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A Novel Autologous CAR-T Therapy, YTB323, with Preserved T-Cell Stemness Shows Enhanced CAR T-Cell Efficacy in Preclinical and Early Clinical Development.

Michael J DickinsonPere BarbaUlrich JägerNirav N ShahDidier BlaiseJavier BrionesLeyla ShuneNicolas BoisselAttilio BondanzaLuisa MaricontiAnne-Laure MarchalDavid S QuinnJennifer YangAndrew PriceAkash SohoniLouise M TreanorElena J OrlandoJennifer MatarazaJaclyn DavisDarlene LuXu ZhuBoris EngelsLaure Moutouh-de ParsevalJennifer L BrogdonMichele MoschettaIan W Flinn
Published in: Cancer discovery (2023)
CAR T-cell product quality and stemness (Tstem) are major determinants of in vivo expansion, efficacy, and clinical response. Prolonged ex vivo culturing is known to deplete Tstem, affecting clinical outcome. YTB323, a novel autologous CD19-directed CAR T-cell therapy expressing the same validated CAR as tisagenlecleucel, is manufactured using a next-generation platform in <2 days. Here, we report preclinical development and preliminary clinical data of YTB323 in adults with r/r DLBCL (NCT03960840). In preclinical mouse models, YTB323 exhibited enhanced in vivo expansion and antitumor activity at lower doses than traditionally manufactured CAR T-cells. Clinically, at doses 25-fold lower than tisagenlecleucel, YTB323 showed 1) promising overall safety (CRS [any-grade, 35%; grade ≥3, 6%], neurotoxicity [any-grade, 25%; grade ≥3, 6%]); 2) ORR of 75% and 80% for DL1 and DL2, respectively; 3) comparable CAR T-cell expansion; and 4) preservation of T-cell phenotype. Current data support continued development of YTB323 for r/r DLBCL.
Keyphrases
  • cell therapy
  • stem cells
  • mesenchymal stem cells
  • machine learning
  • big data
  • quality improvement
  • artificial intelligence
  • data analysis