AI Article Synopsis

  • Researchers developed a new CAR-T cell therapy called RB-340-1 that combines CAR-engineered T cells with CRISPR interference to prevent T cell exhaustion and improve effectiveness against cancer.
  • RB-340-1 is designed to target the PD-1 gene, reducing its expression upon encountering cancer cells, while also boosting the T cells' growth and longevity in the body.
  • In tests, RB-340-1 outperformed traditional CAR-T cells by enhancing immune responses and suppressing the growth of HER2-expressing cancers more effectively.

Article Abstract

Background: Adoptive transfer of chimeric antigen receptor (CAR)-engineered T cells combined with checkpoint inhibition may prevent T cell exhaustion and improve clinical outcomes. However, the approach is limited by cumulative costs and toxicities.

Methods: To overcome this drawback, we created a CAR-T (RB-340-1) that unites in one product the two modalities: a CRISPR interference-(CRISPRi) circuit prevents programmed cell death protein 1 (PD-1) expression upon antigen-encounter. RB-340-1 is engineered to express an anti-human epidermal growth factor receptor 2 (HER2) CAR single chain variable fragment (scFv), with CD28 and CD3ζ co-stimulatory domains linked to the tobacco etch virus (TEV) protease and a single guide RNA (sgRNA) targeting the PD-1 transcription start site (TSS). A second constructs includes linker for activation of T cells (LAT) fused to nuclease-deactivated spCas9 (dCas9)-Kruppel-associated box (KRAB) via a TEV-cleavable sequence (TCS). Upon antigen encounter, the LAT-dCas9-KRAB (LdCK) complex is cleaved by TEV allowing targeting of dCas9-KRAB to the PD-1 gene TSS.

Results: Here, we show that RB-340-1 consistently demonstrated higher production of homeostatic cytokines, enhanced expansion of CAR-T cells in vitro, prolonged in vivo persistence and more efficient suppression of HER2 FaDu oropharyngeal cancer growth compared to the respective conventional CAR-T cell product.

Conclusions: As the first application of CRISPRi toward a clinically relevant product, RB-340-1 with the conditional, non-gene editing and reversible suppression promotes CAR-T cells resilience to checkpoint inhibition, and their persistence and effectiveness against HER2-expressing cancer xenografts.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8573881PMC
http://dx.doi.org/10.1186/s12967-021-03132-6DOI Listing

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