Graduate Institute of Pharmacognosy, Taipei Medical University, 250 Wu-Hsing Street, Taipei, Taiwan.
Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan.
J Biomed Sci. 2023 May 31;30(1):35. doi: 10.1186/s12929-023-00929-z.
Cancer-specific adoptive T cell therapy has achieved successful milestones in multiple clinical treatments. However, the commercial production of cancer-specific T cells is often hampered by laborious cell culture procedures, the concern of retrovirus-based gene transfection, or insufficient T cell purity.
In this study, we developed a non-genetic engineering technology for rapidly manufacturing a large amount of cancer-specific T cells by utilizing a unique anti-cancer/anti-CD3 bispecific antibody (BsAb) to directly culture human peripheral blood mononuclear cells (PBMCs). The anti-CD3 moiety of the BsAb bound to the T cell surface and stimulated the differentiation and proliferation of T cells in PBMCs. The anti-cancer moiety of the BsAb provided these BsAb-armed T cells with the cancer-targeting ability, which transformed the naïve T cells into cancer-specific BsAb-armed T cells.
With this technology, a large amount of cancer-specific BsAb-armed T cells can be rapidly generated with a purity of over 90% in 7 days. These BsAb-armed T cells efficiently accumulated at the tumor site both in vitro and in vivo. Cytotoxins (perforin and granzyme) and cytokines (TNF-α and IFN-γ) were dramatically released from the BsAb-armed T cells after engaging cancer cells, resulting in a remarkable anti-cancer efficacy. Notably, the BsAb-armed T cells did not cause obvious cytokine release syndrome or tissue toxicity in SCID mice bearing human tumors.
Collectively, the BsAb-armed T cell technology represents a simple, time-saving, and highly safe method to generate highly pure cancer-specific effector T cells, thereby providing an affordable T cell immunotherapy to patients.
癌症特异性过继性 T 细胞疗法在多种临床治疗中取得了成功的里程碑。然而，癌症特异性 T 细胞的商业生产通常受到繁琐的细胞培养程序、基于逆转录病毒的基因转染的担忧或 T 细胞纯度不足的限制。
在这项研究中，我们开发了一种非基因工程技术，利用独特的抗癌/抗 CD3 双特异性抗体（BsAb）直接培养人外周血单核细胞（PBMC），快速大量制造癌症特异性 T 细胞。BsAb 的抗 CD3 部分与 T 细胞表面结合，刺激 PBMC 中 T 细胞的分化和增殖。BsAb 的抗癌部分赋予这些 BsAb 武装的 T 细胞靶向癌症的能力，将幼稚 T 细胞转化为癌症特异性 BsAb 武装 T 细胞。
通过该技术，可在 7 天内快速产生大量纯度超过 90%的癌症特异性 BsAb 武装 T 细胞。这些 BsAb 武装的 T 细胞在体外和体内均能有效地聚集在肿瘤部位。BsAb 武装的 T 细胞与癌细胞结合后，细胞毒性物质（穿孔素和颗粒酶）和细胞因子（TNF-α 和 IFN-γ）大量释放，从而产生显著的抗癌效果。值得注意的是，BsAb 武装的 T 细胞在携带人肿瘤的 SCID 小鼠中不会引起明显的细胞因子释放综合征或组织毒性。
总之，BsAb 武装 T 细胞技术是一种简单、省时且高度安全的方法，可产生高度纯的癌症特异性效应 T 细胞，从而为患者提供负担得起的 T 细胞免疫疗法。
