New Stem Cell Strategy Dramatically Increases Production of Cancer-Fighting NK Cells
Researchers in China have announced a significant breakthrough in cancer immunotherapy, developing a more efficient method for generating natural killer (NK) cells – a crucial component of the body’s immune system – for use in treating cancer. The new approach, detailed in , in Nature Biomedical Engineering, promises to lower production costs and increase the scalability of these potentially life-saving therapies.
NK cells are naturally equipped to identify and destroy virus-infected cells and cancer cells, making them an attractive target for cancer treatment. A promising strategy, known as chimeric antigen receptor (CAR)-NK therapy, involves equipping these cells with lab-designed receptors (CARs) that allow them to recognize and attack cancer cells with greater precision. However, traditional methods of producing CAR-NK cells have faced significant hurdles.
Historically, CAR-NK therapies have relied on mature NK cells sourced from peripheral blood or cord blood. This process is often hampered by variability between cells, inefficiencies in genetic modification, high production costs, and lengthy preparation times. The new strategy bypasses these challenges by starting with earlier-stage stem cells.
From Stem Cells to Millions of Tumor-Killing Cells
The research team, led by Prof. WANG Jinyong at the Institute of Zoology of the Chinese Academy of Sciences, focused on CD34+ hematopoietic stem and progenitor cells (HSPCs) derived from cord blood. Instead of attempting to modify mature NK cells directly, they engineered these early-stage cells to generate induced NK (iNK) cells, and CAR-engineered iNK (CAR-iNK) cells.
Previous attempts to produce NK cells from cord blood-derived CD34+ HSPCs were limited by low efficiency and immature cell function. The team addressed these limitations by shifting the genetic engineering step earlier in the developmental process, working directly at the CD34+ HSPC stage. This involved combining CAR transduction, robust expansion of the progenitor cells, and guided commitment to the NK cell lineage.
The process unfolds in three distinct stages. First, the CD34+ HSPCs (or CD19 CAR-transduced HSPCs) are expanded using irradiated AFT024 feeder cells, resulting in a roughly 800- to 1,000-fold increase in cell numbers within . Next, the expanded cells are cultured with OP9 feeder cells, which form artificial hematopoietic organoid aggregates. These aggregates provide an environment conducive to efficient NK cell development, and commitment. Finally, the cells committed to becoming NK cells are allowed to mature and further proliferate, yielding highly pure iNK or CAR-iNK cells that express endogenous CD16.
The results are striking. The researchers demonstrated that a single CD34+ HSPC can generate up to iNK cells or CAR-iNK cells. This suggests that as little as one-fifth of a typical cord blood unit could potentially yield enough cells for thousands, or even tens of thousands, of treatment doses.
Reduced Costs and Improved Efficiency
Beyond the dramatic increase in cell yield, the new method also significantly reduces the amount of viral vector required for CAR engineering. Compared to the quantities typically needed to modify mature NK cells, this approach uses approximately one-140,000th to one-600,000th of the viral vector, depending on the stage of culture ( and respectively).
Laboratory testing confirmed the effectiveness of the newly generated cells. Both iNK and CAR-iNK cells exhibited potent tumor-killing activity in cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) mouse models of human B-cell acute lymphoblastic leukemia (B-ALL). The CD19 CAR-iNK cells, in particular, reduced tumor growth and extended the survival of the animals.
According to the researchers, this innovative approach not only enhances the efficiency of iNK and CAR-iNK cell production but also substantially lowers the cost of CAR engineering, potentially making this promising immunotherapy more accessible to patients in need. The research was supported by funding from the Ministry of Science and Technology of the People’s Republic of China and the National Natural Science Foundation of China.
This development builds on a growing body of research exploring the potential of CAR-NK cell therapy, as highlighted in recent publications, including a article in Nature examining CAR-T and CAR-NK cell therapies for cancer. Further research will be crucial to translate these findings into clinical trials and to improve outcomes for cancer patients.
