Abstract 4709: Induction of enhanced tumor-specific immunity by Hsp90 targeted photodynamic therapy (Hsp90-PDT) combined with immune checkpoint inhibition

Abstract

Abstract Background: Immunotherapy has become an emerging anti-cancer therapy, as immune checkpoint blockade with PD-1 or PD-L1 inhibition have been active against multiple cancer types. Nonetheless, there remain many non-responders, suggesting that combinations may improve activity, particularly combinations which can target tumors and have low toxicity. Methods & Results: We have developed a novel Hsp90 targeted photodynamic therapy (Hsp90-PDT), which causes local anti-tumor responses. Hsp90-PDT can be combined with immune checkpoint blockade to generate potent anti-tumor effects. We synthesized well characterized PDT agent, verteporfin (VP) tethered to a HSP90 small molecule inhibitor, to create a Hsp90-PDT agent (Hsp90i-VP). We first compared the uptake of VP and Hsp90i-VP into the breast cancer cell lines (E0771-OVA) in vitro. Hsp90i-VP showed stronger incorporation than VP when the compounds were added 3μM or less in concentration. We next performed in vitro and vivo PDT with Hsp90i-VP and laser exposure (690 nm wavelength). Killing efficiency of VP and Hsp90i-VP was analyzed by MTT assay, which showed increased killing in a dose dependent manner for both photosensitizers (0-30µM) and laser (0-120J/cm2). Next, we treated E0771-OVA tumor-bearing C57BL/6 mice with Hsp90i-VP (25nmol/mouse) administration alone, laser irradiation (240J/cm2) alone, or the combination of Hsp90i-VP and laser. Suppression of the tumor growth was confirmed only in Hsp90i-VP and laser group. In addition, induction of tumor-specific immune response by PDT was confirmed by ELISA, where the elevation of anti-OVA antibody was seen only in PDT group. Furthermore, combination treatment of Hsp90-PDT and anti-PD-L1 mAbs was able to enhance cytotoxic T-cell response and suppress tumor growth significantly even with relatively PDT-resistant cell line. Conclusions: Hsp90-PDT showed a significant ability to induce antigen-specific immune response in both in vitro and in vivo. These results suggest that Hsp90-PDT can play an important role in anti-cancer immune therapy. Our future plan is to investigate the effect of local photodynamic therapy combined with various types of checkpoint inhibitor in breast cancer models. Citation Format: Kensuke Kaneko, Takuya Osada, Timothy A. Haystead, Michael A. Morse, Herbert K. Lyerly. Induction of enhanced tumor-specific immunity by Hsp90 targeted photodynamic therapy (Hsp90-PDT) combined with immune checkpoint inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4709. doi:10.1158/1538-7445.AM2017-4709