Phase 1 study of GCC2005, an allogeneic CD5-directed CAR-NK therapy, for patients with Relapsed/Refractory NK/T-cell malignancies

Abstract Introduction/Background Relapsed or refractory (R/R) NK and T-cell malignancies remain an area of high unmet need, with limited treatment options and poor clinical outcomes. Autologous CAR-T strategies in T-cell cancers are hampered by fratricide, malignant-cell contamination, and high rates of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). GCC2005 is an off-the-shelf, cord blood–derived allogeneic CAR-NK cell product engineered to target CD5. It secretes soluble IL-15 to enhance persistence. GCC2005 showed significantly enhanced efficacy with superior safety in preclinical studies. Preclinical studies also supported the safety and anti-tumor efficacy of GCC2005, providing the rationale for this first-in-human (FIH) clinical trial. We report the FIH Phase 1 dose-escalation trial evaluating the safety, tolerability, and preliminary efficacy of GCC2005 in adults with R/R NK and T-cell malignancies expressing CD5. Methods This ongoing, FIH open-label Phase 1 trial (NCT06699771) comprises a 3 + 3 dose-escalation stage (Phase 1a) followed by cohort expansion (Phase 1b). Eligible participants are adults (≥19 years) with CD5-positive R/R NK and T-cell malignancies who have received at least two prior lines of systemic therapy with no remaining standard treatment options. Patients received a lymphodepleting regimen of cyclophosphamide and fludarabine (Days –5 to –3), followed by three consecutive weekly infusions of GCC2005 at escalating dose levels (DLs, 1 × 10⁶ to 3 × 10⁷ CAR-NK cells/kg). The primary endpoints are safety—defined by the frequency, severity, and persistence of adverse events (AEs) graded per NCI CTCAE v5.0, including CRS, ICANS, and acute/chronic graft-versus-host disease (GvHD)—and tolerability, as measured by dose-limiting toxicities (DLTs), the maximum tolerated dose (MTD), and the recommended Phase 2 dose (RP2D). Secondary endpoints assess preliminary anti-tumor activity (Lugano classification), pharmacokinetics (PK), and anti-product antibody (APA) development. Results As of the data cut-off on 5 August 2025, seven patients were enrolled—three at DL1 and four at DL2; one DL2 patient withdrew after the initial GCC2005 infusion for not meeting criteria for subsequent dosing. The median age was 64 years (range 55–72), and patients had received a median of three prior systemic therapies. Disease subtypes included nodal TFH-cell lymphoma, angioimmunoblastic type (n = 3), peripheral T-cell lymphoma, not otherwise specified (n = 3), and other subtypes (n = 1). Common AEs, defined as those occurring in ≥2 patients (≥20%), included nausea (86%), vomiting (29%), diarrhea (29%), and neutrophil count decreased (29%); none were considered related to GCC2005. Three events (15% of all AEs) were Grade 3: a therapy-related grade 3 skin rash in DL1; an unrelated grade 3 diarrhea in DL1; and grade 3 neutropenia in DL2 attributed by lymphodepletion. One DL2 patient experienced a transient grade 1 cytokine-release syndrome deemed treatment-related. No DLTs, serious adverse events (SAEs), ICANS, or GvHD of any grade occurred in either DLs. Preliminary efficacy data are available for five patients at DL1 (n=3) and DL2 (n=2): in preliminary response evaluation, objective response rate (ORR) achieved 60% (CR 40%, PR 20%) — one CR in DL1 and one CR / one PR in DL2. The DL2 patient, who received only a single GCC2005 infusion, achieved CR after dosing and continues in remission under observation without further therapy. In the absence of any safety signals to date, the study will proceed with enrollment at the next DL following Safety Monitoring Committee review. Conclusions Although there is limited data from this FIH Ph1a study, it demonstrates that GCC2005, a CD5-targeting allogeneic CAR-NK therapy, has a favorable safety profile, with no DLT, ICANS, or GvHD of any grade observed, and only one transient grade 3 event was evaluated as therapy-related. Ongoing dose escalation will confirm the MTD and further define the safety, pharmacokinetics, and anti-tumor potential of GCC2005.