Theranostics 2020; 10(17):7622-7634. doi:10.7150/thno.43991

Research Paper

Tandem CAR-T cells targeting CD70 and B7-H3 exhibit potent preclinical activity against multiple solid tumors

Meijia Yang1,2*, Xin Tang3*, Zongliang Zhang1*, Lei Gu1, Heng Wei1, Shasha Zhao1, Kunhong Zhong1, Min Mu1, Cheng Huang1, Caiying Jiang1, Jianguo Xu3, Gang Guo1, Liangxue Zhou3✉, Aiping Tong1✉

1. State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan province, China.
2. National Engineering Laboratory for Internet Medical Systems and Applications, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan province, China.
3. Department of Neurosurgery, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan province, China.
*These authors contributed equally to the manuscript.

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Citation:
Yang M, Tang X, Zhang Z, Gu L, Wei H, Zhao S, Zhong K, Mu M, Huang C, Jiang C, Xu J, Guo G, Zhou L, Tong A. Tandem CAR-T cells targeting CD70 and B7-H3 exhibit potent preclinical activity against multiple solid tumors. Theranostics 2020; 10(17):7622-7634. doi:10.7150/thno.43991. Available from http://www.thno.org/v10p7622.htm

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Abstract

Purpose: Given that heterogeneous expression and variants of antigens on solid tumors are responsible for relapse after chimeric antigen receptor (CAR)-T cell therapy, we hypothesized that combinatorial targeting two tumor-associated antigens would lessen this problem and enhance the antitumor activity of T cells.

Methods: The co-expression level of CD70 and B7-H3 was analyzed in multiple tumor tissue samples. Further, two putative antigens were identified in The Cancer Genome Atlas and Gene Expression Profiling Interactive Analysis database. Two CD70 targeted CARs with different antigen binding domain, truncated CD27 and CD70 specific single-chain antibody fragment (scFv), were designed to screen a more suitable target-antigen binding moiety. Accordingly, we designed a bivalent tandem CAR (TanCAR) and further assessed the anti-tumor efficacy of TanCAR-T cells in vitro and in vivo.

Results: Our results indicated that co-expression of CD70 and B7-H3 was observed on multiple tumor types including kidney, breast, esophageal, liver, colon cancer, glioma as well as melanoma. The CD70 targeted CAR-T cells with binding moiety of CD70 specific scFv exhibit a higher affinity and antitumor effect against CD70+ tumor cells. TanCAR-T cells induced enhanced ability of cytolysis and cytokine release over unispecific CAR-T cells when encountering tumor cells expressing two target-antigens. Further, low doses of TanCAR-T cells could also effectively control the lung cancer and melanoma xenografts and improved overall survival of the treated animals.

Conclusion: TanCAR-T cells targeting CD70 and B7-H3 exhibit enhanced antitumor functionality and improve the problem of antigenic heterogeneity and variant in the treatment against solid tumor and melanoma.

Keywords: CD70, B7-H3, Chimeric antigen receptor T cell, Immunotherapy, Solid tumor