Abstract 1306: Radionuclide-specific effects of 90Y-, 177Lu-, or 225Ac-NM600 targeted radionuclide therapy on tumor immunomodulation and enhancing immunotherapy response in murine tumor models
Authors: Kerr Caroline P. , Bates Amber M. , Grudzinski Joseph J. , Ferreira Carolina A. , Sheehan-Klenk Julia , Adam David , Powers Maria , Jin Wonjong , Jagodinsky Justin C. , Sriramaneni Raghava N. , Clark Paul A. , Zangl Luke , Pinchuk Anatoly N. , Onate Alejandro J. , Kumari Ria , Choi Cynthia , Massey Christopher F. , Bednarz Bryan , Hernandez Reinier , Weichert Jamey P. , Morris Zachary S. 
Published: June 2022

Abstract
Purpose: In preclinical studies, we have demonstrated that delivering low dose radiation to all tumor sites utilizing 90Y-NM600 improves the response to immune checkpoint inhibitors (ICIs). NM600 is an alkylphosphocholine analog that is selectively taken up and retained in murine and human tumors. In this study, the immunomodulatory capacities of three distinct radionuclides (90Y, 177Lu, 225Ac) were compared using immunologically cold syngeneic murine tumor models: MOC2 head and neck squamous cell carcinoma (HNSCC) and B78 melanoma. We hypothesized that physical properties of radionuclides (e.g. emission type, linear energy transfer (LET), half-life, dose rate) would differentially impact immunomodulation by TRT and ICI treatment response.
Methods: Dosimetry performed using the Monte Carlo-based RAPID platform utilizing serial 86Y-NM600 PET/CT imaging determined that 100 μCi 90Y-NM600 or 200 μCi 177Lu-NM600 delivered ~12Gy to the MOC2 tumor and ~4Gy to the B78 tumor. 225Ac-NM600 was dosed at activities ≤0.5 μCi, as determined to be safe and effective previously. Mice bearing two MOC2, B78 WT, or Tmem173 -/- CRISPR deletion B78 (STING KO) tumors were randomized to receive external beam radiation therapy (EBRT), an equivalent tumor dose of 90Y- or 177Lu-NM600, 0.25 μCi 225Ac-NM600, or no radiation +/- dual ICI (anti-CTLA4 and anti-PDL1). Tumors, blood, bone marrow, and spleen were harvested at days 4, 7, 14, and 21 post-treatment for flow cytometry and RT-qPCR. Additional mice were monitored for tumor growth and survival following these treatments.
Results: TRT and EBRT induced favorable tumor-specific immune cell infiltration (increased CD8/Treg ratio) at day 7. 225Ac-NM600 additionally induced similar changes at day 21, consistent with the longer half-life radioisotope (90Y: 65h; 177Lu: 161h; 225Ac: 240h). Expression of immune susceptibility markers (Mhc1, Pdl1) and type I interferon (IFN1) response-associated genes (Ifnβ1, Mx1) was upregulated following 12 Gy EBRT or TRT both in vitro and in vivo compared to non-irradiated controls in MOC2 cells and tumors. The timing and magnitude of these effects correlated with radionuclide half-life and LET. 225Ac-NM600 + ICI improved overall survival in B78 WT mice over 90Y- or 177Lu-NM600 + ICI, 225Ac-NM600 or ICI monotherapy, and non-irradiated controls. In the B78 STING KO melanoma cell line, this 225Ac-NM600 + ICI survival benefit was decreased.
Conclusions: These studies demonstrate the capacity to deliver immunomodulatory radiation to tumors using gamma-, beta- or alpha-emitting TRT. The physical properties of the delivered radionuclide dictate timing and magnitude of the IFN1 response stimulated by TRT. Understanding these effects may be critical to safely and effectively integrating TRT and immunotherapies to enhance anti-tumor immunity in cancer patients.
Citation Format: Caroline P. Kerr, Amber M. Bates, Joseph J. Grudzinski, Carolina A. Ferreira, Julia Sheehan-Klenk, David Adam, Maria Powers, Wonjong Jin, Justin C. Jagodinsky, Raghava N. Sriramaneni, Paul A. Clark, Luke Zangl, Anatoly N. Pinchuk, Alejandro J. Onate, Ria Kumari, Cynthia Choi, Christopher F. Massey, Bryan Bednarz, Reinier Hernandez, Jamey P. Weichert, Zachary S. Morris. Radionuclide-specific effects of 90Y-, 177Lu-, or 225Ac-NM600 targeted radionuclide therapy on tumor immunomodulation and enhancing immunotherapy response in murine tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1306.