Combinational dasatinib and dendritic cell-based therapy improves therapeutic protection against melanoma growth (165.11)

Abstract

Abstract The solid tumor microenvironment (TME) is characterized by an abnormal vasculature system that promotes interstitial pressure, hypoxia, and acidity - diminishing the efficacy of standard single agent therapeutics. We hypothesize that combinational strategies that effectively target cancer cell growth and vasculature development will improve the clinical outcome of patients with malignant disease such as melanoma. To address this hypothesis, C57BL/6 mice were challenged subcutaneously with B16 melanoma cells and tumors allowed to progress 7 days. Animals were left untreated or received daily doses of dasatinib (an FDA-approved receptor tyrosine kinase inhibitor drug [TKI]) for one week with/without intratumoral injections of dendritic cells (DCs) transduced with IL-12 (DC.IL12) on days 7 and 14 post-tumor inoculation. Our pre-clinical results indicate synergistic benefits from co-treatment with dasatinib/DC.IL12 therapy based on the magnitude of anti-tumor immune responses promoted and the level of protective T cells recruited into treated tumor lesions. Dasatinib modified the aberrant TME in vivo by diminishing Treg (CD4+Foxp3+) and MDSC (CD11b+Gr1+) frequencies and reducing expression of markers associated with hypoxia, angiogenesis, and cancer stem cells. Overall, these data highlight the advantage of “sensitizing” the host using an anti-vasculature drug to instill an environment conducive to recruiting and sustaining vaccine-initiated anti-tumor immune effector cells.