PPDQ). This study provides the first explanation for photodegradation mechanisms of 6PPD and confirms the pathway of 6PPDQ produced by the photoreaction in water environment.

Famine exposure in early life and type 2 diabetes in adulthood: findings from prospective studies in China.

BACKGROUND/OBJECTIVES: This study examined the relationship between famine exposure in early life and the risk of type 2 diabetes in adulthood during the 1959-1961 Chinese Famine. SUBJECTS/METHODS: A total of 3,418 individuals aged 35-74 years free of diabetes from two studies in 2006 and 2009 were followed up prospectively in 2009 and 2012, respectively. Famine exposure was classified as unexposed (individuals born in 1962-1978), fetal exposed (individuals born in 1959-1961), child exposed (individuals born in 1949-1958), and adolescent/adult exposed (born in 1931-1948). A logistic regression model was used to assess the relationship between famine exposure and diabetes after adjustment for potential covariates. RESULTS: During a three-year follow-up, the age-adjusted incidence rates of type 2 diabetes were 5.7%, 14.5%, 12.7%, and 17.8% in unexposed, fetal-exposed, child-exposed, and adolescent/adult-exposed groups, respectively (P < 0.01). Relative to the unexposed group, the relative risks (95% confidence interval) for diabetes were 2.15 (1.29-3.60), 1.53 (0.93-2.51), and 1.65 (0.75-3.63) in the fetal-exposed, child-exposed, and adolescent/adult-exposed groups, after controlling for potential covariates. The interactions between famine exposure and obesity, education level, and family history of diabetes were not observed, except for the urbanization type. Individuals living in rural areas with fetal and childhood famine exposure were at a higher risk of type 2 diabetes, with relative risks of 8.79 (1.82-42.54) and 2.33 (1.17-4.65), respectively. CONCLUSIONS: These findings indicate that famine exposure in early life is an independent predictor of type 2 diabetes, particularly in women. Early identification and intervention may help prevent diabetes in later life. Trial Registration: ClinicalTrials.gov Identifier: NCT01053195.

A Heat Diffusion Perspective on Geodesic Preserving Dimensionality Reduction.

Diffusion-based manifold learning methods have proven useful in representation learning and dimensionality reduction of modern high dimensional, high throughput, noisy datasets. Such datasets are especially present in fields like biology and physics. While it is thought that these methods preserve underlying manifold structure of data by learning a proxy for geodesic distances, no specific theoretical links have been established. Here, we establish such a link via results in Riemannian geometry explicitly connecting heat diffusion to manifold distances. In this process, we also formulate a more general heat kernel based manifold embedding method that we call heat geodesic embeddings. This novel perspective makes clearer the choices available in manifold learning and denoising. Results show that our method outperforms existing state of the art in preserving ground truth manifold distances, and preserving cluster structure in toy datasets. We also showcase our method on single cell RNA-sequencing datasets with both continuum and cluster structure, where our method enables interpolation of withheld timepoints of data. Finally, we show that parameters of our more general method can be configured to give results similar to PHATE (a state-of-the-art diffusion based manifold learning method) as well as SNE (an attraction/repulsion neighborhood based method that forms the basis of t-SNE).

Incidence, clinical characteristics and prognosis of tumor lysis syndrome following B-cell maturation antigen-targeted chimeric antigen receptor-T cell therapy in relapsed/refractory multiple myeloma.

Background aims: B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor-T cell (CAR-T) therapy is used for refractory or relapsed multiple myeloma (r/r MM). However, CAR-T-related tumor lysis syndrome (TLS) has been observed. We aimed to elucidate the incidence, clinical and laboratory characteristics, and prognosis of CAR-T cell-related TLS. Methods: Patients (n=105) with r/r MM treated with BCMA-targeted CAR-T cell therapy were included. Patient characteristics, laboratory parameters, and clinical outcomes were assessed. Results: Eighteen (17.1%) patients developed TLS after BCMA-targeted CAR-T cell therapy. The median time till TLS onset was 8 days. Patients with TLS had steep rise in uric acid (UA), creatinine, and lactate dehydrogenase (LDH) within 6 days following CAR-T cell infusion and presented earlier and persistent escalation of cytokines (C-reactive protein [CRP], interleukin-6 [IL-6], interferon-γ [IFN-γ], and ferritin levels). All 18 patients had cytokine release syndrome (CRS), of which 13 (72.2%) developed grade 3-4 CRS. Three of 18 patients (16.7%) developed immune effector cell-associated neurotoxicity syndrome (ICANS): two patients with grade 1 ICANS and one with grade 2 ICANS. TLS development had a negative effect on the objective response rate (77.8% in the TLS group vs. 95.4% in the non-TLS group, p<0.01). During the median follow-up of 15.1 months, the median PFS was poorer of patients with TLS (median: 3.4 months in the TLS group vs. 14.7 months in the non-TLS group, p<0.001, hazard ratio [HR]=3.5 [95% confidence interval [CI] 1.5-8.5]). Also, TLS development exhibited significant effects on OS (median: 5.0 months in the TLS group vs. 39.8 months in the non-TLS group, p<0.001, hazard ratio [HR]=3.7 [95% CI 1.3-10.3]). TLS was associated with a higher tumor burden, elevated baseline creatinine and UA levels, severe CRS, pronounced CAR-T cell expansion, and corticosteroid use. Conclusion: TLS is a frequently observed CAR-T therapy complication and negatively influences clinical response and prognosis. Close monitoring for TLS should be implemented during CAR-T cell therapy, especially for those at high TLS risk.

Oviposition Preference and Age-Stage, Two-Sex Life Table Analysis of Spodoptera frugiperda (Lepidoptera: Noctuidae) on Different Maize Varieties.

Host plants play an important role in the growth, development, and reproduction of insects. However, only a few studies have reported the effects of maize varieties on the growth and reproduction of S. frugiperda. In this study, a free-choice test was used to evaluate the oviposition preferences of female adults on ten common maize varieties and ten special maize varieties. The population fitness of S. frugiperda on six different maize varieties was also examined using the age-stage, two-sex life table method. The results showed that S. frugiperda oviposited and completed its life cycle across all maize cultivars. Moreover, the S. frugiperda females exhibited a significantly higher oviposition preference on the special maize varieties than on the common maize varieties. The highest number of eggs and egg masses occurred on Baitiannuo and the lowest on Zhengdan 958. The egg + larval stage, preadult, pupal stage, adult, APOP, TPOP, and total longevity of S. frugiperda were significantly shorter on the special maize varieties than on the common maize varieties. The fecundity, oviposition days, pupal weight, and hatching rate of S. frugiperda were significantly higher on the special maize varieties than on the common maize varieties. Specifically, S. frugiperda had the highest fecundity, female, and male pupal weight on Baitiannuo. Moreover, the net reproductive rate (R0), intrinsic rate of increase (r), and finite rate of increase (λ) of S. frugiperda were the greatest on Baitiannuo, whereas the shortest mean generation time (T) occurred on Zaocuiwang. The lowest R0, r, and λ, and longest T occurred on Zhengdan 958, suggesting that Zhengdan 958 is a non-preferred host plant compared to the other tested maize varieties. The findings of this study can provide a reference for the rational planting of maize and provide basic scientific information for the management of S. frugiperda.

Allogenic and autologous anti-CD7 CAR-T cell therapies in relapsed or refractory T-cell malignancies.

Chimeric antigen receptor-T (CAR-T) therapy remains to be investigated in T-cell malignancies. CD7 is an ideal target for T-cell malignancies but is also expressed on normal T cells, which may cause CAR-T cell fratricide. Donor-derived anti-CD7 CAR-T cells using endoplasmic reticulum retention have shown efficacy in patients with T-cell acute lymphoblastic leukemia (ALL). Here we launched a phase I trial to explore differences between autologous and allogeneic anti-CD7 CAR-T therapies in T-cell ALL and lymphoma. Ten patients were treated and 5 received autologous CAR-T therapies. No dose-limiting toxicity or neurotoxicity was observed. Grade 1-2 cytokine release syndrome occurred in 7 patients, and grade 3 in 1 patient. Grade 1-2 graft-versus-host diseases were observed in 2 patients. Seven patients had bone marrow infiltration, and 100% of them achieved complete remission with negative minimal residual disease within one month. Two-fifths of patients achieved extramedullary or extranodular remission. The median follow-up was 6 (range, 2.7-14) months and bridging transplantation was not administrated. Patients treated with allogeneic CAR-T cells had higher remission rate, less recurrence and more durable CAR-T survival than those receiving autologous products. Allogeneic CAR-T cells appeared to be a better option for patients with T-cell malignancies.

Long-term follow-up of donor-derived CD7 CAR T-cell therapy in patients with T-cell acute lymphoblastic leukemia.

BACKGROUND: Donor-derived CD7-directed chimeric antigen receptor (CAR) T cells showed feasibility and early efficacy in patients with refractory or relapsed T-cell acute lymphoblastic leukemia (r/r T-ALL), in a previous phase I trial report, at a median follow-up of 6.3 months. Here we report long-term safety and activity of the therapy after a 2-year follow-up. METHODS: Participants received CD7-directed CAR T cells derived from prior stem cell transplantation (SCT) donors or from HLA-matched new donors after lymphodepletion. The target dose was 1 × 106 (± 30%) CAR T cells per kg of patient weight. The primary endpoint was safety with efficacy secondary. This report focuses on the long-term follow-up and discusses them in the context of previously reported early outcomes. RESULTS: Twenty participants were enrolled and received infusion with CD7 CAR T cells. After a median follow-up time of 27.0 (range, 24.0-29.3) months, the overall response rate and complete response rate were 95% (19/20 patients) and 85% (17/20 patients), respectively, and 35% (7/20) of patients proceeded to SCT. Six patients experienced disease relapse with a median time-to-relapse of 6 (range, 4.0-10.9) months, and 4 of these 6 patients were found to have lost CD7 expression on tumor cells. Progression-free survival (PFS) and overall survival (OS) rates 24 months after treatment were respectively 36.8% (95% CI, 13.8-59.8%) and 42.3% (95% CI, 18.8-65.8%), with median PFS and OS of respectively 11.0 (95% CI, 6.7-12.5) months and 18.3 (95% CI, 12.5-20.8) months. Previously reported short-term adverse events (< 30 days after treatment) included grade 3-4 cytokine release syndrome (CRS; 10%) and grade 1-2 graft-versus-host disease (GVHD; 60%). Serious adverse events reported > 30 days after treatment included five infections and one grade 4 intestinal GVHD. Despite good CD7 CAR T-cell persistence, non-CAR T and natural killer cells were predominantly CD7-negative and eventually returned to normal levels in about half of the participants. CONCLUSIONS: In this 2-year follow-up analysis, donor-derived CD7 CAR T-cell treatment demonstrated durable efficacy in a subset of patients with r/r T-ALL. Disease relapse was the main cause of treatment failure, and severe infection was a noteworthy late-onset adverse event. TRIAL REGISTRATION: ChiCTR2000034762.

Anti-G Protein-Coupled Receptor, Class C Group 5 Member D Chimeric Antigen Receptor T Cells in Patients With Relapsed or Refractory Multiple Myeloma: A Single-Arm, Phase â ¡ Trial.

PURPOSE: G protein-coupled receptor, class C group 5 member D (GPRC5D) is considered to be a promising surface target for multiple myeloma (MM) immunotherapy. Here, we report the efficacy and safety of anti-GPRC5D chimeric antigen receptor (CAR) T cells in patients with relapsed or refractory (R/R) MM. METHODS: This phase Ⅱ, single-arm study enrolled patients (18-70 years) with R/R MM. Lymphodepletion was performed before patients received 2 × 106/kg anti-GPRC5D CAR T cells. The primary end point was the proportion of patients who achieved an overall response. Safety was also evaluated in eligible patients. RESULTS: From September 1, 2021, to March 23, 2022, 33 patients were infused with anti-GPRC5D CAR T cells. At a median follow-up of 5.2 months (range, 3.2-8.9), the overall response rate was 91% (95% CI, 76 to 98; 30 of 33 patients), including 11 (33%) stringent complete responses, 10 (30%) complete responses, four (12%) very good partial responses, and five (15%) partial responses. Partial responses or better were observed in nine (100%) of nine patients with previous anti-B-cell maturation antigen (BCMA) CAR T-cell therapy, including two patients who had received repeated anti-BCMA CAR T-cell infusions with no responses at the last time. Grade 3 or higher hematologic toxicities were neutropenia (33 [100%]), anemia (17 [52%]), and thrombocytopenia (15 [45%]). Cytokine release syndrome occurred in 25 (76%) of 33 patients (all were grade 1 or 2), and neurotoxicities in three patients (one grade 2 and one grade 3 ICANSs and one grade 3 headache). CONCLUSION: Anti-GPRC5D CAR T-cell therapy showed an encouraging clinical efficacy and manageable safety profile in patients with R/R MM. For patients with MM that progressed after anti-BCMA CAR T-cell therapy or that is refractory to anti-BCMA CAR T cell, anti-GPRC5D CAR T-cell therapy might be a potential alternative option.

HBV reactivation in patients with chronic or resolved HBV infection following BCMA-targeted CAR-T cell therapy.

B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor-T cell (CAR-T) therapy is used for refractory or relapsed multiple myeloma (r/r MM). Concern of the safety and efficacy of CAR-T cell therapy in patients with chronic or resolved HBV infection is raised. In this study, we retrospectively reviewed 99 patients with r/r MM treated with BCMA-targeted CAR-T cell therapy, of which 7 (7.1%) patients had chronic HBV infection, 43 (43.4%) with resolved HBV infection, and the remaining 49 (49.49%) HBV-uninfected. Patients' characteristics before CAR-T cell administration were comparable in different status of HBV infection. Patients' liver function, cytokine levels, CAR-T cell expansion and cytokine release syndrome (CRS) grade after CAR-T cell therapy did not differ in different HBV serologic status. Furthermore, chronic HBV infection or resolved HBV infection did not affect clinical response, progress-free survival (PFS), or overall survival (OS). Four (4.04%) patients experienced HBV reactivation, 3 (6.98%) with resolved HBV infection, and 1 (14.29%) chronic HBV infection. Of 4 patients with HBV reactivation, 2 cases (50%) of severe hepatitis were noted and reported. Drops of serum IgG and elevation of alanine aminotransferase (ALT), alanine aminotransferase (AST), total bilirubin (TB) were observed in all four patients around the date of HBV reactivation.