Abstract 4158: Selective targeting of CD122 combined with radiotherapy triggers CD8 and NK mediated immunity, abrogating metastasis in head and neck squamous cell carcinoma
Authors: Gadwa Jacob , Amann Maria , Bickett Thomas E. , Knitz Michael W. , Darragh Laurel B. , Piper Miles , Van Court Benjamin , Bukkapatanam Sanjana , Pham Tiffany T. , Wang Xiao-Jing , Deak Laura Codarri , Klein Christian , Umana Pablo , D'Alessandro Angelo , Karam Sana 
Published: June 2023

Abstract
The implementation of cancer immunotherapies, while revolutionary in certain cancer types, has seen limited clinical success in head and neck squamous cell carcinomas (HNSCC). This revelation has prompted investigation in alternative targets to invigorate anti-tumor immunity. IL-2 signaling governs the survival and functionality of lymphocytes, thus making IL-2 receptor signaling an attractive target for new immunotherapies. However, therapies to enhance IL-2 signaling are often limited in their efficacy by modulating the activation of regulatory T cells (Tregs), which preferentially binds IL-2 via the high affinity receptor IL-2Rα (CD25). Selectively targeting IL2Rβ (CD122), the intermediate affinity receptor, can be leveraged to induce anti-tumor immune responses in effector T cells and natural killer (NK) cells while limiting negative regulation conferred by Tregs. The novel bispecific immunocytokine PD1-IL2v preferentially activates IL-2 signaling through CD122 on PD-1 expressing cells, activating immune effectors, and preventing immune exhaustion by blockade of PD-1. However, PD-1 blockade can amplify immunosuppression by Tregs, necessitating their depletion using αCD25. Here, we observe that radiation therapy and combination of PD1-IL2v with an Fc-optimized αCD25 antibody induces systemic activation of effector CD4 and CD8 T cells, reducing overall tumor burden. Concordant with improved local tumor control, we also observed a decrease in metastatic spread using a newly developed Kras/smad4/p53 mutated metastatic tumor model. NK cells, which are known to play a central role in the control of tumor cell dissemination though direct cytotoxicity, displayed a phenotypic shift towards an activated state upon treatment with PD1-IL2v, highlighted by enhanced cytotoxicity, NK receptor diversity, and metabolic activity. Although relatively uncommon in comparison to other cancer types, those patients who present with metastases display a substantially poorer outcome, demonstrating the need for therapies which target this axis of cancer disease progression. In summary, we find that radiation therapy and PD1-IL2v imparts potent anti-tumor immunity, reducing local tumor growth and distant tumor spread, which taken together contribute to increased overall survival.
Citation Format: Jacob Gadwa, Maria Amann, Thomas E. Bickett, Michael W. Knitz, Laurel B. Darragh, Miles Piper, Benjamin Van Court, Sanjana Bukkapatanam, Tiffany T. Pham, Xiao-Jing Wang, Laura Codarri Deak, Christian Klein, Pablo Umana, Angelo D'Alessandro, Sana Karam. Selective targeting of CD122 combined with radiotherapy triggers CD8 and NK mediated immunity, abrogating metastasis in head and neck squamous cell carcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4158.