Assessing the impact of PCSK9 inhibition in small cell lung cancer with novel DLL3-targeted bispecific T-cell engager therapy.

Abstract

e20135 Background: B-specific T-cell engagers (BiTEs) such as tarlatamab, have improved upon the efficacy and durability of response in small cell lung cancer (SCLC). However, an unmet need remains due to the known “immune-cold” microenvironment and immune evasion of SCLC. PCSK9 has been shown to enhance tumor immunity by increasing tumor antigen presentation and CD8+ T-cell infiltration. We hypothesized that combining PCSK9 inhibition with tarlatamab would enhance anti-tumor immune responses in SCLC. Methods: Fresh surgically resected SCLC tissue was mechanically minced and enzymatically dissociated using Human Tumor Dissociation (HRA) enzymes (Miltenyi Biotec) to generate single-cell suspensions. Cells were mixed with Matrigel and processed using the MOSgen platform to generate micron-scale Matrigel droplets containing SCLC cells and organoids, forming MicroOrganoSpheres (MOS). SCLC MOS were supplemented with interleukin-2 (IL-2) to preserve immune cells and treated with increasing concentrations of alirocumab (PCSK9 inhibitor) and tarlatamab (DLL3-targeted BiTE), alone and in combination for 72 hours. Cell viability was quantified using CellTiter-Glo (CTG) luminescent ATP assay. Data were normalized to untreated control conditions and expressed as percent viability. Results: To develop a method to predict patient responses to the alirocumab and tarlatamab combination therapy, we leveraged our existing MicroOrganoSphere (MOS) technology. At time of submission, two patient-derived SCLC MOS samples were successfully generated and evaluated. Both samples demonstrated a limited response to alirocumab monotherapy across all tested concentrations. These responses were improved by the addition of tarlatamab. The MOS platform successfully maintained viable tumor architecture and immune cell populations throughout the 72-hour treatment period, enabling functional assessment of immunotherapy combinations. Conclusions: This study establishes the first patient-derived SCLC MOS platform for evaluating PCSK9 inhibition combined with tarlatamab. This proof-of-concept demonstrates technical feasibility for rapid functional drug screening in SCLC. Future studies will expand to additional patient samples with comprehensive immune profiling including T-cell activation markers, cytokine secretion (IFN-γ, TNF-α, granzyme B), and exhaustion markers (PD-1, TIM-3, LAG-3) to identify predictive biomarkers of response. These findings will inform the design of investigator-initiated clinical trials combining PCSK9 inhibitors with tarlatamab ± checkpoint inhibitors in metastatic SCLC patients who have progressed on prior therapy.