Although existing interventions are highly efficacious for the treatment of localized breast cancers, disseminated tumors remain incurable. Therapeutic induction of systemic anti-tumor immunity is a promising approach for treating metastatic disease. We have developed a novel heterologous prime/boost vaccination protocol that significantly reduces metastatic tumor burdens in a pre-clinical murine model of breast cancer.
In our studies, mice were orthotopically challenged with Luciferase-expressing 4T1 adenocarinoma cells. Six days later, mice received a priming therapy that consisted of parental 4T1 tumor lysates encapsulated in poly(lactic-co-glycolic) acid microparticles administered contralateral to the established tumor. On day eleven, mice received a boost therapy that consisted of 4T1 lysates and a cocktail of Toll-like receptor agonists. At the conclusion of the assay (day twenty-five), tumor burdens from excised lungs were quantified using bioluminescent imaging. Therapy-receiving mice showed a significant reduction in lung tumors (Student's T-test: p = 0.002, n = 37 control mice vs. 25 treated mice) with an average 46.66% decrease relative to no therapy control mice. Independent quantification of lung metastases was also performed using a standard 6-thioguanine assay. There was a strong correlation (R^2 = 0.8803) between bioluminescent intensity and 6-thioguanine colony number, demonstrating that the decrease in bioluminescence signal due to therapy is not merely explained by the in vivo loss of Luciferase expression by 4T1 cells.
We are currently characterizing the vaccination-induced differences in the localized immune environment of metastatic lung tumors. Effector T cell activation/exhaustion kinetics and the influx of immunosuppressive cell populations (myeloid-derived suppressor cells and regulatory T cells) are now being explored. These studies will help elucidate the immunological mechanism(s) responsible for the diminished metastatic tumor outgrowth observed with our therapy. In conclusion, our data demonstrate that therapeutic vaccination of tumor lysates is efficacious in controlling spontaneous lung metastases in an aggressive model of murine breast cancer.
Citation Format: Brett P. Gross, Amaraporn Wongrapanich, Meghan Francis, Vijaya B. Joshi, Aliasger K. Salem, Lyse A. Norian. Therapeutic microparticle-based tumor lysate vaccination reduces spontaneous lung metastases in a murine breast cancer model. [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 2885. doi:10.1158/1538-7445.AM2014-2885