Abstract 2863: Immunocytokines with target cell-restricted IL-15 activity for treatment of B cell malignancies
Authors: Hagelstein Ilona , Zekri Latifa , Klimovich Boris , Lutz Martina S. , Greve Carsten , Müller Stefanie , Märklin Melanie , Schmied Bastian , Jung Gundram , Salih Helmut R. 
Published: June 2022

Abstract
Antitumor antibodies like Rituximab and Trastuzumab activate the patient’s immune system to engage malignant cells. Despite the advances achieved by their introduction in cancer treatment, an urgent medical need remains to improve and optimize the efficacy of antibody therapy. This may be achievable using the cytokine IL-15 which induces proliferation and activation of both, NK cells and CD8 T cells, and enhances their cytolytic capacity. So far, short half-life, poor accumulation at the tumor site and severe toxicity upon systemic application due to unspecific immune activation prevent the broad use of IL-15 for treatment of cancer patients (Conlon et al, JCO 2015). IL-15 predominantly acts as part of an immunological synapse with IL-15Rα expressed on antigen-presenting cells, which present IL-15 in trans to IL-15Rβγ receptor expressing cytotoxic lymphocytes. We here report on the generation of so called “modified immunocytokines” (MICs) which consist of an Fc-optimized (SDIE modification) CD19 or CD20 antibody for targeting of (malignant) B cells fused to an IL-15 mutant with abolished binding to IL-15Rα termed MIC19 or MIC20. The abrogation of IL-15Rα binding by the IL-15 mutation enables substitution of the physiological trans-presentation by target binding of the antibody, allowing for target antigen-restricted stimulation of the IL-15Rβγ on NK cells and CD8 T cells. Analyses of activation and toxicity with MIC19 compared to a CD19 immunocytokine with an unmodified IL-15 (IC19) or immunocytokines with unrelated specificity as control confirmed target antigen-restricted function of the MIC proteins. Killing of autologous and allogeneic CD19+/CD20+ target cells was clearly superior as compared to the CD19-directed Fc optimized antibody (Tafasitamab) and Rituximab that bear no cytokine activity. Compared to antibody treatment, the MIC proteins induced a pronounced and long-lasting proliferation of effector cells and were effective to treat leukemia in a xenograft (Nalm-6) leukemia mouse model. Anti-leukemic activity was further confirmed in a murine NSG xenotransplantation model using patient ALL cells and human NK cells as effectors. In summary, MIC constructs consisting of an Fc-optimized antibody and mutated IL-15 with deficient IL-15Rα binding induce target cell restricted activation and proliferation of NK cells, resulting in efficient anti-leukemic activity. Our MICs thus combine the benefits of Fc-optimized antibodies and IL-15 activity and constitute a promising novel treatment modality for B cell malignancies with low side effects that allow the application of truly effective doses.
Citation Format: Ilona Hagelstein, Latifa Zekri, Boris Klimovich, Martina S. Lutz, Carsten Greve, Stefanie Müller, Melanie Märklin, Bastian Schmied, Gundram Jung, Helmut R. Salih. Immunocytokines with target cell-restricted IL-15 activity for treatment of B cell malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2863.