Abstract 2441: hetIL-15 decreases tumor cell dissemination and colonization and synergizes with chemotherapy and surgery to cure murine 4T1 breast tumors
Authors: Stravokefalou Vasiliki , Stellas Dimitris , Karaliota Sevasti , Myers Breana , Bergamaschi Cristina , Dimas Konstantinos , Felber Barbara K. , Pavlakis George N. 
Published: June 2022

Abstract
Introduction: Metastasis is responsible for most of the cancer-related deaths (~ 90%). Metastatic triple negative breast cancer (TNBC) has poor survival and chemotherapy pre- and post-surgery has been the standard treatment for decades. Polymorphonuclear - myeloid derived suppressor cells (PMN-MDSCs) are implicated in the process of metastasis. IL-15 stimulates the proliferation and cytolytic activity of CD8+T cells and Natural Killer cells (NKs) and has been reported to have anti-metastatic activity. We have produced the native heterodimeric form of IL-15 (hetIL-15) which has advanced in clinical trials due to its anticancer activities. Here, we report the anti-metastatic effects of hetIL-15 alone and in combination with doxorubicin and surgery using the 4T1 mouse model of TNBC.
Study design and methods: We studied the efficacy of the chemo-immunotherapeutic regimen with surgery in a neoadjuvant and adjuvant setting or without surgery. The animals were evaluated regarding metastatic disease and survival. The anti-metastatic effect was evaluated by examining the metastatic foci in lungs and the circulating tumor cells (CTCs) in blood by histology and clonogenic assays. Treatment effects in immune populations in blood, spleen and lungs were evaluated by flow cytometry analysis and immunohistochemistry (IHC).
Results: Mice treated with hetIL-15 in combination with doxorubicin had significantly better survival in comparison to monotherapy treatments and control group. H&E histological analysis in the lungs revealed substantially fewer metastatic foci after hetIL-15 monotherapy, and even fewer in the combination group. Furthermore, clonogenic assays from lungs and blood, reinforced these findings showing significantly lower numbers of tumor colonies upon hetIL-15 monotherapy and combination treatment. Immune profiling evaluation of blood, spleen and lungs by flow cytometry and IHC revealed a significant systemic increase of cytotoxic effector cells (CD8+T cells and NKs), combined with reduction of immunosuppressive populations (PMN-MDSCs) especially in the combination group. These findings suggest a synergistic effect of doxorubicin and hetIL-15 in controlling the metastatic disease. Lastly, hetIL-15 monotherapy or co-administration with doxorubicin, together with surgery, led to the cure of approximately 50% of the treated mice.
Conclusions: Our results demonstrate that hetIL-15 reduces metastatic disease and synergizes with doxorubicin and surgery to maximize the effectiveness of the treatment against breast cancer in mice. We suggest that the effect of hetIL-15 on metastatic disease is both at the level of dissemination and also colonization in the metastatic sites. This should be further explored in the clinical setting as a neoadjuvant and adjuvant therapy in combination with chemotherapy and surgery for the treatment of TNBC.
Citation Format: Vasiliki Stravokefalou, Dimitris Stellas, Sevasti Karaliota, Breana Myers, Cristina Bergamaschi, Konstantinos Dimas, Barbara K. Felber, George N. Pavlakis. hetIL-15 decreases tumor cell dissemination and colonization and synergizes with chemotherapy and surgery to cure murine 4T1 breast tumors [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 2441.