Moonlight Bio Opens First-in-Human Trial of Potency-Enhanced CAR T Therapy in Small Cell Lung Cancer
Moonlight Bio, Inc., a Seattle-based cell therapy company founded in 2023, has registered a Phase 1 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, San Francisco, and 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, graded according to CTCAE v5.0 and American Society for Transplantation and Cell Therapy criteria. Secondary endpoints include treatment-emergent adverse events over up to two years, preliminary efficacy assessed by RECIST v1.1, and pharmacokinetic characterization of ML261 through measurement of vector copy number in peripheral blood. ML261 is administered as an intravenous infusion of autologous T cells collected via leukapheresis and engineered ex vivo. Eligible participants must be 18 years or older with an ECOG performance status of 0 or 1 and must have received at least one prior line of systemic therapy. The trial requires histologically or cytologically confirmed relapsed or refractory SCLC, gastroenteropancreatic neuroendocrine carcinoma, high-grade neuroendocrine prostate cancer, or extrapulmonary neuroendocrine carcinoma, with documented DLL3 expression. Mixed histologies are permitted if the neuroendocrine component exceeds 50% (or 20% for neuroendocrine prostate cancer). Patients with prior DLL3-targeted CAR T therapy, prior allogeneic transplant, or active CNS pathology are excluded. The trial is FDA-regulated as a biological product. No trial sites have been disclosed. Primary completion is estimated for Q1 2028, with overall study completion projected for Q3 2030.
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. Garcia et al. reported in Nature (2024) that 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. Manufacturing partnerships include MaxCyte for electroporation-based cell engineering and ScaleReady for G-Rex bioreactor process development.