Summary and comparison of distinct allogeneic NK cell donor sources
| Donor source | Peripheral blood NK (PB-NK) | Umbilical cord blood NK (UB-NK) | NK-92 cell line | iPSC-derived NK (iPSC-NK) |
| Safety | Well tolerated with no severe adverse events commonly reported in clinical data. Contamination with other lymphocytes (T cells) can occur during ex vivo processing and potentially affect toxicity. | Well tolerated with no severe adverse events commonly reported in clinical data. Contamination with other lymphocytes (T cells) can occur during ex vivo processing and potentially affect toxicity. | Well tolerated with no severe adverse events commonly reported in clinical data. Clonal population reduces risk of potential toxicity caused by heterogeneity of product. | Generally well tolerated, although some adverse events were occasionally reported. Clonal population reduces risk of potential toxicity caused by heterogeneity of product. |
| Cytotoxicity | Activation via ex vivo coculture with HLA-deficient K562 cells and IL-2, IL-15, or IL-21 stimulation. Clinical data shows good efficacy in liquid tumors. PB-NK has better cytotoxicity on average than UB-NK cells. However, poor efficacy was seen if cells were cryopreserved. | Activation via ex vivo coculture with HLA-deficient K562 cells and IL-2, IL-15, or IL-21 stimulation. Clinical data show good efficacy in liquid tumors, and UB-NK has better bone marrow homing than PB-NK cells but poorer cytotoxicity. | Poor in vivo expansion due to gamma irradiation, resulting in limited cytotoxicity. Clinical data shows some efficacy, but more limited compared with other NK cell sources. NK-92 cells thus have poor longevity in systemic circulation that prevents a durable response. | Do not require gamma irradiation or a coculture system for expansion. Significant in vivo cytotoxicity has been observed in hematologic and solid tumor models. Clinical data shows good efficacy in hematologic tumors. Ease of engineering makes metabolic reprogramming to boost cytotoxicity and persistence more facile. |
| Manufacturing | NK cells are a small subset of total lymphocyte population that must be expanded ex vivo. | NK cells are more prevalent than in PB but ex vivo expansion still needed. | NK-92 cell line can be easily expanded via culture before dosing. | Differentiating iPSCs to NK cells can be complex, but new methods to bypass single cell adaptation are simplifying manufacturing. |
| Engineering | Difficult to extract a clonal population, and genetic engineering can kill many of the NK cells available. | Difficult to extract a clonal population, and genetic engineering can kill many NK cells present, making the process inefficient. | NK-92 is a clonal population, allowing for homogeneous engineering and genetic manipulation. | iPSC cells provide a clonal population with well-established methods of viral integration to knock in or knock out genetic constructs. |
iPSC, induced pluripotent stem cell; NK, natural killer.