Exploring the dynamic interplay between cancer stem cells and the tumor microenvironment: implications for novel therapeutic strategies

Journal of Translational Medicine, Journal Year: 2023, Volume and Issue: 21(1)

Published: Oct. 2, 2023

Cancer stem cells (CSCs) have emerged as key contributors to tumor initiation, growth, and metastasis. In addition, CSCs play a significant role in inducing immune evasion, thereby compromising the effectiveness of cancer treatments. The reciprocal communication between microenvironment (TME) is observed, with TME providing supportive niche for CSC survival self-renewal, while CSCs, turn, influence polarization persistence TME, promoting an immunosuppressive state. Consequently, these interactions hinder efficacy current therapies, necessitating exploration novel therapeutic approaches modulate target CSCs. this review, we highlight intricate strategies employed by evade surveillance develop resistance therapies. Furthermore, examine dynamic interplay shedding light on how interaction impacts progression. Moreover, provide overview advanced that specifically which hold promise future clinical translational studies treatment.

Language: Английский

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Generation of allogeneic CAR-NKT cells from hematopoietic stem and progenitor cells using a clinically guided culture method

Nature Biotechnology, Journal Year: 2024, Volume and Issue: unknown

Published: May 14, 2024

Abstract Cancer immunotherapy with autologous chimeric antigen receptor (CAR) T cells faces challenges in manufacturing and patient selection that could be avoided by using ‘off-the-shelf’ products, such as allogeneic CAR natural killer ( Allo CAR-NKT) cells. Previously, we reported a system for differentiating human hematopoietic stem progenitor into CAR-NKT cells, but the use of three-dimensional culture xenogeneic feeders precluded its clinical application. Here describe clinically guided method to differentiate expand IL-15-enhanced high yield purity. We generated targeting seven cancers and, multiple myeloma model, demonstrated their antitumor efficacy, expansion persistence. The also selectively depleted immunosuppressive tumor microenviroment antagonized immune evasion via triple CAR, TCR NK receptors. They exhibited stable hypoimmunogenic phenotype associated epigenetic signaling regulation did not induce detectable graft versus host disease or cytokine release syndrome. These properties support potential translation.

Language: Английский

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Immune evasion in cell-based immunotherapy: unraveling challenges and novel strategies

Journal of Biomedical Science, Journal Year: 2024, Volume and Issue: 31(1)

Published: Jan. 12, 2024

Abstract Cell-based immunotherapies (CBIs), notably exemplified by chimeric antigen receptor (CAR)-engineered T (CAR-T) cell therapy, have emerged as groundbreaking approaches for cancer therapy. Nevertheless, akin to various other therapeutic modalities, tumor cells employ counterstrategies manifest immune evasion, thereby circumventing the impact of CBIs. This phenomenon is facilitated an intricately immunosuppression entrenched within microenvironment (TME). Principal mechanisms underpinning evasion from CBIs encompass loss antigens, downregulation presentation, activation checkpoint pathways, initiation anti-apoptotic cascades, and induction dysfunction exhaustion. In this review, we delve into intrinsic underlying capacity resist proffer prospective stratagems navigate around these challenges.

Language: Английский

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Allogeneic CAR-T Therapy Technologies: Has the Promise Been Met?

Cells, Journal Year: 2024, Volume and Issue: 13(2), P. 146 - 146

Published: Jan. 12, 2024

This last decade, chimeric antigen receptor (CAR) T-cell therapy has become a real treatment option for patients with B-cell malignancies, while multiple efforts are being made to extend this other malignancies and broader patient populations. However, several limitations remain, including those associated the time-consuming highly personalized manufacturing of autologous CAR-Ts. Technologies establish "off-the-shelf" allogeneic CAR-Ts low alloreactivity currently developed, strong focus on gene-editing technologies. Although these technologies have many advantages, they also limitations, double-strand breaks in DNA safety risks as well lack modulation. As an alternative, non-gene-editing provide interesting approach support development future, possibilities fine-tuning gene expression easy development. Here, we will review different ways can be manufactured discuss which used. The biggest hurdles successful summarized, finally, overview current clinical evidence comparison its counterpart given.

Language: Английский

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Engineering allorejection-resistant CAR-NKT cells from hematopoietic stem cells for off-the-shelf cancer immunotherapy

Molecular Therapy, Journal Year: 2024, Volume and Issue: 32(6), P. 1849 - 1874

Published: April 6, 2024

The clinical potential of current FDA-approved chimeric antigen receptor (CAR)-engineered T (CAR-T) cell therapy is encumbered by its autologous nature, which presents notable challenges related to manufacturing complexities, heightened costs, and limitations in patient selection. Therefore, there a growing demand for off-the-shelf universal therapies. In this study, we have generated CAR-engineered NKT (

Language: Английский

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Mucosal-associated invariant T cells for cancer immunotherapy

Molecular Therapy, Journal Year: 2022, Volume and Issue: 31(3), P. 631 - 646

Published: Dec. 5, 2022

Human mucosal-associated invariant T (MAIT) cells are characterized by their expression of an TCR α chain Vα7.2-Jα33/Jα20/Jα12 paired with a restricted β chain. MAIT recognize microbial peptides presented the highly conserved MHC class I-like molecule MR1 and bridge innate acquired immune systems to mediate augmented responses. Upon activation, rapidly proliferate, produce variety cytokines cytotoxic molecules, trigger efficient antitumor immunity. Administration representative cell ligand 5-OP-RU effectively activates enhances capacity. In this review, we introduce biology importance in immunity, summarize current development peripheral blood mononuclear cell-derived stem products for cancer treatment, discuss potential genetic engineering off-the-shelf immunotherapy.

Language: Английский

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Advancing cell-based cancer immunotherapy through stem cell engineering

Cell stem cell, Journal Year: 2023, Volume and Issue: 30(5), P. 592 - 610

Published: March 21, 2023

Advances in cell-based therapy, particularly CAR-T cell have transformed the treatment of hematological malignancies. Although an important step forward for field, autologous therapies are hindered by high costs, manufacturing challenges, and limited efficacy against solid tumors. With ongoing progress gene editing culture techniques, engineered stem cells their application therapy poised to address some these challenges. Here, we review immunotherapy approaches, sources, engineering strategies, therapeutic platforms, clinical trials, as well challenges future directions field.

Language: Английский

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Current approaches to develop “off-the-shelf” chimeric antigen receptor (CAR)-T cells for cancer treatment: a systematic review

Experimental Hematology and Oncology, Journal Year: 2023, Volume and Issue: 12(1)

Published: Aug. 21, 2023

Chimeric antigen receptor (CAR)-T cell therapy is one of the most promising advances in cancer treatment. It based on genetically modified T cells to express a CAR, which enables recognition specific tumour interest. To date, CAR-T therapies approved for commercialisation are designed treat haematological malignancies, showing impressive clinical efficacy patients with relapsed or refractory advanced-stage tumours. However, since they all use patient´s own as starting material (i.e. autologous use), have important limitations, including manufacturing delays, high production costs, difficulties standardising preparation process, and failures due patient dysfunction. Therefore, many efforts currently being devoted contribute development safe effective allogeneic use, should be overcome risks entail: immune rejection graft-versus-host disease (GvHD). This systematic review brings together wide range different approaches that been studied achieve discuss advantages disadvantages every strategy. The methods were classified two major categories: those involving extra genetic modifications, addition CAR integration, relying selection alternative sources/subpopulations γδ cells, induced pluripotent stem (iPSCs), umbilical cord blood memory subpopulations, virus-specific cytokine-induced killer cells). We observed that, although modification widely used approach, new combining both emerged. more preclinical research needed determine appropriate strategy bring this antitumour setting.

Language: Английский

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New cell sources for CAR-based immunotherapy

Biomarker Research, Journal Year: 2023, Volume and Issue: 11(1)

Published: May 6, 2023

Chimeric antigen receptor (CAR) T cell therapy, in which a patient's own lymphocytes are engineered to recognize and kill cancer cells, has achieved striking success some hematological malignancies preclinical clinical trials, resulting six FDA-approved CAR-T products currently available the market. Despite impressive outcomes, concerns about treatment failure associated with low efficacy or high cytotoxicity of cells remain. While main focus been on improving exploring alternative cellular sources for CAR generation garnered growing interest. In current review, we comprehensively evaluated other rather than conventional generation.

Language: Английский

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Biological functions and therapeutic applications of human mucosal-associated invariant T cells

Journal of Biomedical Science, Journal Year: 2025, Volume and Issue: 32(1)

Published: March 1, 2025

Abstract Mucosal-associated invariant T (MAIT) cells are a unique subset of innate-like lymphocytes that bridge innate and adaptive immunity. Characterized by their semi-invariant cell receptor (TCR) abundant localization in mucosal tissues, MAIT recognize microbial metabolites, primarily derived from the riboflavin biosynthesis pathway, presented major histocompatibility complex (MHC)-related protein 1 (MR1). This interaction, along with co-stimulatory signals, triggers rapid immune responses, including cytokine secretion cytotoxic activity, highlighting importance maintaining homeostasis combating infections. review provides an in-depth overview biology, development, activation pathways, functional diversity, protective roles immunity, contributions to diseases like cancer inflammatory bowel disease (IBD), context-dependent dual functions health pathology. also highlights emerging therapeutic potential immunotherapy. Their TCR specificity, abundance, tissue-homing properties make them ideal candidates for engineering novel therapies, such as chimeric antigen (CAR)-MAIT cells, targeting infections, cancers, autoimmune diseases. Challenges escape, exhaustion, CAR design optimization must be addressed enhance clinical efficacy. In summary, integral function, presents exciting opportunities treatment wide range Further research is essential unlock full these versatile cells.

Language: Английский

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