Autologous or allogeneic natural killer (NK) cells possess efficient cytotoxicity against tumor cells without severe side effects such as CRS or graft-versus-host disease (GvHD). In addition to chimeric antigen receptor (CAR) strategy, antibody-cell conjugates (ACCTM) platform provides more efficient way to arm NK cells with binding specificity and enhanced potency against target cells. In this work, we develop a NK cell therapy product ACE1702, a novel NK cell line oNK conjugated with Trastuzumab, and assess its potency against HER2+ solid tumors.
oNK cells, a fluorescence-activated cell sorting (FACS) isolated CD16+ population sorted from NK-92 cells, was covalently conjugated with monoclonal antibody Trastuzumab after sublethal irradiation by our patented antibody-cell conjugates (ACCTM) platform to become our cryopreserved final product ACE1702 compliant with current good manufacturing practice (cGMP). Characterization of ACE1702 was analyzed by flow cytometry. Function of ACE1702 was validated by real-time xCELLigence analyzer in vitro. Efficacy of intraperitoneally (ip.) delivered ACE1702 was evaluated in tumor-bearing female immune compromised NSG mice. Tumorigenic potential of non-irradiated oNK and ACE1702 was evaluated in subcutaneous implantation female BALB/c nude mice model.
We demonstrated that newly established CD16+ oNK cells harbor elevated basal cytotoxicity against target cells in the absence of antibodies without tumorigenic potential. The Trastuzumab-armed oNK cells, ACE1702, exerted human epidermal growth factor 2 (HER2) binding specificity and enhanced cytotoxicity against various types of cancer cells with grade 1 (MCF-7), grade 2 (OVCAR-3) and grade 3 (SK-OV-3) HER2 expression compared to control oNK cells in vitro. ACE1702 also displayed similar potency against Herceptin-resistant human breast cancer cell line BT-474 clone 5 and parental BT-474 cells in vitro. Furthermore, in vivo results in human ovarian cancer cell line SK-OV-3-bearing xenograft mouse model supported the in vitro observations. Compared to other immunotherapeutic strategies such as antibody-drug conjugate, allogeneic NK and chimeric antigen receptor (CAR) modification, ACCTM platform underscores its power in compatibility with diverse antibodies, ease for mass production compliant with good manufacturing practice and affordability to patients.
Here we introduced a novel Trastuzumab-modified oNK cell product with enhanced specificity against myriad types of HER2+ cancers even in the presence of Herceptin resistance, and demonstrated the non-tumorigenic potential of non-irradiated oNK cells and ACE1702.
Citation Format: Hao-Kang H. Li, Tai-Sheng E. Wu, Ching-Wen S. Hsiao, Sen-Han S. Yang, Chia-Yun S. Lee, Yan-Liang J. Lin, Zih-Fei Z. Cheng, Yu-Bei Cheng, Yan-Da D. Lai, Hsiu-Ping C. Yang, Sai-Wen S. Tang, Wei-Lun S. Lo, Janet Pan, Shih-Chia S. Hsiao. ACE1702: A potent and off-the-shelf oNK cell therapy product [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2169.