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Related Concept Videos

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.
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When T cells with CD4 markers are activated, they give rise to two types of effector cells: helper T cells and regulatory T cells. Meanwhile, T cells with CD8 markers differentiate into effector cytotoxic T cells. The differentiation of CD4 T cells into helper T cell subsets, such as Th1, Th2, and Th17 cells, is dependent on the antigen type, antigen-presenting cell, and regulatory cytokines.
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B Cell Activation and Differentiation01:24

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The adaptive immune response, a sophisticated defense mechanism, relies on the activation and differentiation of B lymphocytes, or B cells. These processes enable our bodies to mount a tailored response against specific pathogens such as bacteria, free virus particles, toxins, and parasites.
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Cytotoxic T Cells-mediated Immune Response01:27

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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.
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Updated: Aug 19, 2025

Manufacturing Chimeric Antigen Receptor CAR T Cells for Adoptive Immunotherapy
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Activation priming and cytokine polyfunctionality modulate the enhanced functionality of low-affinity CD19 CAR T

Ilaria M Michelozzi1, Eduardo Gomez-Castaneda1, Ruben V C Pohle1

  • 1Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, London, United Kingdom.

Blood Advances
|December 1, 2022
PubMed
Summary

A new low-affinity CD19 chimeric antigen receptor (CAR), CAT, shows improved T cell expansion, efficacy, and safety compared to high-affinity CARs. This enhanced functionality stems from antigen-dependent priming during manufacturing.

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Area of Science:

  • Immunology
  • Oncology
  • Biotechnology

Background:

  • Second-generation CD19 chimeric antigen receptor (CAR) T cell therapies have shown promise in treating B cell malignancies.
  • Tisagenlecleucel, a high-affinity CAR therapy, has demonstrated clinical efficacy but is associated with toxicities.
  • A novel low-affinity CAR, CAT, was developed to potentially improve CAR T cell therapy outcomes.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying the enhanced in vitro and in vivo properties of the low-affinity CAT CAR T cells compared to high-affinity CAR T cells.
  • To characterize the transcriptomic and proteomic changes in CAT CAR T cells following CD19 stimulation.
  • To elucidate the role of antigen-dependent priming in the enhanced functionality of CAT CAR T cells.

Main Methods:

  • Comparative analysis of low-affinity (CAT) and high-affinity (FMC63-based) CD19 CAR T cells.
  • In vitro stimulation with CD19-expressing cells.
  • Transcriptomic analysis using RNA sequencing.
  • Proteomic analysis using cytometry by time of flight (CITE-seq).

Main Results:

  • CAT CAR T cells exhibited enhanced activation, expansion, cytotoxicity, and antitumor efficacy in preclinical models.
  • Phase 1 clinical study showed CAT CAR T cells had an excellent toxicity profile, enhanced in vivo expansion, and long-term persistence.
  • Systematic in vitro characterization revealed distinct transcriptomic and protein profiles in CAT CAR T cells post-stimulation.
  • CAT CAR T cells demonstrated increased activation and cytokine polyfunctionality compared to FMC63 CAR T cells.
  • Enhanced functionality was attributed to antigen-dependent priming by residual CD19-expressing B cells during manufacturing.

Conclusions:

  • Low-affinity CD19 CAR T cells (CAT) possess superior functional properties compared to high-affinity CAR T cells.
  • The enhanced efficacy and persistence of CAT CAR T cells are linked to specific molecular changes and antigen-dependent priming.
  • These findings provide mechanistic insights into the development of next-generation CAR T cell therapies with improved safety and efficacy profiles.