Abstract 4745: TLR8 agonist and Doxil chemotherapy potently activate human antitumor immune response in a human immune system mouse model

Abstract

Abstract Because of differences between mouse and human immune systems, many of the effects of immunomodulatory drugs cannot be fully studied in syngeneic mouse models. We thus generated a novel tumor-bearing mouse model with human immune system (HIS) to study interactions between chemotherapy and immune modulatory therapy. We tested the individual effects and the interactions between doxorubicin, a drug which induces immunogenic tumor cell death and activates antigen-presenting cells, and VTX-2337, a novel small-molecule TLR8 agonist, which induces potent activation and type 1 polarization of human myeloid DCs but is inactive on murine leukocytes. Nod/SCID/ILRγc knock out (NSG) mice were inoculated with human CD34+ cord blood cells from HLA-A2+ human donors; transplanted s.c. with human HLA-A2+ OVCAR5 ovarian cancer tumors; and treated with pegylated liposomal doxorubicin (Doxil); VTX-2337; or a combination. NSG-HIS mice exhibited a full human hematopoietic system, including human monocytes, macrophages and plasmacytoid and myeloid DCs as well as T and B cell subsets. In NSG-HIS mice, VTX-2337 induced dose-dependent activation of human Monocytes CD14+ and CD11c+ cells with upregulation of CD80, CD86, CD83, CD40 and MHCII within 6 hrs. Transient, dose-dependent upregulation of human Th1 cytokines but also IL-10 was observed in the plasma of treated mice, reaching peaks within 6 hrs and subsiding within 24 hrs. Doxil induced mild activation of CD11c+ DCs and mild upregulation of Th1 cytokines. The combination of two drugs induced potent activation of CD11c+ DCs and marked increase in Th1 cytokines with significant decrease of IL-10. HLA-A2+ OVCAR5 tumors were successfully engrafted, exhibiting infiltration by human leukocytes. VTX-2337 and Doxil treatment independently induced tumor-infiltrating lymphocytes and restricted growth of human ovarian tumor xenografts in a dose-dependent manner, while the combination of the two drugs induced the highest frequency of Leukocytes (hCD45) and potently restricted growth of ovarian tumors. Combined activation of innate and adaptive immunity by VTX-2337 and Doxil, as well sensitization of tumor cells by Doxil to adaptive and innate immune effector mechanisms was at the basis of the observed interactions suppressing tumor growth. We conclude that the NSG-HIS provided a suitable tool to establish potent interactions between TLR8 agonist and Doxil chemotherapy, which warrant clinical testing. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4745. doi:10.1158/1538-7445.AM2011-4745