Abstract 6407: Radionuclide-specific effects of90Y-,177Lu-, or225Ac-NM600 targeted radionuclide therapy on tumor immunomodulation and enhanced immunotherapy response in syngeneic murine tumors
Authors: Nguyen Thanh Phuong T. , Kerr Caroline P. , Grudzinski Joseph J. , Ferreira Carolina A. , Sheehan-Klenk Julia , Kwon Ohyun , Powers Maria , Clark Paul A. , Sriramaneni Raghava N. , Hernandez Reinier , Bednarz Bryan , Weichert Jamey P. , Morris Zachary S. 
Published: April 2023

Abstract
Background: Targeted radionuclide therapy (TRT) delivers radiation treatment systemically to tumor sites via a therapeutic radionuclide-linked tumor-selective targeting vector. NM600 is an alkylphosphocholine analog selectively taken up and retained in murine and human tumor cells. We previously showed that low dose radiation delivery with 90Y-NM600 improves tumor response to immune checkpoint inhibitors (ICIs). Understanding the effect of different radionuclide physical properties (emission type, linear energy transfer (LET), half-life, and tissue range) on immunomodulation of metastatic cancers may guide therapy development. Here, we evaluated the type 1 interferon (IFN1) response elicited by 90Y-, 177Lu-, and 225Ac-NM600 in an immunologically cold syngeneic murine tumor model, B78 melanoma. We hypothesized that the unique physical properties of radionuclides will differentially impact immunomodulation by TRT.
Methods: Mice bearing B78 WT or Tmem173 -/- CRISPR deletion B78 (STING KO) tumors were randomized to receive 1.5 Gy external beam radiation (EBRT), an equivalent tumor dose of 90Y-, 177Lu-, or 225Ac-NM600 determined by the Monte Carlo-based RAPID platform, or no radiation on day 1. Tumors were harvested on days 4, 7, and 10 for RT-qPCR. Mice bearing two B78 WT or Tmem173 -/- CRISPR deletion B78 (STING KO) tumors were randomized to receive 4 Gy external beam radiation therapy (EBRT), an equivalent tumor dose of 90Y- or 177Lu-NM600, 0.5 μCi 225Ac-NM600, or no radiation +/- dual ICI (anti-CTLA4 and anti-PDL1). Mice were monitored for tumor growth and survival following these treatments.
Results: Both EBRT and TRT upregulated expression of IFN1 response-associated genes (Ifnβ1, Mx1) in B78 WT tumors. Only TRT induced upregulation of Ifnβ1 and Mx1 in STING KO B78 tumors. Ddx58, which encodes RIG-I, integral to an alternative IFN1 pathway, was upregulated in both B78 WT and STING KO tumors following 225Ac-NM600, but not other treatments. TRT in B78 STING KO tumors had earlier expression of IFN1 response-associated genes than B78 WT, 225Ac-NM600 in combination with dual ICI improved overall survival over 90Y- or 177Lu-NM600 + ICI and 225Ac-NM600 monotherapy.
Conclusions: The distinct physical properties of TRT radiation, γ, β or α, affect the timing, magnitude, and molecular pathways leading to this IFN1 response. Understanding TRT effects on the tumor microenvironment may optimize TRT and immunotherapy.
Citation Format: Thanh Phuong T. Nguyen, Caroline P. Kerr, Joseph J. Grudzinski, Carolina A. Ferreira, Julia Sheehan-Klenk, Ohyun Kwon, Maria Powers, Paul A. Clark, Raghava N. Sriramaneni, Reinier Hernandez, Bryan Bednarz, Jamey P. Weichert, Zachary S. Morris. Radionuclide-specific effects of90Y-,177Lu-, or225Ac-NM600 targeted radionuclide therapy on tumor immunomodulation and enhanced immunotherapy response in syngeneic murine tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6407.