Preclinical Development and Evaluation of Allogeneic CAR T Cells Targeting CD70 for the Treatment of Renal Cell Carcinoma.

Autor:	Panowski SH; Allogene Therapeutics, South San Francisco, California., Srinivasan S; Allogene Therapeutics, South San Francisco, California., Tan N; Allogene Therapeutics, South San Francisco, California., Tacheva-Grigorova SK; Allogene Therapeutics, South San Francisco, California., Smith B; Allogene Therapeutics, South San Francisco, California., Mak YSL; Allogene Therapeutics, South San Francisco, California., Ning H; Allogene Therapeutics, South San Francisco, California., Villanueva J; Allogene Therapeutics, South San Francisco, California., Wijewarnasuriya D; Allogene Therapeutics, South San Francisco, California., Lang S; Allogene Therapeutics, South San Francisco, California., Melton Z; Allogene Therapeutics, South San Francisco, California., Ghosh A; Allogene Therapeutics, South San Francisco, California., Dusseaux M; Cellectis, Paris, France., Galetto R; Cellectis, Paris, France., Heyen JR; Drug Safety Research and Development, Pfizer Worldwide Research and Development, La Jolla, California., Sai T; Pfizer Worldwide Research and Development, South San Francisco, California., Van Blarcom T; Allogene Therapeutics, South San Francisco, California., Chaparro-Riggers J; Pfizer Worldwide Research and Development, South San Francisco, California., Sasu BJ; Allogene Therapeutics, South San Francisco, California.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2022 Jul 18; Vol. 82 (14), pp. 2610-2624.
DOI:	10.1158/0008-5472.CAN-21-2931
Abstrakt:	CD70 is highly expressed in renal cell carcinoma (RCC), with limited expression in normal tissue, making it an attractive CAR T target for an immunogenic solid tumor indication. Here we generated and characterized a panel of anti-CD70 single-chain fragment variable (scFv)-based CAR T cells. Despite the expression of CD70 on T cells, production of CAR T cells from a subset of scFvs with potent in vitro activity was achieved. Expression of CD70 CARs masked CD70 detection in cis and provided protection from CD70 CAR T cell-mediated fratricide. Two distinct classes of CAR T cells were identified with differing memory phenotype, activation status, and cytotoxic activity. Epitope mapping revealed that the two classes of CARs bind unique regions of CD70. CD70 CAR T cells displayed robust antitumor activity against RCC cell lines and patient-derived xenograft mouse models. Tissue cross-reactivity studies identified membrane staining in lymphocytes, thus matching the known expression pattern of CD70. In a cynomolgus monkey CD3-CD70 bispecific toxicity study, expected findings related to T-cell activation and elimination of CD70-expressing cells were observed, including cytokine release and loss of cellularity in lymphoid tissues. Finally, highly functional CD70 allogeneic CAR T cells were produced at large scale through elimination of the T-cell receptor by TALEN-based gene editing. Taken together, these efficacy and safety data support the evaluation of CD70 CAR T cells for the treatment of RCC and has led to the advancement of an allogeneic CD70 CAR T-cell candidate into phase I clinical trials. Significance: These findings demonstrate the efficacy and safety of fratricide-resistant, allogeneic anti-CD70 CAR T cells targeting renal cell carcinoma and the impact of CAR epitope on functional activity. See related commentary by Adotévi and Galaine, p. 2517. (©2022 American Association for Cancer Research.)
Databáze:	MEDLINE
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