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Supplementary Data Figures from A Novel Autologous CAR-T Therapy, YTB323, with Preserved T-cell Stemness Shows Enhanced CAR T-cell Efficacy in Preclinical and Early Clinical Development

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posted on 2023-07-31, 12:20 authored by Michael J. Dickinson, Pere Barba, Ulrich Jäger, Nirav N. Shah, Didier Blaise, Javier Briones, Leyla Shune, Nicolas Boissel, Attilio Bondanza, Luisa Mariconti, Anne-Laure Marchal, David S. Quinn, Jennifer Yang, Andrew Price, Akash Sohoni, Louise M. Treanor, Elena J. Orlando, Jennifer Mataraza, Jaclyn Davis, Darlene Lu, Xu Zhu, Boris Engels, Laure Moutouh-de Parseval, Jennifer L. Brogdon, Michele Moschetta, Ian W. Flinn

Supplementary Fig. S1. Preclinical evaluation and characterization of YTB323 and CTL*019 for Donor 2 and 3; Supplementary Fig. S2. Differential gene expression of CTL*019 cells versus YTB323 cells (preclinical); Supplementary Fig. S3. Preclinical validation of YTB323; Supplementary Fig. S4. Dose-dependent expansion (Cmax and AUC0-21d) of YTB323 and CTL*019 in NSG mice with NALM6; Supplementary Fig. S5. CD4:CD8 ratio comparison of leukapheresis and cell products of YTB323 and tisagenlecleucel; Supplementary Fig. S6. Stemness and memory differentiation gene signatures are retained or enriched for in YTB323 final product; Supplementary Fig. S7. Differential gene expression of tisagenlecleucel versus YTB323 final product; Supplementary Fig. S8. Naive/TSCM cells and a naive stem-like gene signature correlate with higher expansion and a better response; Supplementary Fig. S9. T-cell subset and checkpoint inhibitor analysis by flow cytometry on PBMCs collected post-YTB323 infusion; Supplementary Fig. S10. Pre-clinical T-cell gating strategies.

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ARTICLE 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 the preclinical development and preliminary clinical data of YTB323 in adults with relapsed/refractory diffuse large B-cell lymphoma (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 (i) promising overall safety [cytokine release syndrome (any grade, 35%; grade ≥3, 6%), neurotoxicity (any grade, 25%; grade ≥3, 6%)]; (ii) overall response rates of 75% and 80% for DL1 and DL2, respectively; (iii) comparable CAR T-cell expansion; and (iv) preservation of T-cell phenotype. Current data support the continued development of YTB323 for r/r DLBCL. Traditional CAR T-cell manufacturing requires extended ex vivo cell culture, reducing naive and stem cell memory T-cell populations and diminishing antitumor activity. YTB323, which expresses the same validated CAR as tisagenlecleucel, can be manufactured in <2 days while retaining T-cell stemness and enhancing clinical activity at a 25-fold lower dose.

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