Designing combination therapies for cancer treatment: application of a mathematical framework combining CAR T-cell immunotherapy and targeted radionuclide therapy.

Introduction: Cancer combination treatments involving immunotherapies with targeted radiation therapy are at the forefront of treating cancers. However, dosing and scheduling of these therapies pose a challenge. Mathematical models provide a unique way of optimizing these therapies. Methods: Using a preclinical model of multiple myeloma as an example, we demonstrate the capability of a mathematical model to combine these therapies to achieve maximum response, defined as delay in tumor growth. Data from mice studies with targeted radionuclide therapy (TRT) and chimeric antigen receptor (CAR)-T cell monotherapies and combinations with different intervals between them was used to calibrate mathematical model parameters. The dependence of progression-free survival (PFS), overall survival (OS), and the time to minimum tumor burden on dosing and scheduling was evaluated. Different dosing and scheduling schemes were evaluated to maximize the PFS and optimize timings of TRT and CAR-T cell therapies. Results: Therapy intervals that were too close or too far apart are shown to be detrimental to the therapeutic efficacy, as TRT too close to CAR-T cell therapy results in radiation related CAR-T cell killing while the therapies being too far apart result in tumor regrowth, negatively impacting tumor control and survival. We show that splitting a dose of TRT or CAR-T cells when administered in combination is advantageous only if the first therapy delivered can produce a significant benefit as a monotherapy. Discussion: Mathematical models are crucial tools for optimizing the delivery of cancer combination therapy regimens with application along the lines of achieving cure, maximizing survival or minimizing toxicity.

Two {CuI[P4Mo6]2}-Based Coordination Polymers Incorporating In Situ Converted Tetrapyridyl Ligands for Trace Analysis of Nitrofuran Antibiotics.

Nitrofurans are important synthetic broad-spectrum antibacterial drugs with the basic structure of 5-nitrofuran. Due to their toxicity, it is essential to develop a sensitive sensor with strong anti-interference capabilities for their detection. In this work, two {P4Mo6O31}12--based compounds, [H4(HPTTP)]2{CuI[Mo12O24(OH)6(PO4)3(HPO4)(H2PO4)4]}·xH2O (x = 13 for (1), 7 for (2); HPTTP = 4,4',4″,4‴-(1H-pyrrole-2,3,4,5-tetrayl)tetrapyridine), exhibiting similar coordination but distinct stacking modes. Both compounds were synthesized and used for the electrochemical detection of nitrofuran antibiotics. The tetrapyridine-based ligand was generated in situ during assembly, and its potential mechanism was discussed. Composite electrode materials, formed by mixing graphite powder with compounds 1-2 and physically grinding them, proved to be highly effective in the electrochemical trace detection of furazolidone (FZD) and furaltadone hydrochloride (FTD·HCl) under optimal conditions. Besides, the possible electrochemical detection mechanisms of two nitro-antibiotics were studied.

A scalable Li-Al-Cl stratified structure for stable all-solid-state lithium metal batteries.

Sulfides are promising electrolyte materials for all-solid-state Li metal batteries due to their high ionic conductivity and machinability. However, compatibility issues at the negative electrode/sulfide electrolyte interface hinder their practical implementation. Despite previous studies have proposed considerable strategies to improve the negative electrode/sulfide electrolyte interfacial stability, industrial-scale engineering solutions remain elusive. Here, we introduce a scalable Li-Al-Cl stratified structure, formed through the strain-activated separating behavior of thermodynamically unfavorable Li/Li9Al4 and Li/LiCl interfaces, to stabilize the negative electrode/sulfide electrolyte interface. In the Li-Al-Cl stratified structure, Li9Al4 and LiCl are enriched at the surface to serve as a robust solid electrolyte interphase and are diluted in bulk by Li metal to construct a skeleton. Enabled by its unique structural characteristic, the Li-Al-Cl stratified structure significantly enhances the stability of negative electrode/sulfide electrolyte interface. This work reports a strain-activated phase separation phenomenon and proposes a practical pathway for negative electrode/sulfide electrolyte interface engineering.

Neoadjuvant Photodynamic Therapy: An Updated Therapeutic Approach for Non-Melanoma Skin Cancers.

OPINION STATEMENT: Non-melanoma skin cancers (NMSCs) are the most common malignancy and surgical excision is considered treatment of choice for the majority of cases. However, surgery can be very extensive in cases of large, multiple, or cosmetic-sensitive tumors located on areas such as scalp and face or genital region, leading to significant functional and cosmetic deficit. Aminolaevulinic acid photodynamic therapy (ALA-PDT) has emerged as a widely used approach in a variety of skin diseases, demonstrating remarkable efficacy in treatment of actinic keratosis, Bowen disease and basal cell carcinoma. Besides, when employed as a preoperative intervention, ALA-PDT effectively reduces tumor size and minimizes subsequent local surgical morbidity. With its minimally invasive nature and proven effectiveness, ALA-PDT holds significant promise as a neoadjuvant treatment option for NMSCs. In cases where the tumor is large, invasive, multiple, or located in cosmetically and functionally sensitive areas, or when considering patient factors such as age, comorbidity, willingness to undergo surgery, and post-operative quality-of-life, surgical intervention or radiotherapy alone may be impracticable or unacceptable. In such scenarios, neoadjuvant ALA-PDT can offer remarkable outcomes. In order to further ensure the maximum benefit of patients from neoadjuvant PDT, collaboration with multidisciplinary teams and whole-process management may be in need.

PI3K/HSCB axis facilitates FOG1 nuclear translocation to promote erythropoiesis and megakaryopoiesis.

Erythropoiesis and megakaryopoiesis are stringently regulated by signaling pathways. However, the precise molecular mechanisms through which signaling pathways regulate key transcription factors controlling erythropoiesis and megakaryopoiesis remain partially understood. Herein, we identified heat shock cognate B (HSCB), which is well known for its iron-sulfur cluster delivery function, as an indispensable protein for friend of GATA 1 (FOG1) nuclear translocation during erythropoiesis of K562 human erythroleukemia cells and cord-blood-derived human CD34+CD90+hematopoietic stem cells (HSCs), as well as during megakaryopoiesis of the CD34+CD90+HSCs. Mechanistically, HSCB could be phosphorylated by phosphoinositol-3-kinase (PI3K) to bind with and mediate the proteasomal degradation of transforming acidic coiled-coil containing protein 3 (TACC3), which otherwise detained FOG1 in the cytoplasm, thereby facilitating FOG1 nuclear translocation. Given that PI3K is activated during both erythropoiesis and megakaryopoiesis, and that FOG1 is a key transcription factor for these processes, our findings elucidate an important, previously unrecognized iron-sulfur cluster delivery independent function of HSCB in erythropoiesis and megakaryopoiesis.

Comparing Sonazoid contrast-enhanced ultrasound to contrast-enhanced CT and MRI for differentially diagnosing renal lesions: a prospective multicenter study.

PURPOSE: To evaluate the diagnostic performance of contrast-enhanced (CE) ultrasound using Sonazoid (SNZ-CEUS) by comparing with contrast-enhanced computed tomography (CE-CT) and contrast-enhanced magnetic resonance imaging (CE-MRI) for differentiating benign and malignant renal masses. MATERIALS AND METHODS: 306 consecutive patients (from 7 centers) with renal masses (40 benign tumors, 266 malignant tumors) diagnosed by both SNZ-CEUS, CE-CT or CE-MRI were enrolled between September 2020 and February 2021. The examinations were performed within 7 days, but the sequence was not fixed. Histologic results were available for 301 of 306 (98.37%) lesions and 5 lesions were considered benign after at least 2 year follow-up without change in size and image characteristics. The diagnostic performances were evaluated by sensitivity, specificity, positive predictive value, negative predictive value, and compared by McNemar's test. RESULTS: In the head-to-head comparison, SNZ-CEUS and CE-MRI had comparable sensitivity (95.60 vs. 94.51%, P = 0.997), specificity (65.22 vs. 73.91%, P = 0.752), positive predictive value (91.58 vs. 93.48%) and negative predictive value (78.95 vs. 77.27%); SNZ-CEUS and CE-CT showed similar sensitivity (97.31 vs. 96.24%, P = 0.724); however, SNZ-CEUS had relatively lower than specificity than CE-CT (59.09 vs. 68.18%, P = 0.683). For nodules > 4 cm, CE-MRI demonstrated higher specificity than SNZ-CEUS (90.91 vs. 72.73%, P = 0.617) without compromise the sensitivity. CONCLUSIONS: SNZ-CEUS, CE-CT, and CE-MRI demonstrate desirable and comparable sensitivity for the differentiation of renal mass. However, the specificity of all three imaging modalities is not satisfactory. SNZ-CEUS may be a suitable alternative modality for patients with renal dysfunction and those allergic to gadolinium or iodine-based agents.

Real-world data of 5-aminolevulinic acid-mediated photodynamic therapy for Bowen's disease: A 10-year retrospective study in the skin of color patients (2011-2021).

BACKGROUND: Photodynamic therapy (PDT) has been strongly recommended as an excellent alternative treatment for Bowen's disease (BD). However, reported data on 5-aminolevulinic acid-mediated PDT (ALA-PDT) with red light irradiation are limited and the long-term effectiveness remains to be determined, especially in dark-skinned populations. METHODS: Medical records of BD patients who received ALA-PDT with red light irradiation between February 2011 and June 2021 were reviewed and summarized. Univariate and multivariate analyses of clinically relevant variables that may affect treatment outcomes were performed to identify risk predictors. RESULTS: The overall clearance rate of 122 BD lesions was 89.3% with a median follow-up time of 36 months. The correlation between the effectiveness and fluorescence intensity of pre-PDT or PDT sessions was statistically significant after eliminating the interference of confounding factors. All recurrences occurred in the first two years following ALA-PDT. CONCLUSION: ALA-PDT is an effective treatment for BD in the skin of color patients. Well-executed operation and effective pre-treatment are the determinants of effectiveness. Fluorescence intensity of pre-PDT appeared to be a significant predictor of final effectiveness. In addition, two years of follow-up is necessary following ALA-PDT.

Magnetic composite microspheres with a controlled mesoporous shell for highly efficient DNA extraction and fragment screening.

Rapid extraction and screening of high-purity DNA fragments is an indispensable technology in advanced molecular biology. In this article, mesoporous magnetic composite microspheres (MSP@mTiO2) with tunable pore sizes were successfully fabricated for high-purity DNA extraction and fragment screening. Owing to the strong complexation ability of Ti ions with DNA phosphate groups and the high specific surface area of mesoporous microspheres, the MSP@mTiO2 microspheres possess excellent adsorption performance, where the saturated loading capacity of MSP@mTiO2 with a specific surface area of 122 m2 g-1 is as high as 575 µg mg-1 for a salmon sperm specimen. ITC experiments demonstrated that DNA adsorption on MSP@mTiO2 microspheres is mainly driven by entropy, which gives us more potential ways to regulate the balance of adsorption and desorption. Meanwhile, the mesoporous MSP@mTiO2 microspheres exhibit a much higher extraction efficiency compared with non-porous MSP@TiO2 for whole genome DNA from Arabidopsis thaliana plants. Interestingly, DNA fragments with different lengths could be screened by simply regulating the pore size of MSP@mTiO2 or the concentration of Na3PO4 in the eluent. A small pore size and low phosphate concentration are advantageous for the extraction of short-stranded DNA fragments, and DNA fragments (≤1000 bp) can be efficiently extracted when the mesopore size of MSP@mTiO2 is lower than 7.6 nm. The extraction results from the mesoporous composite microspheres provide new promising insights into the purification and screening of DNA from complex biological samples.

A piezoelectric-driven microneedle platform for skin disease therapy.

With over a million cases detected each year, skin disease is a global public health problem that diminishes the quality of life due to its difficulty to eradicate, propensity for recurrence, and potential for post-treatment scarring. Photodynamic therapy (PDT) is a treatment with minimal invasiveness or scarring and few side effects, making it well tolerated by patients. However, this treatment requires further research and development to improve its effective clinical use. Here, a piezoelectric-driven microneedle (PDMN) platform that achieves high efficiency, safety, and non-invasiveness for enhanced PDT is proposed. This platform induces deep tissue cavitation, increasing the level of protoporphyrin IX and significantly enhancing drug penetration. A clinical trial involving 25 patients with skin disease was conducted to investigate the timeliness and efficacy of PDMN-assisted PDT (PDMN-PDT). Our findings suggested that PDMN-PDT boosted treatment effectiveness and reduced the required incubation time and drug concentration by 25% and 50%, respectively, without any anesthesia compared to traditional PDT. These findings suggest that PDMN-PDT is a safe and minimally invasive approach for skin disease treatment, which may improve the therapeutic efficacy of topical medications and enable translation for future clinical applications.

A review on ferroptosis and photodynamic therapy synergism: Enhancing anticancer treatment.

Ferroptosis is an iron-dependent programmed cell death modality, which has showed great potential in anticancer treatment. Photodynamic therapy (PDT) is widely used in clinic as an anticancer therapy. PDT combined with ferroptosis-promoting therapy has been found to be a promising strategy to improve anti-cancer therapy efficacy. Fenton reaction in ferroptosis can provide oxygen for PDT, and PDT can produce reactive oxygen species for Fenton reaction to enhance ferroptosis. In this review, we briefly present the importance of ferroptosis in anticancer treatment, mechanism of ferroptosis, researches on PDT induced ferroptosis, and the mechanism of the synergistic effect of PDT and ferroptosis on cancer killing.

Hazard evaluation of forest combustibles based on the correlation between pyrolysis products and combustion parameters.

Persistent organic pollutants (POPs) sourced by the forest fire release are emerging as significant contributors. Despite their increasing importance, the impact of forest fires on POPs remains inadequately explored and an unclear understanding. Herein, the research, choosing four typical forest combustibles, focuses on the relationship between typical POPs and wildfire parameters by assessing the predominant compounds and their concentration in POPs emissions from such fuels through molecular-level analysis. Experiments reveal forest combustibles thermally degrade to release products, releasing a variety of products, including acids (>7.94 %), aldehydes (>2.32 %), ketones (>3.40 %), alcohols (>7.70 %), esters (>2.33 %), ethers (>4.44 %), hydrocarbons (>6.36 %), aromatic compounds (>21.40 %), and nitrogen-bearing compounds (>11.83 %); notably, aromatic compounds, containing substantial concentrations, are also recognized as POPs. By delving into the pyrolysis (20 °C·ms-1) and burning processes (25, 35 and 50 kW/m2) of forest combustibles, we can gain a comprehensive understanding of the origin of POPs in wildfires. Moreover, Pearson correlation analysis is employed to establish connections between emitting volatiles and forest fire risk, further unveiling a significant correlation between fire hazards of forest combustibles and the presence of aromatic compounds (Correlation over 0.8). These findings are crucial for comprehending the POPs in forests and evaluating forest fire hazards at the molecular level.

Four POM-Viologen Color-Changing Materials with Fast Color Response under Various External Stimuli.

Four kinds of polyoxometalate (POM)-viologen compounds were synthesized by hydrothermal method, namely (1-cby)2·[H2(SiMo12O40)]·2H2O (1), (1-cby)2·[H2(SiW12O40)]·2H2O (2), (1-cby)2·(1,1'-bcby)2·{H4[Co4(H2O)2(PW9O34)2]}·12H2O (3), (1-cby)·(1,1'-bcby)·[H(α-PW11O39)CoII(1-cby)]·8H2O (4) (1-cby·Br = 1-Cyclopropylmethyl-[4,4']bipyridinyl-1-ium bromide, 1,1'-bcby·Br = 1,1'-Bis-cyclopropylmethyl-[4,4']bipyridinyl-1-ium bromide). These four POM-viologen compounds exhibit one-dimensional supramolecular network structures. Especially, compound 3 contains a rare sandwich POM subunit {Co4(H2O)2(PW9O34)2}10-. These four compounds can be used as color-changing materials, and they all exhibit noticeable color changes upon exposure to light, heat, and electricity. The discoloration mechanism involves viologen derivatives with electron-deficient properties accepting electrons from POM with electron-rich properties under external stimulation, leading to the formation of viologen free radicals. Among them, compounds 1 and 2 also have good properties for ink-free erasable printing, double anticounterfeiting, and ultraviolet detector because of their rapid color response to ultraviolet (UV) light. In addition, compounds 1-4 also show different color changes in the detection of volatile amines.

Impact of baseline and longitudinal allostatic load changes on incident cardiovascular disease and all-cause mortality: A 7-year population-based cohort study in China.

BACKGROUND: We aimed to prospectively examine the association of baseline allostatic load (AL) and longitudinal AL changes with incident cardiovascular disease (CVD) and all-cause mortality among middle-aged and elderly Chinese populations and evaluate the relative contributions of each physiological system of AL. METHODS: Data from the China Health and Retirement Longitudinal Study (CHARLS) among adults aged 45 years or older were analyzed. Cox regression models were used to estimate the hazard ratios (HRs) and 95 % confidence intervals (95 % CIs) for the associations between baseline AL/longitudinal AL changes with incident CVD and all-cause mortality. RESULTS: Compared with adults with AL 0-1, HRs of those with baseline AL 2-3 and AL ≥ 4 were 1.24 (95 % CI: 1.06, 1.45) and 1.51 (95 % CI: 1.27, 1.80) for incident CVD, and 1.39 (95 % CI: 1.11, 1.75) and 2.02 (95 % CI: 1.60, 2.54) for all-cause mortality. Similar results were found when we treated baseline AL as a continuous variable. We also found per AL score increase during 4 years of follow-up was related to a 11 % (HR, 1.11; 95 % CI: 1.03, 1.20) and 21 % (HR, 1.21; 95 % CI: 1.10, 1.34) increase in incident CVD and all-cause mortality, respectively. LIMITATIONS: Self-reported physician-diagnosed CVD was used to assess the incident CVD. CONCLUSIONS: Both baseline AL and longitudinal increases in AL were positively associated with incident CVD and all-cause mortality in middle-aged and elderly adults. Individuals with high AL need to be dynamically monitored for CVD and pre-mature mortality prevention.

Clinical practice guidelines for prevention and treatment of postoperative gastrointestinal disorder with Integrated Traditional Chinese and Western Medicine (2023).

Postoperative gastrointestinal disorder (POGD) was a common complication after surgery under anesthesia. Strategies in combination with Traditional Chinese Medicine and Western medicine showed some distinct effects but standardized clinical practice guidelines were not available. Thus, a multidisciplinary expert team from various professional bodies including the Perioperative and Anesthesia Professional Committees of the Chinese Association of Integrative Medicine (CAIM), jointly with Gansu Province Clinical Research Center of Integrative Anesthesiology/Anesthesia and Pain Medical Center of Gansu Provincial Hospital of Traditional Chinese Medicine and WHO Collaborating Center for Guideline Implementation and Knowledge Translation/Chinese Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) Center/Gansu Provincial Center for Medical Guideline Industry Technology/Evidence-based Medicine Center of Lanzhou University, was established to develop evidence-based guidelines. Clinical questions (7 background and 12 clinical questions) were identified through literature reviews and expert consensus meetings. Based on systematic reviews/meta-analyses, evidence quality was analyzed and the advantages and disadvantages of interventional measures were weighed with input from patients' preferences. Finally, 20 recommendations were developed through the Delphi-based consensus meetings. These recommendations included disease definitions, etiologies, pathogenesis, syndrome differentiation, diagnosis, and perioperative prevention and treatment.

Deciphering the critical role of interstitial volume in glassy sulfide superionic conductors.

Sulfide electrolytes represent a crucial category of superionic conductors for all-solid-state lithium metal batteries. Among sulfide electrolytes, glassy sulfide is highly promising due to its long-range disorder and grain-boundary-free nature. However, the lack of comprehension regarding glass formation chemistry has hindered their progress. Herein, we propose interstitial volume as the decisive factor influencing halogen dopant solubility within a glass matrix. We engineer a Li3PS4-Li4SiS4 complex structure within the sulfide glassy network to facilitate the release of interstitial volume. Consequently, we increase the dissolution capacity of LiI to 40 mol% in 75Li2S-25P2S5 glass. The synthesized glass exhibits one of the highest ionic conductivities among reported glass sulfides. Furthermore, we develop a glassy/crystalline composite electrolyte to mitigate the shortcomings of argyrodite-type sulfides by utilizing our synthesized glass as the filler. The composite electrolytes effectively mitigate Li intrusion. This work unveils a protocol for the dissolution of halogen dopants in glass electrolytes.

Is low-dose computed tomography for lung cancer screening conveniently accessible in China? A spatial analysis based on cross-sectional survey.

BACKGROUND: Regular Low-Dose Computed Tomography (LDCT) for lung cancer high-risk population has been proved to improve health outcomes and relieve disease burden efficiently for both individual and society. With geographical impedance becoming the major barrier preventing patients from getting timely healthcare service, this study incorporated health seeking behavior in estimating spatial accessibility of relative scarce LDCT resource in China, thus to provide real-world evidence for future government investment and policy making. METHODS: Taking Sichuan Province in southwest China as the study area, a cross-sectional survey was first carried out to collect actual practice and preferences for seeking LDCT services. Using Computed Tomography (CT) registration data reported by owner institutions representing LDCT services capacity, and grided town-level high-risk population as demand, the Nearest Neighbor Method was then utilized to calculate spatial accessibility of LDCT services. RESULTS: A total of 2,529 valid questionnaires were collected, with only 34.72% of the high-risk populations (746 individuals) followed the recommended annual screening. Participants preferred to travel to municipal-level and above institutions within 60 min for LDCT services. Currently, every thousand high-risk populations own 0.0845 CT scanners in Sichuan Province, with 96.95% able to access LDCT within 60 min and over half within 15 min. Urban areas generally showed better accessibility than rural areas, and the more developed eastern regions were better than the western regions with ethnic minority clusters. CONCLUSIONS: Spatial access to LDCT services is generally convenient in Sichuan Province, but disparity exists between different regions and population groups. Improving LDCT capacity in county-level hospitals as well as promoting health education and policy guidance to the public can optimize efficiency of existing CT resources. Implementing mobile CT services and improving rural public transportation may alleviate emerging disparities in accessing early lung cancer detection.

Nano-Interfacial Supramolecular Adhesion of Metal-Organic Framework-Based Separator Enables High-Safety and Wide-Temperature-Range Lithium Batteries.

Polyolefin separators are the most commonly used separators for lithium batteries; however, they tend to shrink when heated, and their Li+ transference number (t Li +) is low. Metal-organic frameworks (MOFs) are expected to solve the above problems due to their high thermal stability, abundant pore structure, and open metal sites. However, it is difficult to prepare high-porosity MOF-based membranes by conventional membrane preparation methods. In this study, a high-porosity free-standing MOF-based safety separator, denoted the BCM separator, is prepared through a nano-interfacial supramolecular adhesion strategy. The BCM separator has a large specific surface area (450.22 m2 g-1) and porosity (62.0%), a high electrolyte uptake (475 wt%), and can maintain its morphology at 200 °C. The ionic conductivity and t Li + of the BCM separator are 1.97 and 0.72 mS cm-1, respectively. Li//LiFePO4 cells with BCM separators have a capacity retention rate of 95.07% after 1100 cycles at 5  C, a stable high-temperature cycling performance of 300 cycles at 80 °C, and good capacity retention at -40 °C. Li//NCM811 cells with BCM separators exhibit significantly improved rate performance and cycling performance. Pouch cells with BCM separators can work at 120 °C and have good safety at high temperature.

Disrupted Structural Brain Networks and Structural-Functional Decoupling in First-Episode Drug-Naïve Adolescent Major Depressive Disorder.

PURPOSE: Major depressive disorder (MDD) tends to emerge during adolescence, but the neurobiology of adolescent MDD is still poorly understood. This study aimed to explore the topological organization of white matter structural networks and the relationship between structural and functional connectivity in adolescent MDD. METHODS: Structural and functional magnetic resonance imaging data were acquired from 94 first-episode drug-naïve adolescent MDD patients and 78 healthy adolescents. Whole brain structural and functional brain networks were constructed for each subject. Then, the topological organization of structural brain networks and the coupling strength between structural and functional connectivity were analyzed. RESULTS: Compared with controls, adolescent MDD patients showed disrupted small-world, rich-club, and modular organizations. Nodal centralities in the medial part of bilateral superior frontal gyrus, bilateral hippocampus, right superior occipital gyrus, right angular gyrus, bilateral precuneus, left caudate nucleus, bilateral putamen, right superior temporal gyrus, and right temporal pole part of superior temporal gyrus were significantly lower in adolescent MDD patients compared with controls. The coupling strength between structural and functional connectivity was significantly lower in adolescent MDD patients compared with controls. DISCUSSION: Our findings suggest widespread disruption of structural brain networks and structural-functional decoupling in adolescent MDD, potentially leading to reduced network communication capacity.

Immunometabolic Adaptation of CD19-Targeted CAR T Cells in the Central Nervous System Microenvironment of Patients Promotes Memory Development.

Metabolic reprogramming is a hallmark of T-cell activation, and metabolic fitness is fundamental for T-cell-mediated antitumor immunity. Insights into the metabolic plasticity of chimeric antigen receptor (CAR) T cells in patients could help identify approaches to improve their efficacy in treating cancer. Here, we investigated the spatiotemporal immunometabolic adaptation of CD19-targeted CAR T cells using clinical samples from CAR T-cell-treated patients. Context-dependent immunometabolic adaptation of CAR T cells demonstrated the link between their metabolism, activation, differentiation, function, and local microenvironment. Specifically, compared with the peripheral blood, low lipid availability, high IL15, and low TGFß in the central nervous system microenvironment promoted immunometabolic adaptation of CAR T cells, including upregulation of a lipolytic signature and memory properties. Pharmacologic inhibition of lipolysis in cerebrospinal fluid led to decreased CAR T-cell survival. Furthermore, manufacturing CAR T cells in cerebrospinal fluid enhanced their metabolic fitness and antileukemic activity. Overall, this study elucidates spatiotemporal immunometabolic rewiring of CAR T cells in patients and demonstrates that these adaptations can be exploited to maximize the therapeutic efficacy of CAR T cells. SIGNIFICANCE: The spatiotemporal immunometabolic landscape of CD19-targeted CAR T cells from patients reveals metabolic adaptations in specific microenvironments that can be exploited to maximize the therapeutic efficacy of CAR T cells.