Table 1.

General characteristics of NK cell products.

	Source(s)	Processing Method(s)	Advantage(s)	Disadvantage(s)	Potential Use(s)
Autologous NK cells [9, 42, 58–60]	Recipient's peripheral blood	CD3 depletion  Optional: CD56 selection  Optional: incubation with cytokines (IL-2, IL-15 or combinations)  Optional: expansion in feeder	–Ease of collection –Minimally effective in monotherapy	Difficulty in yielding an adequate cell number (may be overcome with expansion with cytokines; but purity may decrease)	–May be used in combination with other therapies, such as anti-KIR antibodies
Allogeneic NK cells [61–65]	Donor's peripheral blood	CD3 depletion  Optional: CD19 depletion  Optional: CD56 selection  Optional: incubation with cytokines (IL-2, IL-15 or mixture)  Optional: expansion in feeder	Better GvL/GvT effect due to alloreactive NK cells	–Risk of GvHD –Risk of passenger lymphocyte syndrome and EBV reactivation (may be reduced via CD19 depletion)	To optimize the results of allogeneic stem cell transplantation (clinical outcomes in AML are superior if given before or within 2 weeks after HSCT)
CB-derived NK cells [35, 67–69]	Umbilical cord blood units	Co-culturing systems and cytokine combinations	Alternative NK cell source	–Difficulty in yielding an adequate cell number –Lower activity due to lower expression of KIRs (may be overcome partially by ex vivo expansion)	Various hematologic malignancies and solid tumors; alone or in combination with other immunotherapies
BM-derived NK cells [35, 67–69]	Donor's bone marrow harvest	Co-culturing systems and cytokine combinations	Alternative NK cell source	Difficulty in yielding an adequate cell number	–Various hematologic malignancies and solid tumors; alone or in combination with other immunotherapies –Potential for commercial use
NK cells obtained from hESC or iPSC [35, 70, 71]	hESC or iPSC	Complex systems requiring strict GMP criteria	–May enable to produce large scales of universal NK cells lacking KIR expression –Homogenous product	Requires complex processing	–Various hematologic malignancies and solid tumors; alone or in combination with other immunotherapies –Potential for commercial use
NK cell lines [35, 79, 80]	–Malignant cell clones –Seven established lines: NK-92, YT, NKL, HANK-1, KHYG-1, NK-YS, and NKG	Complex systems requiring strict GMP criteria	–Easy to expand –Uniform and reproducible –Can be used “off-the-shelf”	–Concerns about in vivo persistence and the lack of CD16 expression –Limited clinical efficacy	–Generally used in preclinical research –Only NK92 lines are approved for clinical research
CAR-NK cells [9, 58, 81–85]	NK cell lines, PB-derived NK cells, and stem cell-derived NK cells	Genetical engineering of NK cells to express recombinant CARs	–Can be used “off-the-shelf” –Very low risk of GvHD –Intrinsic cytotoxicity may prevent disease escape due to downregulation of CAR target antigens. –Long-term side effects and cytokine release syndrome are less likely due to limited in vivo persistence	–Questions regarding the optimal NK source, strategies for recruitment, activation, and costimulation need further research	–Potential for commercial use –Preclinical and clinical studies ongoing

NK cells: Natural Killer cells; CD: cluster of differentiation; IL: interleukin; GvL: graft versus leukemia; GvT: graft versus tumor; GvHD: graft versus host disease; EBV: Epstein-Barr virus; AML: acute myeloid leukemia; HSCT: hematopoietic stem cell transplantation; CB: cord blood; BM: bone marrow; hESC: Human embryonic stem cells; iPSC: Induced pluripotent stem cells; GMP: good manufacturing practice; KIR: Killer-cell immunoglobulin-like receptor; CAR: Chimeric antigen receptor.