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Knocking Out CD70 Rescues CD70-Specific NanoCAR T Cells from Antigen-Induced Exhaustion.

Stijn De Munter1,2, Juliane L Buhl3, Laurenz De Cock2,4

  • 1Department of Diagnostic Sciences, Ghent University, Ghent, Belgium.

Cancer Immunology Research
|June 14, 2024
PubMed
Summary
This summary is machine-generated.

Optimizing chimeric antigen receptor (CAR) T-cell therapy targeting CD70, researchers found that knocking out CD70 in CAR T cells prevents exhaustion and enhances anti-cancer functionality in models.

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Area of Science:

  • Immunology
  • Oncology
  • Biotechnology

Background:

  • Chimeric antigen receptor (CAR) T-cell therapy shows promise for treating various cancers by targeting antigens like CD70.
  • Existing CD70-specific CAR T-cell therapies exhibit limited effectiveness, necessitating optimization for improved clinical outcomes.

Purpose of the Study:

  • To engineer and evaluate an optimized CD70-specific VHH-based CAR (nanoCAR) T-cell therapy.
  • To investigate the mechanisms underlying the modest efficacy of CD70-specific nanoCAR T cells in preclinical cancer models.

Main Methods:

  • Development of a VHH-based nanoCAR targeting CD70.
  • In vitro co-culture assays with malignant rhabdoid tumor organoids.
  • In vivo studies using a diffuse large B-cell lymphoma patient-derived xenograft (PDX) model.
  • CRISPR/Cas9 gene editing to knock out CD70 in nanoCAR T cells.
  • Single-cell transcriptomics to analyze CAR T-cell exhaustion.

Main Results:

  • Optimized nanoCAR T cells demonstrated high efficiency in organoid co-cultures but modest efficacy in the PDX model.
  • CD70 interaction in cis, not fratricide, was identified as the cause of T-cell exhaustion.
  • CD70 knockout in nanoCAR T cells significantly enhanced anti-tumor activity and protected against antigen-induced exhaustion.
  • Wild-type nanoCAR T cells showed early signs of exhaustion, distinct from exhausted CAR T cells associated with treatment failure.

Conclusions:

  • Targeting endogenous antigens like CD70 with CARs can induce T-cell exhaustion, limiting therapeutic efficacy.
  • Knocking out the target antigen (CD70) in CAR T cells is a viable strategy to overcome exhaustion and improve anti-cancer functionality.
  • This approach holds potential for enhancing CAR T-cell therapy effectiveness against CD70-expressing malignancies.