Abstract 508: Mechanisms of cooperative response to bempegaldesleukin (BEMPEG) and 90Y-NM600 targeted radionuclide therapy in the treatment of a syngeneic murine model of head and neck squamous cell carcinoma
Authors: Emma Sarah E. , Bates Amber M. , Hernandez Reinier , Grudzinski Joseph J. , Marsh Ian R. , Jagodinsky Justin C. , Bednarz Bryan P. , Pieper Alexander A. , Sumiec Elizabeth G. , Nystuen Erin J. , Sosa Gustavo A. , Patel Ravi B. , Weichert Jamey , Morris Zachary S. 
Published: July 2021

Abstract
The purpose of this study was to evaluate mechanisms of cooperative therapeutic effects of bempegaldesleukin (BEMPEG; NKTR-214) and 90Y-NM600 in head and neck squamous cell carcinoma (HNSCC). BEMPEG is a first in class, CD122-preferential interleukin-2 (IL2) pathway agonist tailored to stimulate antitumor immunity through promoting activation and proliferation of CD8+ T and NK cells. We have observed that targeted radionuclide therapy (TRT) delivered at low doses to sites of metastatic cancer can enhance immune susceptibility in immunologically “cold” tumors such as the MOC2 syngeneic mouse HNSCC model. NM600 is an alkylphosphocholine analog that is selectively sequestered and retained by most human and murine cancer cells. We hypothesized that combining BEMPEG and 90Y-NM600 would cooperate to increase immunosusceptibility and immune cell tumor infiltration and create an overall more favorable immune microenvironment in MOC2 HNSCC tumors. MOC2 tumors were engrafted in the flank of C57BL/6 female mice. Once tumors reached ~100 mm³, mice were randomized into one of eight groups for a survival study utilizing varying combinations of BEMPEG (16 µg, days 6, 15, 24 IV), 90Y-NM600 (100 µCi, day 1 IV), and anti-CTLA4 (200 µg, days 4, 7, 10 IP). In vivo dosimetry was performed prior to day 1 using the Monte Carlo based RAPID platform. Serial 86Y-NM600 PET/CT imaging indicated the dose delivered to the tumor was ~8 Gy. Cohorts of mice in a parallel study were treated with PBS (control), BEMPEG, 90Y-NM600, or BEMPEG and 90Y-NM600. Flow cytometry, qPCR analysis, multiplex cytokine analyses were used to evaluate tumors collected at day 14. In this immunologically “cold” murine HNSCC model, a complete tumor response was observed in 62.5% of mice treated with the triple combination therapy of BEMPEG, 90Y-NM600, and anti-CTLA4. Compared to single therapy groups, mice treated with BEMPEG and 90Y-NM600 had increased CD8+ T cell tumor infiltrate, and 90Y-NM600 induced increased expression of the IL2βγ receptor, CD122, on the surface of CD8 T cells. Tumors from mice treated with BEMPEG and 90Y-NM600 had increased expression of genes associated with tumor cell immune susceptibility (Pdl1, Mhc1, Fas), a type 1 interferon response (Mx1, Trex1, Oas2, Oas3), tumor immune cell recruitment (MIP1α , Tnfα, Mac1, Csf1, Cxcl11) activation of cytotoxic T lymphocytes (Ifny, Cxcl10), and production of immune stimulatory cytokines (IFNy, IL3, IL4, IL5, IL17, RANTES, TNFα, MIP1β, MIP1α, CXCL10, CXCL9). These results suggest a synergistic interaction between BEMPEG and 90Y-NM600 that improves the immune microenvironment in this difficult to treat murine model of HNSCC, which may thereby enhance the response to immune checkpoint blockade. Further studies are warranted to examine the therapeutic implications of this combination in patients.
Citation Format: Sarah E. Emma, Amber M. Bates, Reinier Hernandez, Joseph J. Grudzinski, Ian R. Marsh, Justin C. Jagodinsky, Bryan P. Bednarz, Alexander A. Pieper, Elizabeth G. Sumiec, Erin J. Nystuen, Gustavo A. Sosa, Ravi B. Patel, Jamey Weichert, Zachary S. Morris. Mechanisms of cooperative response to bempegaldesleukin (BEMPEG) and 90Y-NM600 targeted radionuclide therapy in the treatment of a syngeneic murine model of head and neck squamous cell carcinoma [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 508.