Abstract 2582: Cytotopic IL-15 as a novel therapeutic for prostate cancer

Abstract

Abstract Introduction & Objectives: Prostate cancer progression can arise by tolerance to, and evasion of tumor cells from immune effector cells such as CD8 T cells and NK cells due to the immunosuppressive tumor microenvironment. Immunotherapeutic drugs can eliminate tumors by breaking this tolerance, and such drugs that can be localized to the prostate will have greater efficacy and less systemic toxicity than drugs administered systemically. It has also been shown that a localized stimulation of the immune system can boost immunity all over the body to clear distant metastases. However, in the highly immunosuppressive prostate cancer microenvironment, most activated effector immune cells are rendered anergic or even regulatory. We have previously shown that IL-15, unlike other therapeutic cytokines such as IL-2 and IL-12, can stimulate expansion and activity of CD8 and NK cells when they are exposed to prostate cancer cells. Therefore, we decided to create a localizable form of this cytokine to study its activity on NK and CD8 T cells in the presence and absence of prostate cancer cells. Material & Methods: The cytokine IL-15 was produced in a modified form to enable its conjugation to a cytotopic “tail” molecule. The “tail” consists of three regions - a thiol reactive region which interacts with free cysteines on the protein of interest, a cationic region, which binds to the negatively charged cell membrane surface, and a hydrophobic region that enters the cell membrane. The cytotopic IL-15 can therefore adhere to cell membranes and can thus localize to any lesion where it is potentially injected. The tailed IL-15 was then compared to non-tailed IL-15 and other cytokines in assays to measure T cell proliferation, and NK and CD8 T cell expansion in the presence and absence of prostate cancer cells. Results: Compared to non-tailed forms of IL-15, the tailed IL-15 induced greater proliferation of a murine T cell line, CTLL-2 and PBMCs . Proliferation levels were up to 20 times greater with the tailed IL-15. In initial experiments, activity of the tailed IL-15 was also greater or equivalent to non tailed IL-15 in its ability to expand NK cells in the presence of a prostate cancer cell line (TRAMP-C1). Conclusion: We have identified a cytokine, IL-15, that can break tolerance to immunity in the prostate cancer microenvironment. A tailed form of this molecule, has equivalent or greater activity in expanding immune effector cells in the presence or absence of prostate cancer cells and its potential for regioselective action makes it therefore a promising new agent for immunotherapy of prostate cancer. Citation Format: Dorota A. Smolarek, Christina A. Sakellariou, Oussama Elhage, Osamu Ukimura, Inderbir Gill, Angus G. Dalgleish, Prokar Dasgupta, Richard A. G. Smith, Christine Galustian. Cytotopic IL-15 as a novel therapeutic for prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2582. doi:10.1158/1538-7445.AM2014-2582