Cited by Comprehensive genome editing confers ‘off-the-shelf’ CAR-T cells superior efficacy against solid tumors

CAR-T cell manufacturing landscape—Lessons from the past decade and considerations for early clinical development DOI

Juliana Dias,

John García,

Giulia Agliardi

et al.

Molecular Therapy — Methods & Clinical Development, Journal Year: 2024, Volume and Issue: 32(2), P. 101250 - 101250

Published: April 16, 2024

CAR-T cell therapies have consolidated their position over the last decade as an effective alternative to conventional chemotherapies for treatment of a number hematological malignancies. With exponential increase in commercial and hundreds phase 1 trials exploring efficacy different settings (including autoimmunity solid tumors), demand manufacturing capabilities recent years has considerably increased. In this review, we explore current landscape discuss some challenges limiting production capacity worldwide. We describe latest technical developments GMP platform design facilitate delivery range increasingly complex products, associated with translation new scientific into clinical products patients. all aspects process, namely early development, technology, quality control, requirements industrial scaling. Finally, faced small academic team, responsible high innovative our experience setup bench-to-clinic pipeline, streamlined workflow, implementation diverse portfolio trials.

Language: Английский

Citations

Reprogramming of Treg cells in the inflammatory microenvironment during immunotherapy: a literature review DOI

Xinyan Wu, Zhigang Zhou, Qiang Cao

et al.

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: Sept. 11, 2023

Regulatory T cells (Treg), as members of CD4+ cells, have garnered extensive attention in the research tumor progression. Treg function inhibiting immune effector preventing tissue damage, and suppressing inflammation. Under stimulation inflammatory microenvironment (IM), reprogramming enhances their suppression responses, ultimately promoting escape or Reducing number IM lowering activity while reprogramming, can help promote body's anti-tumor responses. This review introduces a mechanism IM; discusses regulation on The control response to immunotherapy are analyzed countermeasures proposed. work will provide foundation for downregulating immunosuppressive role environment future immunotherapy.

Language: Английский

Citations

Eras of designer Tregs: Harnessing synthetic biology for immune suppression DOI

Karoliina Tuomela, Kevin Salim, Megan K. Levings

et al.

Immunological Reviews, Journal Year: 2023, Volume and Issue: 320(1), P. 250 - 267

Published: July 31, 2023

Since their discovery, CD4+ CD25hi FOXP3hi regulatory T cells (Tregs) have been firmly established as a critical cell type for regulating immune homeostasis through plethora of mechanisms. Due to immunoregulatory power, delivery polyclonal Tregs has explored therapy dampen inflammation in the settings transplantation and autoimmunity. Evidence shows that Treg is safe well-tolerated, but efficacy remains undefined could be limited by poor persistence vivo lack antigen specificity. With advent new genetic engineering tools, it now possible create bespoke "designer" not only overcome limitations also introduce features. Here, we review development designer perspective three 'eras': (1) era FOXP3 engineering, which breakthroughs biological understanding this transcription factor enabled conversion conventional Tregs; (2) antigen-specificity era, transgenic T-cell receptors chimeric were introduced more potent directed therapies; (3) current harnessing advanced genome-editing techniques refine existing approaches. The year 2022 marked entry into clinic, with exciting potential application wide variety immune-mediated diseases.

Language: Английский

Citations

Label free metabolic imaging to enhance the efficacy of Chimeric Antigen Receptor T cell therapy DOI

Dan L. Pham,

Daniel Cappabianca,

Matthew H. Forsberg

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 23, 2024

Abstract Chimeric antigen receptor (CAR) T cell therapy for solid tumors remains challenging due to the complex manufacturing process and immunosuppressive tumor microenvironment. The condition directly impacts CAR yield, phenotype, metabolism, which correlate with in vivo potency persistence. Optical metabolic imaging (OMI) is a non-invasive, label-free method evaluate single metabolism based on autofluorescent coenzymes NAD(P)H FAD. Using OMI, we identified dominating of media composition over selection antibody stimulation and/or cytokines anti-GD2 activation strength kinetics, phenotype. We demonstrated that OMI parameters were indicative cycle stage optimal gene transfer conditions both viral transduction electroporation-based CRISPR/Cas9. Notably, accurately predicted oxidative phenotype virus-free CRISPR-edited cells correlated higher against neuroblastoma. Our data supports OMI’s potential as robust, sensitive analytical tool enables dynamic increased yield fitness. One sentence summary Autofluorescence informs enhance fitness

Language: Английский

Citations

La dolce vita: fueling chimeric antigen receptor (CAR) T cells with Glut1 to improve therapeutic efficacy DOI

Karen Slattery, David K. Finlay, Phillip K. Darcy

et al.

Immunometabolism, Journal Year: 2025, Volume and Issue: 7(1), P. e00055 - e00055

Published: Jan. 1, 2025

The approval of chimeric antigen receptor (CAR) T cell therapies for the treatment hematological cancers has marked a new era in cancer care, with seven products being FDA approved since 2017. However, challenges remain, and while profound effects are observed initially myeloma, majority patients relapse, which is concomitant poor CAR persistence. Similarly, efficacy therapy limited solid tumors, largely due to tumor heterogeneity, immune evasion mechanisms, infiltration In this recent study, Guerrero et al endeavor improve human cells by overexpressing glucose transporter GLUT1 show that have improved capacity persist control burden vivo.

Language: Английский

Citations

Phosphoglycerate mutase regulates Treg differentiation through control of serine synthesis and one-carbon metabolism DOI

Wesley H. Godfrey,

Kaho Cho,

Xiaojing Deng

et al.

Published: Jan. 30, 2025

The differentiation and suppressive functions of regulatory CD4 T cells (Tregs) are supported by a broad array metabolic changes, providing potential therapeutic targets for immune modulation. In this study, we focused on the role glycolytic enzymes in Tregs identified phosphoglycerate mutase (PGAM) as being differentially overexpressed associated with highly phenotype. Pharmacologic or genetic inhibition PGAM reduced Treg function while reciprocally inducing markers pro-inflammatory, helper 17 (Th17)-like state. was dependent contribution 3-phosphoglycerate (3PG), substrate, to de novo serine synthesis. Blocking synthesis from 3PG reversed effect polarization, exogenous directly inhibited polarization. Additionally, altering levels vivo serine/glycine-free diet increased peripheral attenuated autoimmunity murine model multiple sclerosis. Mechanistically, found that limits polarization contributing one-carbon metabolism methylation Treg-associated genes. Inhibiting both vitro autoimmune colitis. Our study identifies novel physiologic highlights interconnectivity between glycolysis, synthesis, metabolism, epigenetic regulation function.

Language: Английский

Citations

Phosphoglycerate mutase regulates Treg differentiation through control of serine synthesis and one-carbon metabolism DOI

Wesley H. Godfrey,

Kaho Cho,

Xiaojing Deng

et al.

Published: Jan. 30, 2025

Language: Английский

Citations

Role of metabolic transformation in cancer immunotherapy resistance: molecular mechanisms and therapeutic implications DOI

Sandesh Shende, Jaishriram Rathored,

Tanushree Budhbaware

et al.

Discover Oncology, Journal Year: 2025, Volume and Issue: 16(1)

Published: April 2, 2025

Immunotherapy in the treatment of cancer, with immune inhibitors helps many cancer types. Many patients still encounter resistance to these treatments, though. This is mediated by metabolic changes tumour microenvironment and cells. The development novel treatments overcome boost immunotherapy's effectiveness depends on changes. review concentrates molecular mechanisms through which transformation contributes immunotherapy resistance. Additionally, research therapeutic approaches that target pathways enhance for We used databases available PubMed, Scopus, Web Science perform a thorough peer-reviewed literature. focusing tumor microenvironment, mechanisms, metabolism. study covers oxidative phosphorylation, glycolysis, lipid metabolism, amino acid An immunosuppressive produced cells, such as dysregulated enhanced glutaminolysis, increased glycolysis (Warburg effect). Myeloid-derived suppressor cells regulatory T are promoted, responses suppressed, cell activity impaired when lactate other metabolites build up. metabolism acids arginine tryptophan, nutrients crucial function. By enhancing their function alterations aid checkpoint inhibitors. Metabolic change plays key role Gaining knowledge processes can help develop efficient improve effectiveness. In order determine best targets intervention, future studies should concentrate patient-specific profiling.

Language: Английский

Citations

Enhanced tumor control and survival in preclinical models with adoptive cell therapy preceded by low-dose radiotherapy DOI

Nahum Puebla‐Osorio, Natalie W. Fowlkes, Hampartsoum B. Barsoumian

et al.

Frontiers in Oncology, Journal Year: 2024, Volume and Issue: 14

Published: Oct. 9, 2024

Introduction Effective infiltration of chimeric antigen receptor T (CAR-T) cells into solid tumors is critical for achieving a robust antitumor response and improving therapeutic outcomes. While CAR-T cell therapies have succeeded in hematologic malignancies, their efficacy remains limited due to poor tumor penetration an immunosuppressive microenvironment. This study aimed evaluate the potential low-dose radiotherapy (LDRT) administered before T-cell therapy enhance effect by promoting infiltration. We hypothesized that combining LDRT with would improve control survival compared either treatment alone. Methods investigated this hypothesis using two NSG mouse models bearing GSU or CAPAN-2 tumors. The mice were treated engineered targeting guanyl cyclase-C (GCC) mesothelin as monotherapy combination LDRT. Additionally, we extended approach C57BL/6 model implanted MC38-gp100+ cells, followed adoptive transfer pmel+ after Tumor growth outcomes monitored all models. Furthermore, employed atomic force microscopy (AFM) small cohort assess effects on stiffness plasticity, exploring role nanomechanics biomarker efficacy. Results Our results demonstrated enhanced prolonged across led superior suppression monotherapy, highlighting synergistic impact combined approach. AFM analysis revealed significant changes plasticity LDRT, suggesting nanomechanical properties may be predictive response. Discussion findings highlight transformative incorporating precursor By microenvironment, improved outcomes, offering promising strategy overcome challenges associated observed through suggest could biomarkers predicting These support further investigation clinical application cell-based patients

Language: Английский

Citations

Molecular mechanism of co-stimulatory domains in promoting CAR-T cell anti-tumor efficacy DOI

Wanxin Zhao, Yizhou Yao, Qihong Li

et al.

Biochemical Pharmacology, Journal Year: 2024, Volume and Issue: 227, P. 116439 - 116439

Published: July 18, 2024

Language: Английский

Citations