Phase 1b TRICK-NK TROP2-targeted CAR-NK (IL-15 armored, TGFBR2 knockout) + T-DXd

This Phase 1b, open-label dose-escalation then dose-expansion study at MD Anderson tests an allogeneic cord blood–derived NK-cell product engineered with a TROP2-directed CAR plus IL-15 expression (to enhance NK persistence/function) and TGFBR2 knockout (to reduce TGF-β–mediated immunosuppression in the tumor microenvironment). The regimen combines TRICK-NK with trastuzumab deruxtecan (Enhertu; Daiichi Sankyo/AstraZeneca), a HER2-directed antibody–drug conjugate that delivers a DXd topoisomerase I inhibitor payload to HER2-expressing cells, and also includes rimiducid, used here as an inducible “safety switch” activator for the iC9 suicide gene built into the NK cells (not an anticancer mTOR inhibitor). Eligible patients have metastatic or unresectable breast cancer where standard curative/palliative options no longer work; the protocol targets T-DXd–eligible HER2-positive or HER2-low disease, and TNBC patients must have previously received an anti-TROP2 ADC such as sacituzumab govitecan (Gilead). The scientific angle is a dual-antigen/dual-modality approach: a TROP2-targeted cellular therapy layered onto a HER2 ADC backbone, with an optional schedule-optimization phase that tightens the interval between NK infusion and the first T-DXd dose. Today’s care for refractory metastatic breast cancer is sequential systemic therapy (endocrine therapy when eligible, chemo, HER2-targeted agents for HER2+ disease, T-DXd for HER2+ and HER2-low, and ADCs such as sacituzumab for TNBC), and this explores whether an “armored” off-the-shelf NK platform can deepen responses beyond ADCs alone. Houston, TX (single-site, MD Anderson) | NCT07553390