Abstract 5400: Photoimmunotherapy (PIT) combined with a nanosized cancer agent successfully treated heterogenous antigen-expressing tumors based on super-enhanced permeability and retention (SUPR) effect
Authors: Kobayashi Hisataka , Sano Kohei , Nakajima Takahito , Sato Kazuhide , Choyke Peter L. 
Published: May 2015

Abstract
A major barrier to cancer treatment is the inability to deliver sufficient concentrations of drug to the interior of tumors without incurring systemic toxicities. Nanomaterials are appealing because they can carry a large drug payload, however, tumor delivery is limited by modest leakage and retention in most tumors. Photoimmunotherapy (PIT) is a newly developed therapy involving the injection of a conjugate composed of an armed monoclonal antibody (mAb) and a near infrared phthalocyanine dye, IR700 [Mitsunaga M. Nature Med 2011;17:1685]. When exposed to NIR light, the conjugate induces a highly-selective necrotic cell death only in mAb-IR700 bound cancer cells. This target-specific necrotic cell death occurs within 10 minutes of exposure to NIR light and results in rapid morphologic changes including cellular swelling, bleb formation, and rupture of vesicles and cell death. Meanwhile, immediately adjacent receptor-negative cells are unharmed. Because PIT initially damages antigen bearing tumor cells immediately adjacent to the vasculature, it causes marked increases in vascular permeability leading to 20-fold enhanced nano-particle delivery into cancer tissue compared with untreated tumor bed. This effect has been termed “super-enhanced permeability and retention (SUPR)” to differentiate it from enhanced permeability and retention (EPR) which is common in tumors. In this study, we used a mixed tumor model containing 99% (EGFR)-positive A431 cells mixed with 1% EGFR-negative Balb3T3/DsRed cells in order to simulate tumor heterogeneity. Mixed tumors were treated with PIT alone or PIT combined with liposomes containing daunorubicin (Daunoxome), utilizing the SUPR effect. PIT completely treated EGFR+ cells, however, EGFR- cells quickly became the dominant cell type leading to death in mice. However, co-injection of Daunoxome could cure tumors following PIT. Therefore, although PIT alone does not eliminate all cancer cells due to heterogeneity of tumor, SUPR allows the delivery of extremely high concentrations of nano-sized anti-cancer reagents (e.g. Daunoxome), resulting in synergistic therapeutic effects of PIT and nano-sized agents. In conclusion, target-selective PIT can induce a SUPR effect leading to the accumulation of dramatically higher concentrations of nano-sized reagents within tumors thus improving the effectiveness of PIT in heterogeneous tumors.
Citation Format: Hisataka Kobayashi, Kohei Sano, Takahito Nakajima, Kazuhide Sato, Peter L. Choyke. Photoimmunotherapy (PIT) combined with a nanosized cancer agent successfully treated heterogenous antigen-expressing tumors based on super-enhanced permeability and retention (SUPR) effect. [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 5400. doi:10.1158/1538-7445.AM2014-5400