GEM/DOX + TGFBi expanded NK cells

Overview

GEM/DOX + TGFBi expanded NK cells is an investigational, multi‑agent regimen for relapsed/refractory pediatric sarcomas that combines gemcitabine and docetaxel (“GEM/DOX”) with adoptive infusions of universal‑donor natural killer (NK) cells expanded ex vivo under “TGF‑β imprinting” (TGFBi). A multi‑institution Phase 1/2 study (often referenced as the TiNKS trial; NCT05634369) is recruiting to evaluate safety, feasibility, and preliminary efficacy of adding TGFBi NK infusions to GEM/DOX; no human efficacy or safety outcomes have been reported as of October 2025. (cdek.pharmacy.purdue.edu)

Mechanism of action

• TGFBi NK cells: Exposure to TGF‑β during NK‑cell activation/expansion induces a durable transcriptional and epigenetic program that renders NK cells less sensitive to TGF‑β–mediated suppression in the tumor microenvironment, with persistent hypersecretion of IFN‑γ and TNF‑α after TGF‑β withdrawal. Mechanistically, TGFBi NK cells show reduced SMAD3 and T‑bet expression with altered chromatin accessibility; cytotoxic receptor/granzyme profiles can shift in a target‑dependent manner. (mdpi.com)
• Rationale for pairing with chemotherapy: Gemcitabine/docetaxel can debulk tumors and, in some models, modulate tumor‑cell ligand expression (for example, increased MICA/NKG2D ligands) to enhance NK‑cell recognition, supporting chemo‑immunotherapy combinations. Preclinical work in triple‑negative breast cancer showed that adding gemcitabine to TGFBi NK cells plus anti‑GD2 improved tumor control and survival versus gemcitabine alone. (mdpi.com)

Clinical development

• Ongoing trial: Phase 1/2, single‑arm, multi‑center study in relapsed/refractory pediatric bone and soft‑tissue sarcomas. Participants receive 21‑day cycles (up to 8): gemcitabine days 1 and 8; docetaxel day 8; growth‑factor/dexamethasone support; TGFBi NK infusion on day 12 in cycles 1–6. Primary aims include safety/tolerability and 6‑month progression‑free survival; the study is listed as recruiting. No results are posted yet. (siteman.wustl.edu)

Efficacy

• Human data: No efficacy results have been reported for GEM/DOX + TGFBi NK cells to date. (cdek.pharmacy.purdue.edu)
• Preclinical signals: In a TNBC mouse model, TGFBi NK cells combined with anti‑GD2 improved tumor control and survival; addition of gemcitabine further enhanced outcomes and was tolerated in the model. (aacrjournals.org)

Safety

• Human data: No safety outcomes from clinical use of the combination have been posted as of October 2025. The ongoing Phase 1/2 trial includes rolling safety/toxicity analyses to identify adverse events attributable to GEM/DOX + TGFBi NK infusions. (cdek.pharmacy.purdue.edu)

Further reading

• Foltz et al. TGFβ imprinting during activation promotes NK‑cell cytokine hypersecretion (mechanistic foundation of TGFBi NK cells). Cancers (2018). (mdpi.com)
• TiNKS trial listing (NCT05634369): Phase 1/2 GEM/DOX + TGFBi NK cells in pediatric sarcomas; recruiting. (cdek.pharmacy.purdue.edu)
• MD Anderson trial page for TiNKS (study #2022‑0995). (mdanderson.org)
• AACR/SABCS abstract: TGFBi NK + anti‑GD2 ± gemcitabine in TNBC model (preclinical combination rationale). (aacrjournals.org)

Last updated: Oct 2025