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Tumor Immunotherapy01:27

Tumor Immunotherapy

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Immunotherapy is a treatment that boosts or manipulates the immune system to fight diseases, including cancer. For instance, by stimulating an immune response through vaccinations against viruses that cause cancers, like hepatitis B virus and human papillomavirus, these diseases can be prevented. Nonetheless, some cancer cells can avoid the immune system due to their rapid mutation and division. The immune response to many cancers involves three phases: elimination, equilibrium, and escape.
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mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

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The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
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T Cell Activation and Clonal Selection01:22

T Cell Activation and Clonal Selection

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T cells are integral to our adaptive immune system, recognizing and effectively responding to foreign antigens. T cell activation and clonal selection are pivotal in orchestrating this immune response. This article elucidates these mechanisms, detailing the roles of cluster of differentiation (CD) markers, major histocompatibility complex (MHC) molecules, costimulatory signals, and the process of clonal selection.
Naive T cells that have not yet encountered an antigen express two primary CD...
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Inhibition of Cdk Activity02:34

Inhibition of Cdk Activity

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The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
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Targeted Cancer Therapies02:57

Targeted Cancer Therapies

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The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
There are several types of targeted therapies against...
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Cytotoxic T Cells-mediated Immune Response01:27

Cytotoxic T Cells-mediated Immune Response

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Cytotoxic T cells are a vital component of the immune system. They have the remarkable ability to identify and target antigens on infected or abnormal cells. These antigens often originate from intracellular pathogens such as viruses or abnormal proteins cancer cells produce.
Immunological surveillance is the ability of immune cells to monitor and eliminate infected cells with intracellular pathogens, neoplastically transformed cells, and cells with non-self antigens. Cytotoxic T cells and NK...
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Related Experiment Video

Updated: Jul 17, 2025

Author Spotlight: Advancements in Hypoxia-Sensitive CAR-T Therapy for Enhanced Cancer Immunotherapy
09:12

Author Spotlight: Advancements in Hypoxia-Sensitive CAR-T Therapy for Enhanced Cancer Immunotherapy

Published on: June 14, 2024

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FOXO1 Inhibition Generates Potent Nonactivated CAR T Cells against Solid Tumors.

Maude Marchais1,2, Luca Simula2, Mélanie Phayanouvong3

  • 1CNRS UMR9196, Physiologie et Pathologie Moléculaires des Rétrovirus Endogènes et Infectieux, Gustave Roussy, Faculté de Médecine, Université Paris-Sud, Université Paris-Saclay, Villejuif, France.

Cancer Immunology Research
|August 30, 2023
PubMed
Summary

Researchers developed a new method to create chimeric antigen receptor (CAR) T cells without ex vivo preactivation by inhibiting FOXO1. This novel CAR T-cell therapy enhances antitumor functions and shows improved efficacy against solid tumors.

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Area of Science:

  • Immunology
  • Cellular Therapy
  • Oncology

Background:

  • Chimeric antigen receptor (CAR) T-cell therapy shows promise for B-cell malignancies but faces manufacturing challenges.
  • Ex vivo activation, while necessary for CAR T-cell expansion, can reduce their antitumor potential.
  • Improving CAR T-cell properties is crucial for enhancing therapy efficacy, especially for solid tumors.

Purpose of the Study:

  • To develop a protocol for generating CAR T cells without ex vivo preactivation.
  • To investigate the impact of inhibiting the transcription factor FOXO1 on T-cell function and CAR expression.
  • To evaluate the therapeutic potential of these modified CAR T cells (CAR TAS) against solid tumors.

Main Methods:

  • Inhibition of the transcription factor FOXO1 in primary T cells to create T-cell Activation and Survival (TAS) cells.
  • Lentiviral transduction of TAS cells to generate CAR TAS cells without ex vivo preactivation.
  • Assessment of CAR TAS cell phenotype, function (proliferation, cytotoxicity, migration), and in vivo efficacy in solid tumor models.

Main Results:

  • FOXO1 inhibition rendered T cells permissive to lentiviral infection, enabling CAR expression.
  • CAR TAS cells exhibited a stem cell memory phenotype, increased granzyme B and TNFα production.
  • CAR TAS cells demonstrated enhanced proliferative, cytotoxic, and migratory capabilities compared to classical CAR T cells.
  • In vivo studies confirmed superior solid tumor growth control by CAR TAS cells.
  • The protocol's clinical feasibility was validated using patient-derived cells.

Conclusions:

  • Inhibiting FOXO1 is a viable strategy to generate potent CAR T cells without ex vivo preactivation.
  • CAR TAS cells possess enhanced antitumor functions, offering a promising approach for improving CAR T-cell therapy, particularly for solid tumors.
  • This protocol is feasible for clinical application, paving the way for enhanced cell-based cancer immunotherapies.