Targeting of chimeric antigen receptor T cell metabolism to improve therapeutic outcomes

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

Published: March 14, 2023

Genetically engineered chimeric antigen receptor (CAR) T cells can cure patients with cancers that are refractory to standard therapeutic approaches. To date, adoptive cell therapies have been less effective against solid tumors, largely due impaired homing and function of immune within the immunosuppressive tumor microenvironment (TME). Cellular metabolism plays a key role in survival is amenable manipulation. This manuscript provides an overview known aspects CAR describes potential approaches manipulate metabolic features yield better anti-tumor responses. Distinct phenotypes linked cellular profiles associated improved Several steps manufacture process interventions generate maintain favorable intracellular phenotypes. For example, co-stimulatory signaling executed through rewiring. Use regulators during expansion or systemically patient following transfer described as states confer vivo persistence. Cytokine nutrient selection be tailored products more features. In summary, understanding its manipulations guide development therapies.

Language: Английский

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Unlocking the potential of T‐cell metabolism reprogramming: Advancing single‐cell approaches for precision immunotherapy in tumour immunity

Clinical and Translational Medicine, Journal Year: 2024, Volume and Issue: 14(3)

Published: March 1, 2024

Abstract As single‐cell RNA sequencing enables the detailed clustering of T‐cell subpopulations and facilitates analysis metabolic states metabolite dynamics, it has gained prominence as preferred tool for understanding heterogeneous cellular metabolism. Furthermore, synergistic or inhibitory effects various pathways within T cells in tumour microenvironment are coordinated, increased activity specific generally corresponds to functional activity, leading diverse behaviours related immune cells, which shows potential tumour‐specific induce persistent responses. A holistic how heterogeneity governs function subsets is key obtaining field‐level insights into immunometabolism. Therefore, exploring mechanisms underlying interplay between metabolism functions will pave way precise immunotherapy approaches future, empower us explore new methods combating tumours with enhanced efficacy.

Language: Английский

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A Roadmap of CAR-T-Cell Therapy in Glioblastoma: Challenges and Future Perspectives

Cells, Journal Year: 2024, Volume and Issue: 13(9), P. 726 - 726

Published: April 23, 2024

Glioblastoma (GBM) is the most common primary malignant brain tumor, with a median overall survival of less than 2 years and nearly 100% mortality rate under standard therapy that consists surgery followed by combined radiochemotherapy. Therefore, new therapeutic strategies are urgently needed. The success chimeric antigen receptor (CAR) T cells in hematological cancers has prompted preclinical clinical investigations into CAR-T-cell treatment for GBM. However, recent trials have not demonstrated any major success. Here, we delineate existing challenges impeding effectiveness GBM, encompassing cold (immunosuppressive) microenvironment, tumor heterogeneity, T-cell exhaustion, local systemic immunosuppression, immune privilege inherent to central nervous system (CNS) parenchyma. Additionally, deliberate on progress made developing next-generation CAR-T novel innovative approaches, such as low-intensity pulsed focused ultrasound, aimed at surmounting current roadblocks GBM therapy.

Language: Английский

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Empowering the Potential of CAR-T Cell Immunotherapies by Epigenetic Reprogramming

Cancers, Journal Year: 2023, Volume and Issue: 15(7), P. 1935 - 1935

Published: March 23, 2023

T-cell-based, personalized immunotherapy can nowadays be considered the mainstream treatment for certain blood cancers, with a high potential expanding indications. Chimeric antigen receptor T cells (CAR-Ts), an ex vivo genetically modified T-cell therapy product redirected to target of interest, have achieved unforeseen successes in patients B-cell hematologic malignancies. Frequently, however, CAR-T cell therapies fail provide durable responses while they met only limited success treating solid cancers because unique, unaddressed challenges, including poor persistence, impaired trafficking tumor, and site penetration through hostile microenvironment, impede their efficacy. Increasing evidence suggests that CAR-Ts' performance is associated intrinsic features may epigenetically altered or dysregulated. In this review, we focus on impact epigenetic regulation differentiation, exhaustion, tumor infiltration discuss how reprogramming enhance memory phenotype, trafficking, fitness, contributing development new generation potent immunotherapies.

Language: Английский

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The development of chimeric antigen receptor T-cells against CD70 for renal cell carcinoma treatment

Journal of Translational Medicine, Journal Year: 2024, Volume and Issue: 22(1)

Published: April 18, 2024

In this study, we investigated CD70 as a promising target for renal cell carcinoma (RCC) therapy and developed potent chimeric antigen receptor T (CAR-T) cells potential clinical testing. CD70, found to be highly expressed in RCC tumors, was associated with decreased survival. We generated CAR-T expressing VHH sequence of various novel nanobodies from immunized alpaca single-chain variable fragment (scFv) derived human antibody (41D12). our vitro experiments, anti-CD70 effectively eliminated CD70-positive tumor while sparing CD70-negative cells. The nanobody-based demonstrated significantly higher production cytokines such IL-2, IFN-γ TNF-ɑ during co-culture, indicating their enhanced functionality. xenograft mouse model, these exhibited remarkable anti-tumor activity, leading the eradication Importantly, expansion after infusion groups compared scFv group. Upon re-challenging mice cells, treated group remained tumor-free, suggesting robust long-lasting response. These findings provide strong support therapeutic option RCC. This warrants further development consideration future trials applications.

Language: Английский

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Current Strategies to Improve Chimeric Antigen Receptor T (CAR-T) Cell Persistence

Cureus, Journal Year: 2024, Volume and Issue: unknown

Published: July 24, 2024

Chimeric antigen receptor T (CAR-T) cell therapy has transformed the field of immunology by redirecting lymphocytes toward tumor antigens. Despite successes in attaining high remission rates as 90%, performance CAR is limited survival cells. persistence crucial it sustains immune response against malignancies, playing a critical role cancer treatment outcomes. This review explores various approaches to improve CAR-T persistence, focusing on choice between autologous and allogeneic sources, optimization culture conditions for subsets, metabolite adjustments modify metabolism, use oncolytic viruses (OVs), advancements design. Autologous cells generally exhibit longer but are less accessible cost-effective than their counterparts. Optimizing promoting

Language: Английский

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CAR-macrophage: Breaking new ground in cellular immunotherapy

Frontiers in Cell and Developmental Biology, Journal Year: 2024, Volume and Issue: 12

Published: Oct. 3, 2024

Chimeric Antigen Receptor (CAR) technology has revolutionized cellular immunotherapy, particularly with the success of CAR-T cells in treating hematologic malignancies. However, have limited efficacy against solid tumors. To address these limitations, CAR-macrophages (CAR-Ms) leverage innate properties macrophages specificity and potency CAR technology, offering a novel promising approach to cancer immunotherapy. Preclinical studies shown that CAR-Ms can effectively target destroy tumor cells, even within challenging microenvironments, by exhibiting direct cytotoxicity enhancing recruitment activation other immune cells. Additionally, favorable safety profile their persistence tumors position as potentially safer more durable therapeutic options compared This review explores recent advancements including engineering strategies optimize anti-tumor preclinical evidence supporting use. We also discuss challenges future directions developing therapies, emphasizing potential revolutionize By harnessing unique macrophages, offer groundbreaking overcoming current limitations cell paving way for effective sustainable treatments.

Language: Английский

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Current status and future challenges of CAR-T cell therapy for osteosarcoma

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

Published: Dec. 22, 2023

Osteosarcoma, the most common bone malignancy in children and adolescents, poses considerable challenges terms of prognosis, especially for patients with metastatic or recurrent disease. While surgical intervention adjuvant chemotherapy have improved survival rates, limitations such as impractical tumor removal resistance hinder treatment outcomes. Chimeric antigen receptor (CAR)-T cell therapy, an innovative immunotherapy approach that involves targeting antigens releasing immune factors, has shown significant advancements hematological malignancies. However, its application solid tumors, including osteosarcoma, is constrained by factors low specificity, limited persistence, complex microenvironment. Research on osteosarcoma ongoing, some targets promising results pre-clinical studies. This review summarizes current status research CAR-T therapy compiling recent literature. It also proposes future directions to enhance osteosarcoma.

Language: Английский

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Dynamic surveillance of lymphocyte subsets in patients with non-small cell lung cancer during chemotherapy or combination immunotherapy for early prediction of efficacy

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: Feb. 28, 2024

Background Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related deaths worldwide. Lymphocytes are primary executors immune system and play essential roles in tumorigenesis development. We investigated dynamic changes peripheral blood lymphocyte subsets to predict efficacy chemotherapy or combination immunotherapy NSCLC. Methods This retrospective study collected data from 81 patients with NSCLC who received treatments at First Affiliated Hospital Zhengzhou University May 2021 2023. Patients were divided into response non-response groups, first-line multiline groups. analyzed absolute counts each subset baseline after treatment cycle. Within-group between-group differences using paired Wilcoxon signed-rank Mann-Whitney U tests, respectively. The ability was receiver operating characteristic curve logistic regression. Results group significantly increased first cycle immunotherapy, whereas those showed persistent decreases. Ratios able early. Combination could increase compared alone. In addition, receiving for time mainly presented elevated levels, continuous reductions. Conclusion Dynamic surveillance reflect a more actual status protected levels rapid decrease undergoing prone lymphopenia than treatment. provides reference early prediction clinical tumor timely improvement status.

Language: Английский

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Immunotherapy for colorectal cancer

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: Aug. 21, 2024

Colorectal cancer is the third most common and second lethal in world. The main cause of disease due to dietary behavioral factors. treatment this complex mainly based on traditional treatments, including surgery, radiotherapy, chemotherapy. Due its high prevalence morbidity, more effective treatments with fewer side effects are urgently needed. In recent years, immunotherapy has become a potential therapeutic alternative one fastest-developing treatments. Immunotherapy inhibits tumor growth by activating or enhancing immune system recognize attack cells. This review presents latest immunotherapies for checkpoint inhibitors, cell therapy, tumor-infiltrating lymphocytes, oncolytic viruses. Some these have shown promising results clinical trials used treatment.

Language: Английский

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