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

Table 1 Summary of preclinical studies investigating stem cell-derived immune cell-based therapies in pediatric patients with cancer

Pediatric malignancy/classification	Stem cell-based platform and experimental models	Key preclinical outcomes	Mechanistic rationale and translational relevance	Ref.
Broad preclinical context	Advanced in vitro functional systems and pediatric xenograft models	Consistent antitumor efficacy with reproducible safety and mechanistic validation	Provides foundation for clinical translation	[39]
ALL	iPSC-derived CD19-CAR NK cells; NSG xenografts (Nalm-6, REH)	Potent cytotoxicity with tumor regression and survival benefit without toxicity	Comparable or superior to CAR-T with reduced GvHD risk	[53,55]
ALL - cytokine enhancement	IL-15-expressing CD19-CAR iPSC-NK; persistence xenografts	Enhanced persistence and durable tumor control without systemic cytokines	Autocrine IL-15 improves durability and clinical feasibility	[45]
Neuroblastoma	Activated and stem cell-derived NK cells; GD2-CAR iPSC-NK; PDX models	High NK sensitivity and robust tumor clearance	Missing-self recognition and GD2 tumor selectivity	[58,62]
Osteosarcoma	Primary samples; iPSC-NK; IL-15 activation	> 60% cytotoxicity in primary tumors with enhanced efficacy	HLA-independent recognition enables allogeneic strategies	[63-65]
Other pediatric solid tumors	NK receptor-ligand profiling; cytotoxicity screens	Variable but measurable NK responsiveness	Guides tumor-specific NK optimization	[55]
Mechanistic advantages	Engineered NK vs CAR-T comparative studies	Multi-receptor recognition limits antigen escape	Enhanced efficacy in heterogeneous tumors	[56]
Immunomodulatory effects	Immune coculture and in vivo remodeling models	Activation of dendritic cells and T-cell priming	Supports durable immune surveillance	[57]
Integrated translational outlook	Aggregate pediatric tumor models	Strong rationale for clinical translation	Guides biomarker-driven development strategies	[50-69]

The table provides an overview of preclinical research on stem cell-derived immune effector cells, with a focus on induced pluripotent stem cell-derived natural killer cells, which target both pediatric hematologic and solid malignancies. Data from in vitro functional assays and in vivo xenograft models demonstrate robust antitumor efficacy, favorable safety profiles, and insights into the underlying biological mechanisms. Genetic enhancements, including chimeric antigen receptor integration and cytokine pathway optimization, such as interleukin-15 expression, are highlighted for their role in increasing the cytotoxic potency, persistence, and durability of antitumor responses. Overall, these studies underscore the promising translational and clinical potential of stem cell-based immune therapies in pediatric cancer treatment. ALL: Acute lymphoblastic leukemia; iPSCs: Induced pluripotent stem cells; CAR: Chimeric antigen receptor; NK: Natural killer; GvHD: Graft-vs-host disease; IL: Interleukin; HLA: Human leukocyte antigen.

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.