This study tests the safety and preliminary anti-tumor activity of an investigational dual-target chimeric antigen receptor natural killer (CAR-NK) cell therapy in adults with advanced breast cancer. After a tumor antigen assessment (HER2/ERBB2, MUC1, ROR1, and in some TNBC cases mesothelin), each participant will receive the most suitable dual-target CAR-NK product for their tumor profile, following short-course lymphodepleting chemotherapy.
Natural killer (NK) cells can recognize and kill abnormal cells as part of the innate immune system. CAR engineering can enhance NK-cell recognition of tumor-associated antigens and may improve anti-tumor activity in solid tumors. This is a two-part, first-in-program study. Part A uses dose escalation to identify a safe and feasible dose of a dual-target CAR-NK cell product. Part B evaluates preliminary efficacy in biomarker-defined expansion cohorts for HER2-positive breast cancer and triple-negative breast cancer (TNBC). Target selection is biomarker-guided. A fresh or archival tumor sample is tested by immunohistochemistry (IHC) for HER2/ERBB2, MUC1, and ROR1 expression. Participants are assigned to one of three dual-target CAR-NK constructs based on a predefined algorithm prioritizing highest and most homogeneous target expression. In TNBC, mesothelin testing may be performed to support an exploratory sub-cohort. All participants receive lymphodepleting chemotherapy (fludarabine + cyclophosphamide) before CAR-NK infusion. The CAR-NK product is an allogeneic, cryopreserved NK-cell therapy engineered to express a dual-specific CAR and an inducible safety switch; the product is administered intravenously.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
60
Route: IV infusion. Schedule: single infusion on Day 0; optional second infusion on Day 7 in the absence of dose-limiting toxicity (DLT) and with adequate clinical status.
fludarabine (Days -5 to -3) and cyclophosphamide (Days -5 to -4), prior to CAR-NK infusion.
Premedication per institutional standard (e.g., acetaminophen and antihistamine). Tumor lysis and infection prophylaxis per institutional guidelines.
Peking University Shenzhen Hospital
Shenzhen, Guangdong, China
RECRUITINGIncidence of dose-limiting toxicities (DLTs)
Incidence of dose-limiting toxicities (DLTs) (including cytokine release syndrome and neurotoxicity) graded by CTCAE v5.0 and ASTCT consensus criteria for CRS/ICANS
Time frame: 28 Days
Safety profile
Safety profile by type, frequency, severity, and relatedness of treatment-emergent adverse events (AEs) and serious AEs.
Time frame: 12 months
Recommended Phase 2 Dose
Recommended Phase 2 Dose (RP2D) based on DLTs, overall safety, and biologic activity (CAR-NK expansion/persistence).
Time frame: 56 days
Objective response rate (ORR) by RECIST v1.1 (and iRECIST, if immunotherapy response patterns are suspected).
Time frame: 12 months
Disease control rate (DCR)
Disease control rate (DCR) (CR+PR+SD)
Time frame: 12 months
Duration of response (DoR).
Time frame: 24 months
Progression-free survival (PFS)
Time frame: 24 months
Overall survival (OS)
Time frame: 24 months
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