Abstract 6651: Combination of hetIL-15 with chemotherapy in triple negative breast and pancreatic cancer mouse models increases tumor necrosis and alleviates metastatic disease
Authors: Stellas Dimitris , Stravokefalou Vasiliki , Karaliota Sevasti , Nagy Bethany , Koslov Serguei , Dimas Konstantinos , Felber Barbara K. , Pavlakis George N. 
Published: September 2020

Abstract
Introduction: We evaluated the potential therapeutic benefit of conventional chemotherapy combined with hetIL-15 immunotherapy in two mouse models of pancreatic and breast cancer. IL-15 is an important cytokine that stimulates the proliferation and cytotoxic functions of CD8+ T cells and NK cells. We have produced the native heterodimeric form of IL-15 (hetIL-15), which has advanced in clinical trials due to its anticancer activities.
Study design and methods: We assessed the efficacy of hetIL-15 immunotherapy in combination with the chemotherapeutic agents gemcitabine or doxorubicin on the growth of primary pancreatic and breast tumors, and on the metastatic disease. We used the genetically engineered mouse model (GEMM) KPC of pancreatic cancer (LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre) and the orthotopic 4T1 triple negative breast cancer (TNBC) model. We analyzed the tumor infiltrating lymphocytes (TILs) by flow cytometry and immunohistochemistry (IHC) and evaluated the extent of necrosis on the primary tumors by H&E and cytokeratin staining. We also evaluated the lung metastatic burden by histology.
Results: The combination of hetIL-15 and doxorubicin significantly delayed 4T1 tumor growth. In addition, histological analysis showed an increase in the percentage of the necrotic areas of the primary tumors in the combination group. hetIL-15 treated groups also showed increased necrotic areas of the primary pancreatic tumors, although tumor growth showed no significant change compared to the control group. Flow analysis of TILs showed increased CD8+/CD4+ T cell ratios in tumors of hetIL-15 treated groups in both cancer models, which was confirmed by IHC. Importantly, the evaluation of the metastatic disease showed that hetIL-15 treated animals in both cancer models had reduced metastatic foci and in some cases were completely disease free. Chemotherapy did not significantly reduce the numbers of the total metastatic lesions but reduced their size.
Conclusions: Chemotherapy can be combined with hetIL-15 treatment in both breast and pancreatic mouse models. Despite small beneficial results in the size of primary tumor, histological evaluation revealed increased tumor necrosis and potential synergy of chemotherapy and immunotherapy. The observed decreased metastatic burden in the lungs in both cancer models indicates that hetIL-15 strongly reduces metastases in several cancer types and suggests that hetIL-15 is a promising therapeutic agent against metastatic disease.
Citation Format: Dimitris Stellas, Vasiliki Stravokefalou, Sevasti Karaliota, Bethany Nagy, Serguei Koslov, Konstantinos Dimas, Barbara K. Felber, George N. Pavlakis. Combination of hetIL-15 with chemotherapy in triple negative breast and pancreatic cancer mouse models increases tumor necrosis and alleviates metastatic disease [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 6651.