Multi-gene Edited iPSC-Derived CD70-Targeted CAR-NK Cells Exhibit Potent Anti-Tumor Activity and Enhanced In Vivo Persistence

Jan 11, 2025 14:29 CST Updated 14:30

Qihan Biotech

Gene Editing Technology Developer

Although chimeric antigen receptor (CAR)-T therapy has demonstrated superior efficacy in the treatment of relapsed and refractory hematologic malignancies,However, with the promotion of clinical applications, its limitations have gradually become apparent. First, most of the CAR-T cells currently on the market are autologous, which require a long preparation period, and patients may miss the optimal treatment window. Second, the incidence and severity of adverse reactions to CAR-T cell therapy are high, potentially life-threatening. Lastly, traditional single-target CAR-T cells have limited tumor coverage, benefiting only a subset of cancer patients. Therefore, there is an urgent need in clinical practice to develop a new generation of safe, controllable, broad-spectrum, and universal cell immunotherapy products.

NK cells are innate immune cells that can recognize and eliminate abnormal cells. They lack TCR expression and thus pose no risk of inducing graft-versus-host disease when infused between allogeneic individuals, making them a natural universal cell therapy product. However, the multi-gene editing and in vitro expansion efficiency of primary cells remain relatively limited. Therefore, our team has established a robust production system for NK cells derived from iPSCs to achieve batch production. Additionally, iPSC-derived NK cells are amenable to multi-gene editing, enabling the updating and iteration of cellular products, and hold great promise for clinical applications.

Recently, Zhejiang University has collaborated with Hangzhou Qihan Biotech Co., Ltd. inCell Reports Medicine Published online titledCD70-Targeted iPSC-Derived CAR-NK Cells Display Potent Function Against Tumors and Alloreactive T cells Research Paper.

Weak tumor clearance ability and short persistence in vivo are the current bottlenecks of NK cell therapy. Based on the advantage that iPSCs are amenable to multi-gene editing, our team introduced various functional components into iPSCs. To enhance anti-tumor capability, our team incorporated a CD70-targeting CAR molecule for pan-tumor targeting and hnCD16 to strengthen the inherent ADCC effect of NK cells. For NK cell persistence and proliferation capacity, we introduced CD70 KO to avoid 70CAR-mediated self-killing, along with IL15RF to enhance the expansion capability of NK cells.

Furthermore, the research team successfully directed the differentiation of multi-gene edited iPSCs into 70CAR-iNK cells, which can effectively eliminate various solid tumor and hematological tumor cells through the inherent anti-tumor effects of NK cells and the CD70-CAR component. In xenograft mouse tumor models, the research team further confirmed that 70CAR-iNK cells can effectively suppress the progression of lymphoma and renal cancer in mice. Additionally, the study found that allogeneic reactive T cells induced in vitro...（alloT）The expression level of CD70 in cells gradually increases, and the expression of CD70 is closely related to the allogeneic reactivity of T cells. 70CAR-iNK cells can eliminate CD70-positive alloT cells, thereby reducing their activity of rejecting NK cells through allogeneic reactions in vivo, thus improving the in vivo persistence of iNK cells.

The study constructed iPSC-derived multi-gene edited CD70 CAR-NK cells and revealed their potent anti-tumor function as well as the ability to kill alloT cells, promoting in vivo persistence, providing crucial evidence for clinical translation.。

Professors Huang He and Hu Yongxian from Zhejiang University, Researcher Wang Dongrui, and Dr. Luhan Yang from Hangzhou Qihan Biotech Co., Ltd. are the corresponding authors. Lin Qin Wang, Yiyun Wang, former doctoral students at Zhejiang University, Xiangjun He from Qihan Biotech, and Postdoctoral Fellow Zhuoao Mo from Liangzhu Laboratory of Zhejiang University are the co-first authors.

Original link: https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(24)00660-8

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