Pieper et al. treated tumor-bearing mice with local radiation therapy (RT) and bempegaldesleukin (BEMPEG), a PEGylated, CD122-engaging IL-2 receptor agonist. Compared to the single therapies, this combination improved tumor control in B78 melanoma, MOC2 head and neck carcinoma, and 4T1 breast cancer models. RT of B78 tumors increased CD122 expression on splenic T cells and, with BEMPEG, CD8+ T cell tumor infiltration; depleting T cells eliminated antitumor efficacy. Adding immune checkpoint blockade (anti-CTLA-4 or anti-PD-L1) to the combination treatment further suppressed larger tumors and metastases.
Contributed by Alex Najibi
ABSTRACT
BACKGROUND: Current clinical trials are using radiation therapy (RT) to enhance an antitumor response elicited by high-dose interleukin (IL)-2 therapy or immune checkpoint blockade (ICB). Bempegaldesleukin (BEMPEG) is an investigational CD122-preferential IL-2 pathway agonist with prolonged in vivo half-life and preferential intratumoral expansion of T effector cells over T regulatory cells. BEMPEG has shown encouraging safety and efficacy in clinical trials when used in combination with PD-1 checkpoint blockade. In this study, we investigated the antitumor effect of local RT combined with BEMPEG in multiple immunologically 'cold' tumor models. Additionally, we asked if ICB could further enhance the local and distant antitumor effect of RT+BEMPEG in the setting of advanced solid tumors or metastatic disease. METHODS: Mice bearing flank tumors (B78 melanoma, 4T1 breast cancer, or MOC2 head and neck squamous cell carcinoma) were treated with combinations of RT and immunotherapy (including BEMPEG, high-dose IL-2, anti(_)-CTLA-4, and _-PD-L1). Mice bearing B78 flank tumors were injected intravenously with B16 melanoma cells to mimic metastatic disease and were subsequently treated with RT and/or immunotherapy. Tumor growth and survival were monitored. Peripheral T cells and tumor-infiltrating lymphocytes were assessed via flow cytometry. RESULTS: A cooperative antitumor effect was observed in all models when RT was combined with BEMPEG, and RT increased IL-2 receptor expression on peripheral T cells. This cooperative interaction was associated with increased IL-2 receptor expression on peripheral T cells following RT. In the B78 melanoma model, RT+BEMPEG resulted in complete tumor regression in the majority of mice with a single ~400_mm(3) tumor. This antitumor response was T-cell dependent and supported by long-lasting immune memory. Adding ICB to RT+BEMPEG strengthened the antitumor response and cured the majority of mice with a single ~1000_mm(3) B78 tumor. In models with disseminated metastasis (B78 primary with B16 metastasis, 4T1, and MOC2), the triple combination of RT, BEMPEG, and ICB significantly improved primary tumor response and survival. CONCLUSION: The combination of local RT, BEMPEG, and ICB cured mice with advanced, immunologically cold tumors and distant metastasis in a T cell-dependent manner, suggesting this triple combination warrants clinical testing.
Author Info: (1) Department of Human Oncology, University of Wisconsin Madison, Madison, Wisconsin, USA. (2) Department of Human Oncology, University of Wisconsin Madison, Madison, Wisconsin, U
Author Info: (1) Department of Human Oncology, University of Wisconsin Madison, Madison, Wisconsin, USA. (2) Department of Human Oncology, University of Wisconsin Madison, Madison, Wisconsin, USA. (3) Department of Human Oncology, University of Wisconsin Madison, Madison, Wisconsin, USA. (4) Department of Radiation Oncology, University of Pittsburgh Hillman Cancer Center, Pittsburgh, Pennsylvania, USA. (5) Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, Wisconsin, USA. (6) Department of Human Oncology, University of Wisconsin Madison, Madison, Wisconsin, USA. (7) Department of Human Oncology, University of Wisconsin Madison, Madison, Wisconsin, USA. (8) Nektar Therapeutics, San Francisco, California, USA. (9) Department of Human Oncology, University of Wisconsin Madison, Madison, Wisconsin, USA. (10) Department of Human Oncology, University of Wisconsin Madison, Madison, Wisconsin, USA. (11) Nektar Therapeutics, San Francisco, California, USA. (12) Department of Human Oncology, University of Wisconsin Madison, Madison, Wisconsin, USA. (13) Department of Human Oncology, University of Wisconsin Madison, Madison, Wisconsin, USA pmsondel@humonc.wisc.edu. Department of Pediatrics, University of Wisconsin Madison, Madison, Wisconsin, USA.
