Abstract 2149: Copper-67 based targeted radioligand therapy to the somatostatin receptor 2 (SSTR2) provides added efficacy and may prime small cell lung cancer for immunotherapy

Abstract Background and Purpose: Immune checkpoint therapy (ICT) has revolutionized cancer treatment; however, efficacy remains poor for some cancers, including small cell lung cancer (SCLC). Strategies to enhance immune responses include combining ICT with other existing cancer therapies. Targeted radioligand therapy uses a radiolabeled cancer-targeting vector, allowing for specific delivery of radiation to all tumor sites while minimizing radiation exposure to healthy tissues. Targeted Copper Theranostics (TCTs) is a targeted radioligand platform utilizing copper-64/67. We evaluated [67Cu]Cu-SARTATE in combination with ICT in a murine animal model using RP116 tumor cells. Methods: We administrated ∼5 MBq [64Cu]Cu-SARTATE to RP116 (a murine SCLC cell line expressing SSTR2) tumor-bearing immunocompetent C57BL/6 mice and assessed biodistribution and tumor uptake via PET imaging at 1, 4 and 24 h post IV injection. After completion of a dose escalation study, an efficacy study using [67Cu]Cu-SARTATE, mouse ICT analogues and the combination of [67Cu]Cu-SARTATE and ICT treatment groups in the same animal model was performed to evaluate therapeutic efficacy of copper-67-based TCT. Results: Tumor uptake of [64Cu]Cu-SARTATE was visualized by PET imaging over the first 24 h post-injection with high tumor uptake, consistent with multiple studies previously published showing uptake in human xenograft models with the same product. Tumor uptake of [67Cu]Cu-SARTATE was confirmed by ex vivo biodistribution and Cherenkov imaging, with no significant radiotoxicity observed via body condition and body weight measurements in mice receiving injected activities up to the maximum tested dose of 30 MBq. The combination of 30 MBq [67Cu]Cu-SARTATE, with both anti-PD-L1 and anti-CTLA4, improved median survival by 3, 7, or 13 days, compared to ICT-only (anti-PD-L1 plus anti-CTLA4), [67Cu]Cu-SARTATE-only or saline-only treated groups respectively. Conclusion: Biodistribution studies demonstrated high tumor-specific uptake for [64Cu]- and [67Cu]-Cu-SARTATE in this mouse syngeneic SCLC model. A dose escalation study demonstrated copper-67-based TCT could be used to effectively inhibit tumor growth with minimal radiotoxicity. The combination of TCT with ICTs improved overall survival compared to single-treatment control groups. Collectively, our results demonstrate that [67Cu]Cu-SARTATE in combination with ICTs improves overall survival. [67Cu]Cu-SARTATE may prime immunologically “cold” SCLC tumors to improve responsiveness to ICTs through a synergistic response. Tumor biomarkers are being investigated to understand how immune infiltration differs depending on treatment regime. Citation Format: Jaclyn L. Lange, Lachlan E. Mclnnes, Kurt R. Gehlsen, Jessica Van Zuylekom, Benjamin Blyth, Stacey E. Rudd, Paul S. Donnelly, Matthew Harris. Copper-67 based targeted radioligand therapy to the somatostatin receptor 2 (SSTR2) provides added efficacy and may prime small cell lung cancer for immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2149.