1. Academic Validation
  2. Preclinical development and evaluation of nanobody-based CD70-specific CAR T cells for the treatment of acute myeloid leukemia

Preclinical development and evaluation of nanobody-based CD70-specific CAR T cells for the treatment of acute myeloid leukemia

  • Cancer Immunol Immunother. 2023 Mar 17. doi: 10.1007/s00262-023-03422-6.
Jiali Cheng # 1 Tong Ge # 1 Xiaojian Zhu # 1 Jue Wang 1 Yuhao Zeng 2 Wei Mu 1 Haodong Cai 1 Zhenyu Dai 1 Jin Jin 1 Yongkun Yang 3 Guang Hu 3 Xia Mao 1 Jianfeng Zhou 1 Li Zhu 4 Liang Huang 5
Affiliations

Affiliations

  • 1 Department of Hematology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Qiaokou District, 1095 Jiefang Avenue, Wuhan, China.
  • 2 Department of Internal Medicine, Cleveland Clinic, Akron General, Akron, OH, USA.
  • 3 IASO Biotherapeutics, Nanjing, China.
  • 4 Department of Hematology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Qiaokou District, 1095 Jiefang Avenue, Wuhan, China. [email protected].
  • 5 Department of Hematology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Qiaokou District, 1095 Jiefang Avenue, Wuhan, China. [email protected].
  • # Contributed equally.
Abstract

Background: Acute myeloid leukemia (AML) treatment remains challenging. CD70 was reported as a promising AML-specific antigen. Preclinically, CAR T-cell with single-chain-variable fragment (scFv) or truncated CD27 targeting CD70 has been reported to treat AML. However, various disadvantages including spontaneous exhaustion, proteinase-mediated loss of functional receptors, and high immunogenicity, limited its further application to clinical settings. Alternatively, the single-variable domain on heavy chain (VHH), also known as nanobodies, with comparable binding ability and specificity, provides an optional solution.

Method: We generated CD70 knocked-out novel nanobody-based anti-CD70-CAR T-cells (nb70CAR-T) with two different VHHs for antigen detection. Next, we detected the CD70 expression on primary AML blasts by flow cytometry and associated the efficacy of nb70CAR-T with the target antigen density. Finally, epigenetic modulators were investigated to regulate the CD70 expression on AML cells to promote the functionality of nb70CAR-T.

Results: Our nb70CAR-T exhibited expected tumoricidal functionality against CD70-expressed cell lines and primary AML blasts. However, CD70 expression in primary AML blasts was not consistently high and nb70CAR-T potently respond to an estimated 40.4% of AML patients when the CD70 expression level was over a threshold of 1.6 (MFI ratio). Epigenetic modulators, Decitabine and Chidamide can up-regulate CD70 expression on AML cells, enhancing the treatment efficacy of nb70CAR-T.

Conclusion: CD70 expression in AML blasts was not fully supportive of its role in AML targeted therapy as reported. The combinational use of Chidamide and Decitabine with nb70CAR-T could provide a new potential for the treatment of AML.

Keywords

AML; Antigen density; CD70; Chidamide; Decitabine; Nanobody-CAR T-cells.

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