GC-511B

Moonlight Bio, Inc., a Seattle-based cell therapy company founded in 2023, has registered a Phase I first-in-human clinical trial (NCT07488923) of ML261, an autologous anti-DLL3 CAR T-cell therapy engineered with a CARD11-PIK3R3 fusion transgene, in patients with relapsed or refractory small cell lung cancer and select neuroendocrine carcinomas. The trial, named SPECTRAL-1, is listed as not yet recruiting, with an estimated start date of May 2026 and planned enrollment of 110 participants. ML261 is the first CAR T-cell product to incorporate the CARD11-PIK3R3 potency-enhancement platform in a clinical setting, a technology derived from academic research at Northwestern University and the University of California, published in Nature in February 2024. The Moonlight Bio SCLC program enters a competitive DLL3-targeting landscape but does so with a distinct biological approach that has not previously been tested in humans. SPECTRAL-1 is an open-label, sequential dose-escalation study. The primary endpoint is the incidence of dose-limiting toxicities within a 28-day observation period, while treatment-emergent adverse events, preliminary efficacy, and pharmacokinetics will also be assessed. ML261 is administered as an intravenous infusion of autologous T cells collected via leukapheresis and engineered ex vivo. Eligible participants must have confirmed relapsed or refractory SCLC, gastroenteropancreatic neuroendocrine carcinoma, high-grade neuroendocrine prostate cancer, or extrapulmonary neuroendocrine carcinoma, with documented DLL3 expression, and have received at least one prior line of systemic therapy (excluding prior DLL3 CAR-T). Primary completion is estimated for Q1 2028. The biological rationale for ML261 rests on two elements. First, DLL3 is an inhibitory Notch pathway ligand aberrantly expressed on the surface of neuroendocrine tumor cells — present in approximately 80–90% of SCLC tumors — while largely absent from normal adult tissues. This expression pattern makes it a tumor-selective target. Second, the CARD11-PIK3R3 fusion gene, originally identified as a gain-of-function driver mutation in CD4+ cutaneous T-cell lymphoma by Jaehyuk Choi’s laboratory at Northwestern University, was repurposed by researchers including Kole Roybal at UCSF to enhance CAR T-cell function. The fusion amplifies signaling through the CARD11-BCL10-MALT1 complex, increasing cytokine production, T-cell persistence, and proliferation in preclinical solid tumor models. The modification reduced the CAR T-cell dose required for tumor control and diminished dependence on lymphodepletion preconditioning. Moonlight Bio licensed this technology from its academic originators; both Choi and Roybal serve on the company’s strategic advisory team, alongside Sean Parker of the Parker Institute for Cancer Immunotherapy. ML261 enters a DLL3-targeting field that already includes an approved product. Tarlatamab (Imdelltra, Amgen), a DLL3×CD3 bispecific T-cell engager, received FDA approval for relapsed SCLC and is being studied in Phase 3 trials and in extrapulmonary neuroendocrine carcinomas. HPN328 (Harpoon Therapeutics), a DLL3-targeting tri-specific T-cell engager, is in Phase 1/2 development. Among CAR T approaches, academic-sponsored programs in China — including GC511B and an anti-PD-L1/4-1BB DLL3 CAR T from Sichuan University — are in early-phase testing. ML261 is differentiated by its CARD11-PIK3R3 potency-enhancement platform, which is designed to address the persistent failure of conventional CAR T cells in solid tumors due to T-cell exhaustion and immunosuppressive microenvironments. Whether this translates into clinical benefit over bispecific engagers or unmodified CAR T constructs remains to be determined by SPECTRAL-1 data. Moonlight Bio initiates first-in-human trial of ML261, a potency-enhanced anti-DLL3 CAR T therapy, in relapsed SCLC and neuroendocrine carcinomas. Your email address will not be published. Required fields are marked * Comment * Name * Email * Website