Abstract 679: In vivo synergy of 90Y-NM600 and Bempegaldesleukin improves anti-tumor efficacy of immune checkpoint inhibitors in syngeneic murine cancer models
Authors: Sumiec Elizabeth G. , Bates Amber M. , Hernandez Reinier , Grudzinski Joseph J. , Marsh Ian R. , Emma Sarah E. , Nystuen Erin J. , Jagodinsky Justin C. , Pieper Alexander A. , Sosa Gustavo A. , Bednarz Bryan P. , Patel Ravi B. , Weichert Jamey , Morris Zachary S. 
Published: July 2021

Abstract
We have observed in preclinical studies that the delivery of low dose targeted radionuclide therapy (TRT) therapy to sites of primary and metastatic cancer can improve the anti-tumor immune response to immune checkpoint inhibition (ICI) with anti-CTLA4 or anti-PDL1. NM600, an alkylphosphocholine that can be radiolabeled with 90Y, is taken up and retained in most cancer cells following intravenous injection. Bempegaldesleukin (BEMPEG) is a first in class, CD122-preferential IL2 pathway agonist that can selectively stimulate an immune response. We hypothesized that combining low dose TRT with BEMPEG would increase immune activation to enhance the response to ICIs in immunologically “cold” murine cancer models. C57Bl/6 female mice were subcutaneously engrafted in the flank with the murine head and neck squamous cell carcinoma (HNSCC) cell line, MOC2. In vivo dosimetry performed using the Monte Carlo based RAPID platform following serial 86Y-NM600 PET/CT imaging demonstrated that 100 µCi of 90Y-NM600 would deliver ~8 Gy to the MOC2 tumor. Mice bearing MOC2 tumors (mean volume ~100 mm3) received combinations of 90Y-NM600 (100 µCi, day 1 IV), BEMPEG (16 µg, days 6, 15, and 24 IV), and anti-CTLA4 (200 µg, days 4, 7, and 10 IP) using a 2x2x2 study design. Tumor growth and survival were monitored. Blood was collected weekly and analyzed on the Abaxis VetScan HM5 to evaluate for toxicity. In a parallel 2x2x2 survival study, an orthotopic model generated by engrafting MOC2 tumors in the cheek was used, and mice were treated with combinations of BEMPEG, 90Y-NM600, and anti-PDL1 (200 µg, days 4, 7, and 10, IP). Mice were euthanized when &gt;25% weight loss was observed. Similar experiments using 90Y-NM600 and BEMPEG were performed in additional syngeneic mouse cancer models including SCC7 (HNSCC), 4T1 (breast), LLC (lung), and Panc02 (pancreatic). In the immunologically “cold” MOC2 HNSCC model, 62.5% of mice treated with 90Y-NM600 (TRT), BEMPEG, and anti-CTLA4; and 44.4% of mice treated with 90Y-NM600, BEMPEG, and anti-PDL1 experienced complete tumor response with no observable primary or metastatic disease at day 60. In mice treated with 90Y-NM600 and BEMPEG, tumor regression followed by escape was seen without ICI. By day 60, no mice receiving single or dual treatment combinations exhibited a complete tumor response. Comprehensive whole blood analysis did not show any major hematologic toxicities. This treatment was explored in mice bearing SCC7, 4T1, Panc02, and LLC tumors, and similar trends were seen. Combination of 90Y-NM600, BEMPEG, and ICI displays robust anti-tumor activity that prevents metastatic disease progression and prolongs survival in spontaneously metastatic, immunologically “cold” tumor models. Clinical studies are warranted to test the safety and efficacy of this promising combined modality treatment regimen.
Citation Format: Elizabeth G. Sumiec, Amber M. Bates, Reinier Hernandez, Joseph J. Grudzinski, Ian R. Marsh, Sarah E. Emma, Erin J. Nystuen, Justin C. Jagodinsky, Alexander A. Pieper, Gustavo A. Sosa, Bryan P. Bednarz, Ravi B. Patel, Jamey Weichert, Zachary S. Morris. In vivo synergy of 90Y-NM600 and Bempegaldesleukin improves anti-tumor efficacy of immune checkpoint inhibitors in syngeneic murine cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 679.