90Y-, 177Lu-, and 225Ac-NM600 dose rate effect on immune response in murine tumor models

Abstract

Background: Targeted radionuclide therapy (TRT) is an emerging treatment for metastatic disease that delivers systemic radiation via a therapeutic radionuclide-linked, tumor-targeting vector. We have previously shown that low dose radiation delivery with 90Y-NM600 improves tumor response to immune checkpoint inhibitors (ICIs). NM600 is selectively taken up and retained in murine and human tumors. Understanding the effect of different radionuclide physical properties (emission type, linear energy transfer (LET), half-life, and tissue range) on immunomodulation of immunologically cold cancers can improve clinical treatment and avoid immunosuppression encountered with systemic external beam radiation therapy (EBRT). Here, we study 90Y, 177Lu, and 225Ac in immunologically cold syngeneic murine tumor models, MOC2 head and neck squamous cell carcinoma and B78 melanoma, monitoring cGAS/STING mediated type 1 interferon (IFN1) responses. We hypothesized that the radionuclide’s physical properties would differentially impact immunomodulation. Methods: 90Y, 177Lu, or 225Ac were added to culture media in activities estimated by the Medical Internal Radiation Dose method to deliver 12 Gy (MOC2) or 4 Gy (B78) to the cell monolayer by an infinite timepoint. qPCR was performed on cDNA from cells that were irradiated with EBRT, 90Y, 177Lu, or 225Ac, and harvested on days 1, 3, or 7. Mice bearing B78 WT or Tmem173 -/- CRISPR deletion B78 (STING KO) tumors were randomized to receive 1.5 Gy EBRT, an equivalent tumor dose of 90Y- or 177Lu-NM600 determined by the Monte Carlo-based RAPID platform, 0.5 μCi 225Ac-NM600, or no radiation on day 1. Tumors were harvested on days 4, 7, and 10 for RT-qPCR. Results: Expression of immune susceptibility markers (Mhc1, Pdl1) and IFN1 response- associated genes (Ifnβ1, Mx1) was upregulated in MOC2 and B78 cells following EBRT/TRT, compared to controls. The timing and magnitude of these effects correlated with radionuclide half-life and LET. Conclusion: These studies show the capacity to deliver immunomodulatory radiation to tumors using γ-, β- or α-emitting TRT. Understanding TRT effects on the tumor microenvironment may pave integration of TRT and immunotherapies into clinical care to enhance anti-tumor immunity.