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

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Publication Year:
2022
Authors:
Siler H Panowski, Surabhi Srinivasan, Nguyen Tan, Silvia K Tacheva-Grigorova, Bryan Smith, Yvonne Mak, Hongxiu Ning, Jonathan Villanueva, Dinali Wijewarnasuriya, Shanshan Lang, Zea Melton, Adit Ghosh, Mathilde Dusseaux, Roman Galetto, Jonathan R Heyen, Tao Sai, Thomas J Van Blarcom, Javier Chaparro-Riggers, Barbra J Sasu
PubMed ID:
35294525
Funding Grants:
Public Summary:
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 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 masked CD70 detection in cis and provide protection from CD70 CAR T-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. Lastly, 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 candidate into phase I clinical trials.
Scientific Abstract:
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 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 masked CD70 detection in cis and provide protection from CD70 CAR T-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. Lastly, 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 candidate into phase I clinical trials.