Abstract 2262: Low-dose targeted radionuclide therapy has favorable local and systemic effects on immune populations in a murine prostate cancer model
Authors: Potluri Hemanth Kumar , Hernandez Reinier , Zahm Christopher D. , Grudzinski Joseph , Massey Christopher , Weichert Jamey , McNeel Douglas G. 
Published: September 2020

Abstract
Introduction: Prostate cancer remains the second leading cause of cancer-related death in American men because of its metastatic, incurable form. Prostate cancer responds poorly to checkpoint blockade likely due to its immunosuppressive microenvironment with relatively few infiltrating CD8+ T cells, limited mutational burden, and activity of myeloid-derived suppressor cells (MDSCs). External beam radiotherapy (EBRT) has been shown to help overcome this suppressive state, but EBRT is infeasible for patients with widely metastatic disease. Our group has developed a compound called NM600 that can be used to deliver radiation to all sites of disease simultaneously in an approach called Targeted radionuclide therapy (TRT). However, the effects of TRT on immune populations within prostate tumors are not yet well described. In this study, we examined the effects of TRT in the form of 90Y-NM600 on mice bearing Myc-CaP prostate tumors.
Methods: 6-week old male FVB mice were implanted subcutaneously with Myc-CaP cells, then given a single intravenous injection of either 50 (“low-dose”) or 250 (“high-dose”) μCi of 90Y-NM600, estimated to deliver 3.1 Gy or 15.5 Gy to 300 mm3 tumors, respectively. Groups of mice (n=3) were then euthanized at several timepoints following TRT administration. Their tumors and spleens were collected for analysis by flow cytometry and Luminex cytokine analysis. A separate group (n=5) were followed for survival to 2000 mm3.
Results: Flow cytometry of splenocytes revealed that high-dose, but not low-dose TRT caused a 6-fold increase in numbers of MDSCs (p = 0.002) at Day 21 compared to baseline. Additionally, low-dose TRT caused a 2-fold (p = 0.005) increase in CD8+ T cells at Day 21 compared to baseline, unlike in the high-dose condition. These CD8+ T cells in the low-dose TRT condition were predominantly proliferating naïve T cells. Flow cytometry of tumor infiltrating lymphocytes showed a 13% increase in CD8+ T cells in both dose conditions at Day 14 (p = 0.03). Returning CD8+ T cells displayed high expression of PD-1, CTLA-4, and LAG-3. Within the tumor, there was an 8-fold increase in chemokines including CXCL1, Rantes, and MIP2 at Day 21, suggesting that there may be further recruitment of tumor infiltrating cells even three weeks following treatment. Mice treated with high-dose TRT (median survival 37 days, p = .029) had significantly improved median survival compared to control (median survival 23 days), unlike low-dose treated mice (median survival 29 days, p =.250).
Conclusions: These data suggest that low-dose TRT is superior for immunomodulation because, although it has little effect on tumor growth, it increases intratumoral CD8+ T cell infiltration while avoiding deleterious systemic immune effects. We hypothesize that immunomodulatory TRT combined with checkpoint blockade will improve anti-tumor efficacy compared to high-dose TRT.
Citation Format: Hemanth Kumar Potluri, Reinier Hernandez, Christopher D. Zahm, Joseph Grudzinski, Christopher Massey, Jamey Weichert, Douglas G. McNeel. Low-dose targeted radionuclide therapy has favorable local and systemic effects on immune populations in a murine prostate cancer model [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2262.