Abstract 903: In vivo efficacy of bempegaldesleukin, immune checkpoint inhibition, and targeted radionuclide therapy in immunocompetent murine model of head and neck cancer
Authors: Sosa Gustavo A. , Bates Amber M. , Patel Ravi , Hernandez Reinier , Grudzinski Joseph J. , Marsh Ian , Bednarz Bryan , Pieper Alexander , Nystuen Erin , Emma Sarah , Sumiec Elizabeth G. , Weichert Jamey P. , Morris Zachary S. 
Published: September 2020

Abstract
In preclinical studies, we have demonstrated that delivering low dose radiation therapy to all sites of metastatic cancer using targeted radionuclide therapy (TRT) can improve the response to immune checkpoint blockade. NM600 is a tumor-targeting alkylphosphocholine radiolabeled with 90Y. Following intravenous administration, NM600 is selectively taken up and retained in most murine and human cancer cells. Bempegaldesleukin (NKTR-214) is a first in class, CD122-preferential interleukin-2 (IL2) pathway agonist being studied for its ability to influence the IL2 pathway and selectively stimulate an immune response. The primary objective of this study was to test the hypothesis that NKTR-214 and 90Y-NM600 would increase the response to immune checkpoint blockade in the immunologically “cold” MOC2 syngeneic mouse model of head and neck squamous cell carcinoma (HNSCC). C57BL/6 female mice were engrafted with MOC2, a murine HNSCC cell line, in the right flank. When mean tumor volume reached ~100mm3, mice were randomized into eight treatment groups using a 2 × 2 × 2 study design for combinations of NKTR-214, 90Y-NM600, and anti-CTLA4. 100 µCi 90Y-NM600 was administered intravenously (IV, treatment day 1). Prior in vivo dosimetry performed using the Monte Carlo based RAPID platform following serial 86Y-NM600 PET/CT imaging demonstrated that this activity delivered ~8Gy to the MOC2 tumor. 200 µg anti-CTLA4 was delivered by intraperitoneal injection on days 4, 7, and 10. 16 µg NKTR-214 was given IV on days 6, 15, and 24. Tumor growth was monitored. In a parallel study, cohorts of mice were treated with PBS (control), NKTR-214, 90Y-NM600, or NKTR-214 + 90Y-NM600, and tumors were collected at day 14 for flow cytometry analysis. In the spontaneously metastatic, immunologically “cold” MOC2 HNSCC tumor model, 62.5% of mice treated with the combination of 90Y-NM600, NKTR-214, and anti-CTLA4 experienced complete tumor response, and these mice showed no observable primary or metastatic disease 60 days after treatment initiation. No mice receiving single or dual therapy combinations exhibited complete tumor response (p = &lt;0.01). Treatment with NKTR-214 + 90Y-NM600 resulted in increased tumor infiltration by CD8+ T cells. Intriguingly, 90Y-NM600 triggered increased expression of the IL-2β receptor, CD122, on the surface of tumor infiltrating CD8+ T cells, suggesting a novel mechanism of synergy with NKTR-214. Combination therapy with NKTR-214, 90Y-NM600, and anti-CTLA4 resulted in complete and durable tumor response in a difficult to treat murine model of HNSCC. Therapeutic interaction between TRT and NKTR-214 may be a result from low dose radiation increasing the expression of CD122 on tumor infiltrating lymphocytes. Further preclinical and early phase clinical investigations are warranted to evaluate the therapeutic potential of such combinations.
Citation Format: Gustavo A. Sosa, Amber M. Bates, Ravi Patel, Reinier Hernandez, Joseph J. Grudzinski, Ian Marsh, Bryan Bednarz, Alexander Pieper, Erin Nystuen, Sarah Emma, Elizabeth G. Sumiec, Jamey P. Weichert, Zachary S. Morris. In vivo efficacy of bempegaldesleukin, immune checkpoint inhibition, and targeted radionuclide therapy in immunocompetent murine model of head and neck cancer [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 903.