90Y-NM600 Immunomodulates the Tumor Microenvironment of a Syngeneic Murine Model of Head and Neck Cancer to Improve Response to Bempegaldesleukin (NKTR-214) and Immune Checkpoint Inhibition

406 Objectives: The prognosis of metastatic head and neck squamous cell carcinoma (HNSCC) is dismal with median survival ranging between 6 and 12 months. Due to a predominantly suppressive tumor microenvironment (TME), immunotherapy has shown modest activity against head and neck squamous cell carcinoma (HNSCC) with objective responses only around 20%. The aim of this study was to test whether targeted radionuclide therapy can immunomodulate the TME of HNSCC to enhance the response to immunotherapies. Methods: C57BL/6 female mice (n = 4) bearing MOC2 (murine HNSCC) tumors were administered 9.25 MBq of the positron-emitting 86Y-NM600 - an alkylphosphocholine metal chelate with broad-scope tumor targeting - and longitudinal static microPET/CT scans were acquired at 3, 24, 48, and 72 h post-injection. A region-of-interest analysis of the PET images quantified the radiotracer uptake in MOC2 tumors and healthy tissues and afforded dosimetry estimation of 90Y-NM600 using Monte Carlo simulation. In therapy studies, mice bearing subcutaneous MOC2 tumors (n = 8; 100 mm3) received combinations of a CD122-biased agonist, Bempegaldesleukin (NKTR-214), 90Y-NM600, and anti-CTLA4. An injected activity of 90Y-NM600, estimated to deliver a tumor dose of 8 Gy, was administered i.v. on day 1 followed by anti-CTLA4 (200 µg) i.p. injections on days 4, 7, and 10. NKTR-214 (16 µg) was given i.v. on days 6, 15, and 24 post administration of 90Y-NM600. Tumors from a subgroup of treated mice (n = 10 per treatment group) were collected at day 14 for flow cytometry analysis. Survival and tumor growth were tracked until day 60. Results: microPET/CT imaging confirmed selective uptake and retention of NM600 in MOC2 tumors and gradual clearance from normal tissues. Tumor concentration peaked at 24 h p.i. with 9.76 ± 1.02 %IA/g with a tumor-to-muscle ratio approximately 10. Absorbed doses per 90Y-NM600 injected activity of 3.15 ± 0.39, 1.52 ± 0.38, and 0.65 ± 0.19 Gy/MBq were estimated for the tumor, spleen, and muscle, respectively. In the 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 < 0.01). Treatment with 90Y-NM600 and NKTR-214 resulted in increased CD8+ T cell tumor infiltration. Interestingly, 90Y-NM600 triggered increased expression of the IL2-beta receptor, CD122, on tumor infiltrating CD8+ T cells, indicating a sensitization of T-cells for NKTR-214. Conclusions: 90Y-NM600 was able to target and immunomodulate the TME of a murine model of HNSCC leading to complete and durable tumor responses when combined with NKTR-214 and anti-CTLA4. We hypothesize that 90Y-NM600 enhances the effect of NKTR-214 by increasing the expression of the IL2-beta receptor on tumor infiltrating T-cells. Further preclinical investigations are warranted to elucidate the mechanisms of such potential synergies.