Abstract LB210: Preclinical development and evaluation of allogeneic CAR T cells targeting CD70 for the treatment of renal cell carcinoma

Abstract

Abstract CD70 is highly expressed on renal cell carcinoma (RCC), with limited normal tissue expression, making it an attractive CAR T target for an immunogenic solid tumor indication. Here we generated and characterized a panel of anti-CD70 scFv-based CAR T cells. Despite the expression of CD70 on T cells, production of CAR T from a subset of scFvs with potent in vitro activity was achieved. Expression of CD70 CARs was found to mask CD70 detection in cis and provide protection from CD70 CAR T-mediated fratricide. Two unique classes of CAR T cells were identified with differing memory phenotype, activation status, and cytotoxic activity. Epitope mapping revealed CARs binding to the membrane distal region of the CD70 extracellular domain (ECD) fall into the more active and differentiated class, as compared to CARs binding the membrane proximal region of the CD70 ECD. CD70 CAR T cells were evaluated with rituximab-based off switches to provide control over CAR T function and displayed robust antitumor activity against RCC cell lines and patient-derived xenografts in mouse models. Tissue cross reactivity studies to evaluate off-target binding with two lead CARs showed membrane staining in rare tissue-resident lymphocytes, thus matching the known expression pattern of CD70. Expected findings related to T cell activation, and elimination of CD70-expressing cells were observed in a cynomolgus monkey CD3-CD70 bispecific toxicity study and included cytokine release and loss of cellularity in lymphoid tissues. Lastly, highly functional CD70 allogeneic CAR T cells were produced at large scale through elimination of the T cell receptor by TALEN® gene editing. Taken together, these efficacy and safety data support the evaluation of CD70 CAR T cells for the treatment of RCC and led to the advancement of an allogeneic CD70 CAR T candidate into Phase I clinical trials. Citation Format: Siler Panowski, Surabhi Srinivasan, Nguyen Tan, Silvia Tacheva-Grigorova, Bryan Smith, Yvonne Mak, Hongxiu Ning, Jonathan Villanueva, Dinali Wijewarnasuriya, Shanshan Lang, Zea Melton, Adit Ghosh, Mathilde Dusseaux, Roman Galetto, Jonathan Heyen, Tao Sai, Thomas Van Blarcom, Javier Chaparro-Riggers, Barbra Sasu. Preclinical development and evaluation of allogeneic CAR T cells targeting CD70 for the treatment of renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB210.