Dickinson, Michael, Barba, Pere, Jäger, Ulrich, Shah, Nirav N., Blaise, Didier, Briones, Javier, Shune, Leyla, Boissel, Nicolas, Bondanza, Attilio, Mariconti, Luisa, Marchal, Anne-Laure, Quinn, David, Yang, Jennifer, Price, Andrew, Sohoni, Akash Kamalakar, Treanor, Louise, Orlando, Elena, Mataraza, Jennifer, Davis, Jaclyn, Lu, Darlene, Xu, Zhu, Engels, Boris, Brogdon, Jennifer, de Parseval, Laure, Moschetta, Michele and Flinn, Ian (2023) A Novel Autologous CAR-T Therapy, YTB323, with Preserved T-Cell Stemness Shows Enhanced CAR T-Cell Efficacy in Preclinical and Early Clinical Development. Cancer discovery. ISSN 2159-8290

Abstract

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.

Item Type:	Article
Date Deposited:	11 Jul 2023 00:45
Last Modified:	11 Jul 2023 00:45
URI:	https://oak.novartis.com/id/eprint/50335