Table 1.

Overview of advantages and challenges of cord blood-derived cellular therapies .

Cellular component	Product or indication	Clinical development phase	Advantages	Challenges	Future development
T-cell	CAR T	Ongoing Phase I	• More naïve T-cell phenotype, may translate into better in vivo expansion and persistence (15) • Ability to generate an off-the-shelf bank matching HLA of most population, avoiding GvH and HvG effects without genome editing (16) • Able to incorporate CB-HCT before or after CAR T-cell therapy (17) • CB stored at birth can be used autologously avoiding contamination from T-cell leukemia	• Limited starting material • Lack proof-of-concept early phase clinical trial	• Proof-of-concept clinical trials with HLA-matched CB-derived CAR T-cell product demonstrating in vivo expansion and persistence • Use techniques such as iPSC to generate bulks of T-cells
	Treg	Phase I/II, preclinical for CAR-Tregs	• Higher percentage of Tregs in CB (18) • Allogeneic and off-the-shelf ability given HLA-mismatch tolerance	• Limited starting material • Limited persistence in blood, may need repeated infusion (19)	• CAR-Tregs to target specific antigen • Use techniques such as iPSC to generate bulks of Tregs
	VST	Phase I/II	• Able to utilize 20% of CB units for CB-HCT to generate VST (12)	• Naïve CB T-cells lacking virus-experienced T-cells • Prolonged production time due to limited starting material (12)	• Allogeneic PB-derived VST likely a better source than CB-derived VST
NK-cell	NK infusion	Phase I/II	• Higher percentage of NK cells in CB (2) • Improved persistence of HLA-matched CB-derived NK cells • Bulk production of HLA-matched CB-derived NK cells through induced differentiation of HSCs (20)	• Limited activity in early phase trials (21) • Reduced cytotoxicity compared to PB NK cells if without cytokine stimulation (22) • Lack of in vivo expansion and persistence (23) • Poor intra-tumoral infiltration (24) • Cryopreservation of CB can damage NK cell cytotoxicity (25)	• Combine other agents such as interleukin, TGFβ receptor inhibitor to improve efficacy • Genetically engineered NK cells, such as self-IL-15 secretion, to improve expansion and persistence
	CAR NK	Phase I/II	• Favorable safety profile without risk of GvHD, CRS, or ICANS (26) • Enhanced killing through both CAR and innate receptor, theoretically reducing CAR antigen escape (27) • Higher percentage of phenotypically naïve NK cells in CB promoting in vivo expansion (28) • Lack of innate inhibitory NK signal given the allogeneic nature • As a CB-derived product, readily available cord banks and high proliferative potential	• Requires ex vivo expansion • Limited in vivo persistence, leading to early relapse (26) • Tumor suppressive environment hindering efficacy (29) • Feasibility of large-scale manufacturing	• Genetically engineered NK cells to improve expansion and persistence • Approaches to tackle trogocytosis
	NKCE+NK	Phase I/II	• Proven off-the-shelf ability (30) • Favorable safety profile without risk of GvHD, CRS, or ICANS (30) • Relatively lower cost than genetically engineered cells • Multiple indications with the same platform	• Limited efficacy if without co-infusion of preactivated NK cells; cumbersome to administer (31)	• Confirmation trials with a larger population • Expansion of indications in other types of malignancies
Stem cell	CB-HCT	FDA-approved	• Readily available source • Less stringent HLA-matching requirement (32) • Less chronic GvHD (33) • FDA-approved ex vivo expanded CB products enhancing engraftment (34)	• Low stem cell dose • Slow engraftment, leading to increased transplant-related morbidity and mortality (35) • Increased resource utilization • Extra processing time and cost for ex vivo expanded CB products	• Increased utilization of ex vivo expanded CB products, such as omidubicel, in the clinical setting • Further development of ex vivo expanded CB products • Reducing cost for ex vivo expanded CB products
MSC	GvHD	Phase II	• Easily obtained source • Good safety profile (36) • Efficacy in early phase trials (37–39) • Off-the-shelf ability	• A phase III trial of BM-derived MSCs failed to show improved efficacy over existing care (40)	• Carefully designed phase III trials in later lines of therapy for GvHD • Efficacy in chronic GvHD • Identify markers to predict responders

CAR, chimeric antigen receptor; HLA, human leukocyte antigen; GvH, graft-versus-host; HvG, host-versus-graft; CB, cord blood; HCT, hematopoietic cell transplantation; iPSC, induced pluripotent stem cells; VST, virus-specific T-cells; PB, peripheral blood; HSC, hematopoietic stem cells; CRS, cytokine release syndrome; ICANS, immune effector cell-associated neurotoxicity syndrome; NKCE, natural killer cell engager; ARDS, acute respiratory distress syndrome; BM, bone marrow.