Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “controllable CAR”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources
PubMed2026

Engineering controllable CAR T-cell therapies: from binary safety switches to programmable immunity.

Chimeric antigen receptor (CAR) T-cell therapy has revolutionised cancer gene therapy, yet its expansion into solid tumours is hindered by a critical vulnerability: the autonomous, "always-on" nature of conventional CAR constructs. This unregulated activity drives severe toxicities, including cytokine release syndrome (CRS) and on-target/off-tumour damage, while constitutive signalling in hostile tumour microenvironments (TMEs) accelerates T-cell exhaustion. Early safety strategies relied on irreversible genetic "kill switches," which sacrifice the therapeutic cell population entirely. This review traces the conceptual evolution of CAR T-cell controllability from binary elimination towards platforms enabling graded, reversible, and spatiotemporally precise regulation. We examine the transition from calibrated signalling architectures and small-molecule-regulated split-CARs to advanced optogenetic and sonogenetic controllers, detailing the biophysics of photoreceptor pairs and their preclinical efficacy. Furthermore, we explore complementary architectures, including autonomous logic-gated receptors. Finally, we propose that the optimal next-generation CAR T product will integrate calibrated signalling, external control, and context-dependent armouring to achieve truly programmable, safe, and durable cellular immunotherapy.

Humans↗
PubMed2025

Engineering TME-activated CD47-specific CAR macrophage via Arg1 promoter for safe and effective solid tumor immunotherapy.

BACKGROUND: Chimeric antigen receptor macrophage (CAR-Mφ) therapy has promising therapeutic potential in solid tumors, yet challenges remain in target compatibility and systemic toxicity. METHODS: In this study, we screened the CD47-scFv sequence of CAR-Mφ as the extracellular structure. We then constructed a classical CD47 CAR-Mφ incorporated the costimulatory domain of the α1β1 integrin-mediated Fc-gamma receptor I (FcγRI) signaling component. Subsequently, we developed a tumor microenvironment (TME)-responsive CAR macrophage platform by the arginase 1 (Arg1) promoter to target CD47, a highly expressed but clinically challenging immune checkpoint in solid tumors. RESULTS: We found that anti-CD47-scFv-mediated macrophages can effectively kill tumor cells both in vivo and in vitro. Furthermore, by integrating an α1β1 integrin-mediated FcγRI signaling domain, CD47 CAR-Mφ exhibited superior antitumor activity in hCD47+4T1 and SGC-7901 cells in vitro, which demonstrated that the CD47 CAR-Mφ was effective against solid tumors. Subsequently, Arg1-mediated activated pArg1 CD47 CAR-Mφ exhibited strong cytotoxicity against target cancer cells. We further demonstrated TME-controllable CAR gene expression in situ and induced a significant regression of established tumors in vivo. Besides, TME-dependent activation of CD47 CAR Mφ reduced the cytotoxic killing effect on erythrocytes. CONCLUSIONS: Our findings confirmed that the TME-specific activation mechanism of pArg1 CD47 CAR-Mφ based on intrinsic Arg1 promoter reprogramming endowed CAR-Mφ to effectively mitigate erythrocyte toxicity while enabling safe multidose administration regimens. This Trojan horse-like CAR-Mφ system achieves tumor-specific activation while minimizing systemic toxicity, offering a novel strategy to expand CAR-Mφ applications for solid tumors.

Animals↗
PubMed1979

Effects of pretreatment with 6-hydroxydopamine or noradrenergic receptor blockers on the clonidine-induced distruption of conditioned avoidance responding.

The effects of clonidine were assessed on conditioned avoidance responses (CAR) in control, 6-hydroxy-dopamine (6-OHDA)- and vehicle-treated rats, using a shuttle box device. Clonidine (100--400 micrograms/kg) produced a significant decrease of CAR in control and vehicle-treated animals. On the other hand, avoidance responding was only slightly inhibited in the 6-OHDA-lesioned rats. Pretreatment with the alpha-adrenergic blocking drugs yohimbine or phentolamine (1--8 mg/kg) prevented the CAR disrupting effects of clonidine. When animals were pretreated with the beta-adrenergic blocking agent propranolol (1--8 mg/kg) the ensuing injection of clonidine caused a greater CAR depression. Our results further support the hypothesis relating the conditioned performance depression observed after clonidine to the activation of a presynaptic negative feedback mechanism mediated by alpha-adrenoceptors. It is also suggested that propranolol increases the clonidine inhibition through the blockade of a positive feedback mechanism dependent on the activation of presynaptic beta-receptors.

Animals↗
PubMed1979

The actions of dopaminergic and noradrenergic antagonists on conditioned avoidance responses in intact and 6-hydroxydopamine-treated rats.

The actions of various doses of haloperidol, pimozide, clozapine, and phenoxybenzamine were assessed on a conditioned-avoidance response (CAR) in control and 6-hydroxydopamine-treated rats, using a pole-climbing device. Haloperidol proved to be the most potent in disrupting the CAR. Pimozide was about 1.6 times less potent, and clozapine and phenoxybenzamine were approximately 52 and 155 times less potent than haloperidol, respectively. Prior treatment with 6-hydroxydopamine slightly enhanced the sensitivity to some of the doses of the DA and NE antagonists. Significantly lower levels of responding, however, were observed only after the highest dose of primozide. Clonidine was not only ineffective in reverting avoidance decrements, but also induced a further decline of the CAR. Apomorphine produced a partial, but significant, reversal of the haloperidol and pimozide-induced depression of conditioned responses. Regarding the clozapine-pretreated animals, a significant antagonism was observed only with the smaller dose of apomorphine. The highest dose induced a further decline of the CAR. The DA agonist was also ineffective in the phenoxybenzamine-injected rats. Amphetamine was effective in antagonizing the avoidance decrements produced by all the CA antagonists. Our results support the suggestion that CAR depends on both DA and NE mechanisms. DA seems to be more significant that NE, however, since the CAR was more depressed when receptors depending on the former neurotransmitter were blocked.

Amphetamine↗
PubMed2026

CERTOMICS: trusted single-cell multiomics pipeline for high-resolution profiling of adoptive cellular immunotherapies.

SUMMARY: Adoptive cellular immunontherapies, such as chimeric antigen receptor (CAR) T cell therapy, have transformed cancer treatment, yet challenges such as resistance, relapse, and high costs limit their efficacy and accessibility. A comprehensive understanding of cellular heterogeneity and molecular profiles is essential to improve these therapies. Advanced single-cell multiomics technologies have the power to analyze the complex interactions between CAR-engineered cells, immune cells, and tumor cells. However, standardized single-cell multiomics computational pipelines specifically tailored to CAR-engineered cell products are lacking. Due to the synthetic nature of CAR transgenes, additional steps for reliable identification and characterization of CAR-positive cells are required but not included in existing data-processing workflows. To address this, we present CERTOMICS, a Nextflow-based, CAR-aware pipeline offering enhanced CERTainty in immunophenotyping and data interpretation, tailored for single-cell multiOMICSprofiling of adoptive cellular immunotherapies. The pipeline standardizes processing 10x Genomics single-cell multiomics data and integrates CAR-specific identification and quality control. Additionally, a curated repository of CAR construct sequences and annotation data is provided, serving as an extensible resource to support the analysis and development of CAR T cell therapies. AVAILABILITY AND IMPLEMENTATION: Detailed documentation of this pipeline, along with a resource on latest FDA-approved CAR therapies is available on our website: https://fraunhofer-izi.github.io/Living-Drugs-Wiki/. The data underlying this article are available on GitHub at https://github.com/fraunhofer-izi/CERTOMICS. The code is also published on Zenodo at https://doi.org/10.5281/zenodo.18709693.

Multiomics↗
PubMed2026

Recent advances in molecular mechanisms to improve the efficacy of CAR-T cell therapy for viral diseases, cancer, and autoimmune diseases.

Chimeric antigen receptor (CAR)-T cell therapy has transformed the treatment of hematological malignancies, yet its broader application to solid tumors, chronic viral infections, and autoimmune diseases remains constrained by antigen heterogeneity, immunosuppressive tissue microenvironments, T-cell exhaustion, limited persistence, and treatment-associated toxicities. These challenges have shifted the field from optimizing individual receptor constructs toward engineering CAR-T cells as programmable immune systems capable of adapting to diverse disease contexts. This review synthesizes recent advances in molecular engineering strategies that enhance CAR-T cell function beyond conventional receptor design. We discuss how receptor engineering, genome editing, transcriptional and epigenetic regulation, metabolic reprogramming, synthetic gene circuits, and safety-control platforms collectively reshape CAR-T cell fate, persistence, and therapeutic efficacy. Rather than functioning independently, these engineering strategies are increasingly integrated to generate context-specific cellular therapies capable of adapting to diverse disease environments, including cancer, autoimmune diseases, and chronic viral infections. We also highlight the potential for translation into clinical practice or clinical translation and discuss the major challenges associated with clinical implementation. Next-generation CAR-T therapies will increasingly integrate molecular engineering strategies or will rely on molecular engineering strategies to integrate antigen recognition, cellular fitness, immune regulation, and longevity rather than simply maximizing cytotoxic activity. Recent advances in programmable cellular engineering coupled with rigorous clinical evaluation as well as scalable manufacturing technologies or scalable manufacturing platforms in the treatment of other diseases beyond oncology will facilitate the development of safer, more durable, and broadly applicable cellular therapies.

Humans↗
PubMed2025

Installation of Dominant-Negative Mutations in FAS and TGFβR2 via Base Editing in Primary T Cells.

Adoptive cell transfer (ACT) of engineered T cells is effective against B-cell malignancies but has faltered against solid tumors due to the immunosuppressive tumor microenvironment (TME). FASL and TGFβ are key mediators of T cell dysfunction in the TME and overexpressing dominant negative (dn) forms of their receptors in T cells increases anti-tumor efficacy in solid tumor models. However, an approach which directly targets the endogenous genes would be more amenable to multiplex editing and reduce competition with WT alleles. Here, we employ base editing (BE) in primary human T cells to install naturally occurring dominant negative FAS and TGFβR2 mutations. In vitro survival and proliferation assays demonstrate that BE T cells are resistant to pro-apoptotic and anti-proliferative effects of FAS and TGFβ signaling. CAR-T cells with BE-installed dn TGFβR2 or dn FAS exhibit improvements in cytotoxicity, while dn TGFβR2 CAR T demonstrate increased persistence and reduced expression of phenotypic markers of exhaustion compared to controls. Moreover, BE-engineered dn CAR T outperform lentiviral-engineered cDNA over expression counterparts in several functional assays. Considering the efficiency of BE and its amenability for multiplex editing, our novel approach lends itself to engineering strategies necessary to overcome T cell dysfunction in solid tumors.

CAR T↗
PubMed2026

CircRNA-based CD19-targeted CAR-NK therapy for B-cell acute lymphoblastic Leukemia using a Coccidioides immitis-derived group II intron platform.

Chimeric antigen receptor (CAR)-T cell therapy targeting CD19 has demonstrated notable clinical efficacy in the treatment of B-cell acute lymphoblastic leukemia (B-ALL), but its wider clinical applicability is constrained by long manufacturing processes, substantial costs, and severe adverse events. A potentially safer and more accessible alternative is provided by CAR-Natural killer (CAR-NK) cell therapy. Currently, most CAR-NK cells are generated using viral transduction, which is labor-intensive and associated with risks of genomic integration. Electroporation of CAR-encoding mRNA provides a non-integrating alternative but results in only transient CAR expression. Circular RNA (circRNA), owing to its enhanced stability and prolonged protein expression capacity, has recently emerged as a promising alternative to linear mRNA. To overcome the limitations of transient mRNA expression, we generated circRNA using a Group II intron-mediated cyclization system incorporating a newly selected Coccidioides immitis-derived Group II intron. The newly established Coccidioides immitis-derived Group II intron circularization system efficiently generated circRNA and supported more durable EGFP expression than linear mRNA in both HEK293T and NK92 cells. Using this system, we successfully developed a circRNA-based CD19-targeted CAR-NK platform. CircRNA-engineered CD19-targeted CAR-NK92 cells maintained more durable CAR expression and showed stronger antitumor activity at later time points. In mouse models of B-ALL, circRNA-engineered CAR-NK92 cells demonstrated better tumor control and extended survival compared with their linear mRNA-engineered counterparts. These results support the potential of circRNA-based CAR-NK therapy as an effective approach for enhancing the safety and efficacy of cancer immunotherapy.

Humans↗
PubMed1977

Differential airway reactivity to carbachol and physostigmine sulfate in rhesus monkeys with and without reagin-mediated respiratory responses.

Bronchial airway reactivity to carbachol (CAR) and physostigmine (PHY) was individually measured in three rhesus monkeys with and three rhesus monkeys without reagin-mediated respiratory responses (RR). The three monkeys with reagin-mediated RR demonstrated bronchial hyperreactivity to CAR (p less than 0.25) but not PHY when compared with the three control monkeys. No correlation between airway reactivity to CAR and PHY was noted in all six monkeys. We conclude that monkeys with reagin-mediated RR possess airway hyperreactivity to the exogenously administered acetylcholine analogue CAR, but not to the endogenous acetylcholine which is released in vivo by PHY.

Aerosols↗
PubMed1979

[The severely disabled: a new way of driving a car (author's transl)].

In many cases, the provision of an automobile equipped with a special control system is a necessary part of the rehabilitation of the severely disabled. The car is so important to the disabled as it enables him to overcome daily the distance between home and place of work, hence increasing his mobility and life quality. The presented care control system was developed to meet the individual needs of a particular disability. It is, however, possible to use this system for, or adapt it to, similar types of disabilities. This problem complex has been overcome by following innovations: 1. The electronically controlled accelerator which can be operated with minimal finger pressure. 2. The LIDA shoulder device for tetraplegics, a connecting piece between the shoulder and the manually operated brake lever. 3. The removable armrest on the right hand side of the driver's seat to improve the sitting stability. The car can be easily be converted for "normal driving". The author received financial assistance.

Automobile Driving↗
PubMed1979

Hyperactives as young adults: a controlled prospective ten-year follow-up of 75 children.

This study reports on a variety of outcome variables from 75 hyperactive and 44 matched control subjects aged 17 to 24 years (mean ages, 19.5 and 19.0 years, respectively). All hyperactive subjects have been followed up for 10 to 12 years; they were first evaluated at 6 to 12 years of age. None of the hyperactive subjects was treated with methylphenidate, although a subgroup received chlorpromazine or a mixture of drugs (excluding methylphenidate). The hyperactive subjects had less education than the controls and a history of more car accidents and more geographical moves. However, only a minority were still engaged in continued antisocial behavior or had evidence of severe psychopathology. No subjects were found to be psychotic, but two were diagnosed as borderline psychotic. There was evidence that hyperactive subjects had some continued symptoms from the hyperkinetic child syndrome, including impulsive personality traits.

Adolescent↗
PubMed1976

Social learning approaches to health education: utilization of infant auto restraint devices.

There has been little critical evaluation of which methods achieve the desired results in health education. Using purchase of proper infant auto restraint devices as an objective, we assessed the effectiveness of three educational approaches. Only 37% of control families had purchased an acceptable car seat, compared to 54% of those who received descriptive literature alone, 71% of those that received literature and had been shown a descriptive film, and 60% of those who were given literature, shown the film, and been provided with a demonstration of the seat. Purchase of car seats was positively correlated with social class and knowledge of auto safety, but not with a history of auto accidents. Utilization of auto restraint devices is an example of how social learning theory can be applied in health education.

Adolescent↗
PubMed1977

Child automobile restraints: evaluation of health education.

An experimental design was used to test the effectiveness of three modalities of instruction in pediatricians' offices. Parents in the experimental and control groups were asked if their children wore a car seat restraint on the way to the office. The parents in the experimental group were encouraged to have their children use restraints via one of the following methods: a pamphlet alone; a pamphlet and verbal instruction by the pediatrician; or a pamphlet, verbal instruction, and a brief slide-tape show. The parents were contacted by telephone, mail, or in person two weeks later and asked if their child used a restraint on their last car trip. There were no statistically significant changes in behavior in any of the gourps. Although the group that received all forms of instruction had the highest mean score, the greatest increase occurred with the control group.

Adolescent↗
PubMed2025

Integrated epigenetic and genetic programming of primary human T cells.

Targeted epigenetic engineering of gene expression in cell therapies would allow programming of desirable phenotypes without many of the challenges and safety risks associated with double-strand break-based genetic editing approaches. Here, we develop an all-RNA platform for efficient, durable and multiplexed epigenetic programming in primary human T cells, stably turning endogenous genes off or on using CRISPRoff and CRISPRon epigenetic editors. We achieve epigenetic programming of diverse targeted genomic elements without the need for sustained expression of CRISPR systems. CRISPRoff-mediated gene silencing is maintained through numerous cell divisions, T cell stimulations and in vivo adoptive transfer, avoiding cytotoxicity or chromosomal abnormalities inherent to multiplexed Cas9-mediated genome editing. Lastly, we successfully combined genetic and epigenetic engineering using orthogonal CRISPR Cas12a-dCas9 systems for targeted chimeric antigen receptor (CAR) knock-in and CRISPRoff silencing of therapeutically relevant genes to improve preclinical CAR-T cell-mediated in vivo tumor control and survival.

Humans↗
PubMed1979

Children's autokinetic movement as a function of inferred movement of target shape.

Four target shapes, a control stimulus (circle) and one each representing geometrical (arrow), representational (car), and symbolic (cross) implied movement were presented to 10 children in each of five age groups of boys and girls (4, 6, 8, 10, 12 yr.) in an autokinetic movement task. While there were no differences in direction of perceived movement with regard to the control stimulus (circle), all other target shapes showed a decrease in the effects of implied movement with increases in age. The minor sex differences were not reported.

Child↗
PubMed1977

[Immunotherapy of warts. Is it an experimental model for cancer immunotherapy?].

The warts produced by virus Papova, provedly cancerous, have immunological characteristics that allow to establish some analogies with cancer. Its immunotherapy is studied with levamisole and by means of a delayed immunity reaction "in situ" with regulated intensity. The level of delayed immunity in the patient with warts is established by quantitative DNCB test, finding that the same is impaired in 60% of men and 87% of women. The levamisol therapy cures 54% of warts. The patients that not cure but improve their delayed immunity level after the treatment with levamisol, are submitted to external application of DNCB, using a concentration calculated on the quantitative test results. With regard to their delayed immunity we introduce a new group of patients: the hiperergic type or reactive to 2,5 microgram of DNCB that cures their warts by the sole action of the test. Once obtained the curve of the distribution of delayed immunity values in the warts population before and after the levamisole therapy, we observe that the first is identical to that of cancer patients. In view of the tight relation among diseases with impaired delayed immunity, such as warts, herpes, aphtas, piodermitis and cancer (residual or postsurgical), we propose the same management, control and immunotherapy for all of them.

Clinical Trials as Topic↗
PubMed1979

Crossed acoustic response combined with visual and somatosensory evoked responses in the diagnosis of multiple sclerosis.

The crossed acoustic response, (CAR), a recently introduced test of brainstem function, has been studied in 66 patients with multiple sclerosis and 53 control subjects, and compared with conventional visual and somatosensory evoked responses (VER, SER). A latency abnormality was found in the CAR in 73% of patients, in the VER in 63%, and in the SER in 37%. Abnormalities have been related to the presence or absence of clinically detectable signs. All three responses detected subclinical lesions by showing abnormality in a proportion of multiple sclerosis patients who had no corresponding abnormal clinical signs (CAR 69%, VER 42%, SER 29%). The best diagnostic combination of responses was VER and CAR. Ninety per cent of patients had at least one of these two responses abnormal.

Acoustic Stimulation↗