Stem cell-derived immune cells in pediatric cancer therapy: From bench to bedside

Table 2 Translational and early clinical evidence supporting stem cell-derived natural killer cell therapies

Domain/emphasis	Therapeutic product or platform	Clinical development stage and context	Principal clinical observations and translational implications	Ref.
Overall field evolution	iPSC-derived NK cell platforms (collective experience)	Multiple first-in-human and phase I trials in adult and pediatric cohorts	Over the last five years, stem cell-derived NK therapies have progressed rapidly into clinical testing, with early trials demonstrating acceptable safety profiles and initial signals of antitumor activity, particularly in hematologic malignancies	[70]
Most advanced candidate -FT596	FT596 (fate therapeutics): Allogeneic, off-the-shelf iPSC-NK incorporating CD19-directed CAR, high-affinity noncleavable CD16, and IL-15 receptor fusion	Phase I trials in relapsed/refractory B-cell lymphomas; evaluated alone and in combination with rituximab	Early clinical evaluation indicates good tolerability with no dose-limiting toxicities or graft-vs-host disease; objective responses including partial and complete remissions observed. Combination with rituximab enhances antibody-dependent cytotoxicity, achieving approximately 60% response rates in heavily pretreated patients and supporting prolonged in vivo persistence	[59-61]
Broadly applicable iPSC-NK platform - FT516	FT516: IPSC-derived NK cells engineered with enhanced Fc receptor signaling but lacking tumor-specific CAR	Phase I studies combined with monoclonal antibodies (e.g., trastuzumab in HER2-positive solid tumors; rituximab in B-cell malignancies)	Demonstrates the ability to safely potentiate antibody-mediated antitumor effects via enhanced ADCC, without introducing significant additional toxicity; exhibits consistent pharmacokinetic behavior and reliable dosing across treated individuals	[62,63]
Clinical proof-of-concept -cord blood CAR-NK	Cord blood-derived CD19 CAR-NK cells expressing IL-15 (Liu et al[1])	Phase I study in relapsed/refractory CD19-positive lymphoid cancers, including pediatric patients	High clinical activity observed, with objective responses in 73% of patients and durable complete remissions exceeding one year in several cases; notably absent were cytokine release syndrome, neurotoxicity, and graft-vs-host disease, allowing outpatient administration in many instances	[64,65]
Aggregate efficacy across CAR-NK trials	Pooled early-phase CAR-NK clinical experience	Early-phase studies in heavily pretreated hematologic malignancies	Across studies, response rates generally range between approximately 40% and 70%, comparing favorably with available salvage therapies while maintaining substantially lower rates of severe immune-related toxicities	[79]
Off-the-shelf and cryopreservation benefits	Banked iPSC-derived NK cell products	Clinical, translational, and operational evaluations	iPSC-derived NK cells preserve functional activity following cryopreservation and thawing, enabling immediate treatment availability, scalable manufacturing, and efficient global distribution	[80]
Manufacturing scalability and consistency	Master iPSC cell banks with multi-lot GMP production	GMP manufacturing programs with extensive lot release testing	A single well-characterized iPSC clone can generate thousands of therapeutic doses; repeated manufacturing runs yield products with stable genetic, phenotypic, and functional characteristics, supporting predictable clinical outcomes	[83]
Combination-based therapeutic strategies	NK cell therapies combined with monoclonal antibodies, immune checkpoint inhibitors, or small-molecule agents	Early-phase combination cohorts and translational correlative analyses	Emerging evidence supports synergistic antitumor effects in selected patient populations, providing a strong rationale for combination regimens designed to enhance efficacy and overcome tumor immune resistance	[84]
Pediatric trial considerations	Pediatric-inclusive early-phase trials with adapted protocols	Trials incorporating age-adjusted dosing, intensified safety monitoring, tailored supportive care, and long-term follow-up	The favorable toxicity profile of NK-based therapies has enabled early inclusion of pediatric patients; ongoing surveillance aims to identify potential delayed effects on immune maturation and long-term health	[85]

iPSCs: Induced pluripotent stem cells; NK: Natural killer; CAR: Chimeric antigen receptor; IL: Interleukin; ADCC: Antibody-dependent cellular cytotoxicity; GMP: Good manufacturing practice.