Co-Stimulatory Receptor Signaling in CAR-T Cells

Biomolecules, Journal Year: 2022, Volume and Issue: 12(9), P. 1303 - 1303

Published: Sept. 15, 2022

T cell engineering strategies have emerged as successful immunotherapeutic approaches for the treatment of human cancer. Chimeric Antigen Receptor (CAR-T) therapy represents a prominent synthetic biology approach to re-direct specificity patient’s autologous cells toward desired tumor antigen. CAR-T is currently FDA approved hematological malignancies, including subsets B lymphoma, acute lymphoblastic leukemia (ALL) and multiple myeloma. Mechanistically, CAR-mediated recognition antigen results in propagation activation signals, co-stimulatory signal, resulting activation, proliferation, evasion apoptosis, acquisition effector functions. The importance domain CARs was recognized following limited success early iteration designs lacking co-stimulation. Today, all clinical use contain either CD28 or 4-1BB domain. Preclinical investigations are exploring utility additional molecules such ICOS, OX40 CD27 various combinations domains. Clinical preclinical evidence implicates signal several aspects response kinetics, persistence durability, toxicity profiles each which impact safety anti-tumor efficacy this immunotherapy. Herein we provide an overview co-stimulation by prototypical receptors discuss current emerging modulate signals enhance function.

Language: Английский

---

Effects of dietary intervention on human diseases: molecular mechanisms and therapeutic potential

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: March 11, 2024

Abstract Diet, serving as a vital source of nutrients, exerts profound influence on human health and disease progression. Recently, dietary interventions have emerged promising adjunctive treatment strategies not only for cancer but also neurodegenerative diseases, autoimmune cardiovascular metabolic disorders. These demonstrated substantial potential in modulating metabolism, trajectory, therapeutic responses. Metabolic reprogramming is hallmark malignant progression, deeper understanding this phenomenon tumors its effects immune regulation significant challenge that impedes eradication. Dietary intake, key environmental factor, can tumor metabolism. Emerging evidence indicates might affect the nutrient availability tumors, thereby increasing efficacy treatments. However, intricate interplay between pathogenesis other diseases complex. Despite encouraging results, mechanisms underlying diet-based remain largely unexplored, often resulting underutilization management. In review, we aim to illuminate various interventions, including calorie restriction, fasting-mimicking diet, ketogenic protein restriction high-salt high-fat high-fiber aforementioned diseases. We explore multifaceted impacts these encompassing their immunomodulatory effects, biological impacts, molecular mechanisms. This review offers valuable insights into application therapies

Language: Английский

---

Simultaneous targeting of PD-1 and IL-2Rβγ with radiation therapy inhibits pancreatic cancer growth and metastasis

Cancer Cell, Journal Year: 2023, Volume and Issue: 41(5), P. 950 - 969.e6

Published: April 27, 2023

In pancreatic ductal adenocarcinoma (PDAC) patients, we show that response to radiation therapy (RT) is characterized by increased IL-2Rβ and IL-2Rγ along with decreased IL-2Rα expression. The bispecific PD1-IL2v a PD-1-targeted IL-2 variant (IL-2v) immunocytokine engineered cis targeted PD-1 abolished binding, which enhances tumor-antigen-specific T cell activation while reducing regulatory (Treg) suppression. Using in orthotopic PDAC KPC-driven tumor models, marked improvement local metastatic survival, profound increase tumor-infiltrating CD8

Language: Английский

---

Spatial metabolomics: from a niche field towards a driver of innovation

Nature Metabolism, Journal Year: 2023, Volume and Issue: 5(9), P. 1443 - 1445

Published: Sept. 7, 2023

Language: Английский

---

Differential peripheral immune signatures elicited by vegan versus ketogenic diets in humans

Nature Medicine, Journal Year: 2024, Volume and Issue: 30(2), P. 560 - 572

Published: Jan. 30, 2024

Abstract Nutrition has broad impacts on all physiological processes. However, how nutrition affects human immunity remains largely unknown. Here we explored the impact of a dietary intervention both and microbiota by performing post hoc analysis clinical trial in which each 20 participants sequentially consumed vegan or ketogenic diets for 2 weeks ( NCT03878108 ). Using multiomics approach including multidimensional flow cytometry, transcriptomic, proteomic, metabolomic metagenomic datasets, assessed diet, switch, host microbiota. Our data revealed that overall, diet was associated with significant upregulation pathways enrichment cells adaptive immune system. In contrast, had innate system, antiviral immunity. Both significantly differentially impacted microbiome host-associated amino acid metabolism, strong downregulation most microbial following compared baseline diet. Despite diversity participants, also observed tightly connected network between datasets driven compounds acids, lipids Collectively, this work demonstrates diverse controlled is sufficient to divergently immunity, could have implications precision nutritional interventions. ClinicalTrials.gov registration: .

Language: Английский

---

A versatile CRISPR-Cas13d platform for multiplexed transcriptomic regulation and metabolic engineering in primary human T cells

Cell, Journal Year: 2024, Volume and Issue: 187(5), P. 1278 - 1295.e20

Published: Feb. 1, 2024

Language: Английский

---

A guide to adaptive immune memory

Nature reviews. Immunology, Journal Year: 2024, Volume and Issue: unknown

Published: June 3, 2024

Language: Английский

---

Metformin-based nanomedicines for reprogramming tumor immune microenvironment

Theranostics, Journal Year: 2024, Volume and Issue: 15(3), P. 993 - 1016

Published: Dec. 2, 2024

Immunotherapy has transformed current cancer management, and it achieved significant progress over last decades. However, an immunosuppressive tumor microenvironment (TME) diminishes the effectiveness of immunotherapy by suppressing activity immune cells facilitating immune-evasion. Adenosine monophosphate-activated protein kinase (AMPK), a key modulator cellular energy metabolism homeostasis, gained growing attention in anti-tumor immunity. Metformin is usually considered as cornerstone diabetes its role activating AMPK pathway also been extensively explored therapy although findings on remain inconsistent. nanomedicine formulation found to hold potential reprogramming TME through immunometabolic modulation both cells. This review elaborates foundation via metformin-based nanomedicines, offering valuable insights for next generation therapy.

Language: Английский

---

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

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

---

The roles of KRAS in cancer metabolism, tumor microenvironment and clinical therapy

Molecular Cancer, Journal Year: 2025, Volume and Issue: 24(1)

Published: Jan. 13, 2025

Abstract KRAS is one of the most mutated genes, driving alternations in metabolic pathways that include enhanced nutrient uptaking, increased glycolysis, elevated glutaminolysis, and heightened synthesis fatty acids nucleotides. However, beyond mechanisms KRAS-modulated cancer metabolisms remain incompletely understood. In this review, we aim to summarize current knowledge on KRAS-related alterations cells explore prevalence significance mutation shaping tumor microenvironment influencing epigenetic modification via various molecular activities. Given rely these changes sustain cell growth survival, targeting processes may represent a promising therapeutic strategy for KRAS-driven cancers.

Language: Английский

---