Deciphering and advancing CAR T-cell therapy with single-cell sequencing technologies.

Chimeric antigen receptor (CAR) T-cell therapy has made remarkable progress in cancer immunotherapy, but several challenges with unclear mechanisms hinder its wide clinical application. Single-cell sequencing technologies, with the powerful unbiased analysis of cellular heterogeneity and molecular patterns at unprecedented resolution, have greatly advanced our understanding of immunology and oncology. In this review, we summarize the recent applications of single-cell sequencing technologies in CAR T-cell therapy, including the biological characteristics, the latest mechanisms of clinical response and adverse events, promising strategies that contribute to the development of CAR T-cell therapy and CAR target selection. Generally, we propose a multi-omics research mode to guide potential future research on CAR T-cell therapy.

Light shift suppression with pulsed light detection in magnetic-state-selected cesium beam clocks.

Light detection is widely used in atomic clocks. The simple detecting structure induces the light shift which influences the clock's long-term stability. We introduce a new method to suppress light shift by using pulsed light instead of continuous light to detect atomic states. Under a suitable pulsed sequence, the part of the atoms which do not simultaneously interact with light and microwave field are detected. We demonstrate the validity of our approach in a magnetic-state-selected cesium beam clock. Using a well-tuned sequence, the light shift coefficient is reduced by a factor of about 10, in comparison with the continuous light detection scheme. In a clock stability test with extra light power noise, the result shows good immunity of the method to laser power fluctuations. We also analyze the sources of the clock short-term stability degradation, including the Dick effect and the fact that a reduced number of atoms is detected in the pulsed detection case.

Macrophages in cardiovascular diseases: molecular mechanisms and therapeutic targets.

The immune response holds a pivotal role in cardiovascular disease development. As multifunctional cells of the innate immune system, macrophages play an essential role in initial inflammatory response that occurs following cardiovascular injury, thereby inducing subsequent damage while also facilitating recovery. Meanwhile, the diverse phenotypes and phenotypic alterations of macrophages strongly associate with distinct types and severity of cardiovascular diseases, including coronary heart disease, valvular disease, myocarditis, cardiomyopathy, heart failure, atherosclerosis and aneurysm, which underscores the importance of investigating macrophage regulatory mechanisms within the context of specific diseases. Besides, recent strides in single-cell sequencing technologies have revealed macrophage heterogeneity, cell-cell interactions, and downstream mechanisms of therapeutic targets at a higher resolution, which brings new perspectives into macrophage-mediated mechanisms and potential therapeutic targets in cardiovascular diseases. Remarkably, myocardial fibrosis, a prevalent characteristic in most cardiac diseases, remains a formidable clinical challenge, necessitating a profound investigation into the impact of macrophages on myocardial fibrosis within the context of cardiac diseases. In this review, we systematically summarize the diverse phenotypic and functional plasticity of macrophages in regulatory mechanisms of cardiovascular diseases and unprecedented insights introduced by single-cell sequencing technologies, with a focus on different causes and characteristics of diseases, especially the relationship between inflammation and fibrosis in cardiac diseases (myocardial infarction, pressure overload, myocarditis, dilated cardiomyopathy, diabetic cardiomyopathy and cardiac aging) and the relationship between inflammation and vascular injury in vascular diseases (atherosclerosis and aneurysm). Finally, we also highlight the preclinical/clinical macrophage targeting strategies and translational implications.

A new magnetic state selection method in high-performance optically detected compact cesium beam clocks.

We perform a new scheme of magnetic state selection in optically detected compact cesium beam clocks. Unlike the conventional method, we select atoms in the ground state |F = 4, mF ≠ -4⟩ by pointing the atomic collimator to the convex pole of the magnet realizing the two-wire magnetic field and detect atoms in |F = 3⟩ after interacting with the microwave field using a distributed feedback laser. The fluorescence background is greatly reduced as the inherent residual atoms |F = 4, mF = -4⟩ are avoided in this reversed scheme. The velocity distribution is narrowed, and the most probable velocity is decreased, since atomic trajectories are close to the weak-field region. We also investigate the relationship between the position of the atomic collimator and the distributions of the atomic beam, which is consistent with the Monte Carlo-based simulation model. By applying the reversed scheme and setting the deviated position of the collimator to 1.3 mm, the signal contrast is improved from 0.7 to 3, and the short-term frequency stability reaches 3.0 × 10-12 τ-1/2, nearly three times better than that of the high-performance version of Microsemi 5071A.

Donor-derived and off-the-shelf allogeneic anti-CD19 CAR T-cell therapy for R/R ALL and NHL: A systematic review and meta-analysis.

Allogeneic anti-CD19 chimeric antigen receptor (CAR) T-cell therapy has the potential for extensive clinical applications. This study aimed to evaluate its efficacy and safety in treating relapsed or refractory (R/R) acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL). Four databases were searched for relevant studies. Among patients treated with donor-derived CAR T-cell therapy, ALL patients had a complete remission (CR) rate of 80 % and a 1-year overall survival rate of 51 %. The graft-versus-host disease (GvHD) rate was 4 %, cytokine release syndrome was 69 %, and immune effector cell-associated neurotoxicity syndrome was 8 %. For off-the-shelf CAR T-cell therapy, the CR rate for ALL was 70 %, and for NHL, it was 52 %. The objective response rate for NHL was 72 %. The pooled GvHD of off-the-shelf CAR T-cell therapy for ALL and NHL combined was 0 %. Allogeneic anti-CD19 CAR T-cell therapy are effective and safe for treating R/R ALL and NHL. AVAILABILITY OF DATA AND MATERIALS: All datasets generated in this study are included in the article/Supplementary Material.

Mechanisms of cytokine release syndrome and neurotoxicity of CAR T-cell therapy and associated prevention and management strategies.

Chimeric antigen receptor (CAR) T-cell therapy has yielded impressive outcomes and transformed treatment algorithms for hematological malignancies. To date, five CAR T-cell products have been approved by the US Food and Drug Administration (FDA). Nevertheless, some significant toxicities pose great challenges to the development of CAR T-cell therapy, most notably cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Understanding the mechanisms underlying these toxicities and establishing prevention and treatment strategies are important. In this review, we summarize the mechanisms underlying CRS and ICANS and provide potential treatment and prevention strategies.

Consolidative Hematopoietic Stem Cell Transplantation After CD19 CAR-T Cell Therapy for Acute Lymphoblastic Leukemia: A Systematic Review and Meta-analysis.

BACKGROUND: This study aimed to systematically evaluate and compare the efficacy and safety of consolidative hematopoietic stem cell transplantation (HSCT) after CD19 chimeric antigen receptor T (CAR-T) therapy with non-HSCT in the treatment of acute lymphoblastic leukemia (ALL). METHODS: The PubMed, Embase, Cochrane Library and Web of Science databases were searched for clinical trials. Pooled hazard ratios (HRs) for overall survival (OS), relapse rate, and leukemia-free survival (LFS) as well as overall incidence rates for transplant-related mortality (TRM), acute graft-versus-host disease (aGVHD), chronic graft-versus-host disease (cGVHD), and infections were calculated using Stata software. RESULTS: We screened 3,441 studies and identified 19 eligible studies with 690 patients. Among the patients who achieved complete remission (CR) after CD19 CAR-T therapy, consolidative HSCT was beneficial for OS (HR = 0.34, 95% CI, 0.170.68, P = 0.003), the relapse rate (HR = 0.16, 95% CI, 0.100.25, P < 0.001), and LFS (HR = 0.15, 95% CI, 0.080.28, P < 0.001). For patients who achieved MRD-negative (neg) CR after CD19 CAR-T therapy, consolidative HSCT was beneficial for OS (0.57, 95% CI, 0.330.99, P = 0.045), the relapse rate (0.14, 95% CI, 0.060.31, P < 0.001), and LFS (0.21, 95% CI, 0.120.35, P < 0.001). Regarding safety, we calculated pooled incidence rates for TRM (8%, 95% CI, 0.020.15), aGVHD (44%, 95% CI, 0.230.67), cGVHD (36%, 95% CI, 0.170.56), and infections (39%, 95% CI, 0.030.83). CONCLUSIONS: Compared with non-HSCT treatment, consolidative HSCT after CD19 CAR-T therapy for R/R B-ALL patients can prolong OS and LFS and reduce the risk of relapse. The incidence rates for adverse events are acceptable. More high-quality randomized controlled trials are required to avoid bias and further determine the efficacy of HSCT.

Improving the short-term frequency stability of a magnetic-state-selected cesium beam clock with optical detection.

The microwave spectrum line shape and the signal-to-noise ratio of a compact optically detected magnetic-state-selection cesium beam clock are analyzed in this paper. As the noise analysis shows, the performance is related to the atomic utilization ratio and locking parameters when the laser frequency noise is the dominant noise source. Methods are adopted for realizing better short-term frequency stability of the clock, including using a highly efficient state-selection cesium beam tube, optimizing the locking parameters, and stabilizing the microwave power to maximize the error signal. After optimization, the signal-to-noise ratio of the clock reaches 7.0 × 103 in a bandwidth of 1 Hz and the clock demonstrates a short-term stability of 4.1 × 10-12 τ-1/2. The five-day Allan standard deviation reaches 7.7 × 10-15.

Challenges and Clinical Strategies of CAR T-Cell Therapy for Acute Lymphoblastic Leukemia: Overview and Developments.

Chimeric antigen receptor (CAR) T-cell therapy exhibits desirable and robust efficacy in patients with acute lymphoblastic leukemia (ALL). Stimulated by the revolutionized progress in the use of FDA-approved CD19 CAR T cells, novel agents with CAR designs and targets are being produced in pursuit of superior performance. However, on the path from bench to bedside, new challenges emerge. Accessibility is considered the initial barrier to the transformation of this patient-specific product into a commercially available product. To ensure infusion safety, profound comprehension of adverse events and proactive intervention are required. Additionally, resistance and relapse are the most critical and intractable issues in CAR T-cell therapy for ALL, thus precluding its further development. Understanding the limitations through up-to-date insights and characterizing multiple strategies will be critical to leverage CAR T-cell therapy flexibly for use in clinical situations. Herein, we provide an overview of the application of CAR T-cell therapy in ALL, emphasizing the main challenges and potential clinical strategies in an effort to promote a standardized set of treatment paradigms for ALL.