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

Dickinson, MJ; Barba, P; Jager, U; Shah, NN; Blaise, D; Briones, J; Shune, L; Boissel, N; Bondanza, A; Mariconti, L; Marchal, AL; Quinn, DS; Yang, J; Price, A; Sohoni, A; Treanor, LM; Orlando, EJ; Mataraza, J; Davis, J; Lu, D; Zhu, X; Engels, B; Moutouh-de Parseval, L; Brogdon, JL; Moschetta, M; Flinn, IW

Author(s): Dickinson, MJ; Barba, P; Jager, U; Shah, NN; Blaise, D; Briones, J; Shune, L; Boissel, N; Bondanza, A; Mariconti, L; Marchal, AL; Quinn, DS; Yang, J; Price, A; Sohoni, A; Treanor, LM; Orlando, EJ; Mataraza, J; Davis, J; Lu, D; Zhu, X; Engels, B; Moutouh-de Parseval, L; Brogdon, JL; Moschetta, M; Flinn, IW;
Details: Publication Year 2023-09-06,Volume 13,Issue #9,Page 1982-1997
Journal Title: Cancer Discovery
Publication Type: Research 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. SIGNIFICANCE: 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. See related commentary by Wang, p. 1961. This article is featured in Selected Articles from This Issue, p. 1949.
Publisher: American Association for Cancer Research
Keywords: Mice; Animals; Immunotherapy, Adoptive; *Receptors, Chimeric Antigen; *Lymphoma, Non-Hodgkin; *Lymphoma, Large B-Cell, Diffuse; Cell Culture Techniques; Antigens, CD19
Department(s): Clinical Haematology
PubMed ID: 37249512
Publisher's Version: https://doi.org/10.1158/2159-8290.CD-22-1276
Open Access at Publisher's Site: https://doi.org/10.1158/2159-8290.Cd-22-1276
Terms of Use/Rights Notice: Refer to copyright notice on published article.

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Last Modified: 2023-11-14 03:58:49