Abstract 4440: Bempegaldesleukin (NKTR-214), a CD122 preferential IL-2 pathway agonist, augments the in situ vaccine response to radiation of an extracranial tumor in a murine melanoma model, conferring response at non-radiated tumor sites in the brain

Brain metastases develop in many patients with advanced metastatic cancers, and this challenging clinical scenario demands improved treatment approaches. We previously observed that an in situ vaccination (ISV) regimen combining local radiation (RT) and intratumoral (IT) injection of the radiated tumor site with interleukin-2 (IL2) resulted in enhanced response to immune checkpoint inhibition (ICI: αCTLA4 Ab) in immunologically cold murine models of melanoma. This ISV treatment resulted in complete response (CR) at both the ISV-targeted tumor and at distant extracranial tumor sites in most mice. However, in a model of melanoma brain metastases, this same ISV provided only a modest improvement in survival with all mice succumbing to progressive tumor burden in the brain (Sriramaneni et al., 2020 AACR submitted abstract). Bempegaldesleukin (NKTR-214, Nektar Therapeutics) is a PEGylated derivative of IL2 that can be administered systemically with minimal toxicity, has a longer half-life (~20 hours), and preferentially activates cytotoxic (CD8+) T cells and NK cells over regulatory T-cells within the tumor microenvironment. We hypothesized that these qualities of NKTR-214 could enhance immune response and efficacy of ISV against brain melanoma metastases, and therefore we tested in combination with local RT targeting an extracranial tumor site. Immunologically cold B78 melanoma tumor cells were implanted into the right flank and the right striatum of the brain in syngeneic C57BL/6 mice. Right flank tumors (150-200 mm3) were irradiated (12 Gy) on treatment day 1. NKTR-214 was administered intravenously on treatment days 6, 15, 24. NKTR-214 combined with RT significantly extended survival in these mice, compared to RT or NKTR-214 alone (p=0.008). Twenty percent of these mice treated with right flank RT + NKTR-214 exhibited durable CR at all tumor sites, whereas no CR was observed in mice treated with RT or NKTR-214 alone. Using this same regimen, we treated mice bearing a right flank B78 melanoma tumor (targeted by local RT) and non-radiated B78 melanoma tumors on the left flank and in the brain. In these mice, we compared the immune response in the brain and left flank tumors following treatment with right flank RT + systemic NKTR-214. Analysis of these tumors by microscopy at treatment day 15 demonstrated significantly increased CD8+ T cell infiltrate and an increased ratio of CD8+ T cells: FOXP3+ regulatory T cells in both the left flank and brain tumors compared to untreated control mice. In contrast to our prior observations with RT + IT-IL2, the combination of RT + NKTR-214 triggered a comparable immune response in both the brain and left flank tumors with respect to the degree of CD8+ T cell infiltration and the ratio of CD8+ effector: FOXP3+ regulatory T cells. These results suggest that a combination of RT + NKTR-214 may elicit an ISV effect that is capable of conferring enhanced anti-tumor immune response against brain metastases, and could potentially abrogate the need for direct brain radiation or surgery. Citation Format: Paul A. Clark, Raghava N. Sriramaneni, Alexander Pieper, Amber M. Bates, Bryce R. Anderson, Wonjong Jin, Justin C. Jagodinsky, Alexander L. Rakhmilevich, Zachary S. Morris. Bempegaldesleukin (NKTR-214), a CD122 preferential IL-2 pathway agonist, augments the in situ vaccine response to radiation of an extracranial tumor in a murine melanoma model, conferring response at non-radiated tumor sites in the brain [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 4440.