Abstract 294: A novel cancer therapeutic strategy: inducing cytotoxic functions in tumor-associated macrophages
Authors: Barham Whitney , Tikhomirov Oleg , Ortega Ryan , Saskowski Jeannette , Thompson Courtney S. , Wilson Andrew , Blackwell Timothy , Mirafzali Zahra , Khabele Dineo , Giorgio Todd , Yull Fiona E. 
Published: August 2015

Abstract
Macrophages are recognized as an important component of the tumor microenvironment. Previous studies have shown that they promote tumor growth and participate in the initiation and progression of metastatic spread. Methods are being developed to eliminate macrophages from the tumor, thereby inhibiting their negative effects. However, we believe that the best approach would be to transform the tumor-helping macrophages into tumor-killing macrophages that would both eliminate tumor cells directly and re-invigorate other immune cells around them to better fight the tumor. Our data indicates that we have found a way to induce this transformation.
We utilized a novel transgenic mouse model to determine the effects of activating Nuclear Factor Kappa-B (NF-κB) signaling specifically in macrophages in vivo during different stages of tumor progression. Our data shows that activated macrophages not only inhibit primary tumor growth but also reduce tumor cell seeding and colonization of distant organs, such as the lung. This is accomplished at least in part through direct tumor cell killing by the macrophages. We have further modeled this mechanism in vitro through co-culture assays of macrophages and a variety of tumor cell lines, including breast, ovarian, and melanoma. In each case, activation of NF-κB in macrophages induces a tumoricidal phenotype, in which macrophages directly attack the tumor cells significantly depleting them by three days of co-culture. Having established macrophage NF-κB activation as a promising strategy, we have turned our focus to translating these findings into a therapy that can be delivered to patients in the clinic. We are testing two different approaches. The first is liposomal-encapsulated mifamurtide, a synthetic peptide that mimics a component of bacterial cell walls and thus activates NF-κB in macrophages. This drug is approved for use in osteosarcoma patients, and could be rapidly moved into clinical trials if our studies prove its efficacy in other tumor models. We are currently determining the most advantageous liposome formulation and delivery method in the setting of breast and ovarian cancer. The second strategy is to employ novel, polymeric nanoparticles to deliver siRNA against the inhibitor of kappa-B alpha (IκBα) to tumor associated macrophages (TAMs). We have synthesized these particles and determined that they can be safely delivered to mice in vivo. Furthermore, our studies indicate that the nanoparticles are preferentially taken-up by TAMs and that siRNA inhibition of IκBα induces an anti-tumor macrophage phenotype. Taken together, we have generated convincing evidence that activation of NF-κB in macrophages is a promising strategy to convert TAMs into cytotoxic macrophages. We are actively developing novel tools to translate this approach into immunotherapy that could be effective across a wide spectrum of solid tumors and metastatic disease.
Citation Format: Whitney Barham, Oleg Tikhomirov, Ryan Ortega, Jeannette Saskowski, Courtney S. Thompson, Andrew Wilson, Timothy Blackwell, Zahra Mirafzali, Dineo Khabele, Todd Giorgio, Fiona E. Yull. A novel cancer therapeutic strategy: inducing cytotoxic functions in tumor-associated macrophages. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 294. doi:10.1158/1538-7445.AM2015-294