Dataset Information

Photoimmunotherapy targeting biliary-pancreatic cancer with humanized anti-TROP2 antibody.

ABSTRACT: Photoimmunotherapy (PIT) is a new type of tumor-specific treatment utilizing monoclonal antibody (mAb)-photosensitizer conjugates and near-infrared (NIR) light irradiation. One potential PIT target, the type I transmembrane protein TROP2, is expressed at high levels in many cancers, including pancreatic carcinoma (PC) and cholangiocarcinoma (CC), in which its expression is correlated with poor prognosis and tumor aggressiveness. In this study, we assessed the efficacy of PIT utilizing newly developed humanized anti-TROP2 mAb conjugated to the photosensitizer IR700 (TROP2-IR700) for PC and CC. Immunohistochemistry on PC and CC tissue microarrays confirmed that TROP2 is overexpressed in about half of PC and CC specimens. Using cultured PC and CC cells, TROP2-IR700 localized TROP2-specific and target-specific cell killing was observed after NIR light irradiation. In addition, TROP2-IR700 was localized to mouse xenograft tumors expressing TROP2 after intravenous injection. PC and CC xenograft tumor growth was significantly inhibited by TROP2-targeted PIT relative to controls. The efficacy of TROP2-targeted PIT in vitro and against xenografted tumors in vivo suggests promise as a therapy for human PC and CC, both of which currently have dismal prognoses and limited therapeutic options.

SUBMITTER: Nishimura T

PROVIDER: S-EPMC6912056 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Photoimmunotherapy targeting biliary-pancreatic cancer with humanized anti-TROP2 antibody.

Nishimura Takashi T Mitsunaga Makoto M Sawada Ryoichi R Saruta Masayuki M Kobayashi Hisataka H Matsumoto Noriko N Kanke Toru T Yanai Hiroyuki H Nakamura Koji K

Cancer medicine 20191101 18

Photoimmunotherapy (PIT) is a new type of tumor-specific treatment utilizing monoclonal antibody (mAb)-photosensitizer conjugates and near-infrared (NIR) light irradiation. One potential PIT target, the type I transmembrane protein TROP2, is expressed at high levels in many cancers, including pancreatic carcinoma (PC) and cholangiocarcinoma (CC), in which its expression is correlated with poor prognosis and tumor aggressiveness. In this study, we assessed the efficacy of PIT utilizing newly deve ...[more]

PMID: 31674732

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Project description:Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease characterized by increased levels of desmoplasia that contribute to reduced drug delivery and poor treatment outcomes. In PDAC, the stromal content can account for up to 90% of the total tumor volume. The complex interplay between stromal components, including pancreatic cancer-associated fibroblasts (PCAFs), and PDAC cells in the tumor microenvironment has a significant impact on the prognoses and thus needs to be recapitulated in vitro when evaluating various treatment strategies. This study is a systematic evaluation of photodynamic therapy (PDT) in 3D heterotypic coculture models of PDAC with varying ratios of patient-derived PCAFs that simulate heterogeneous PDAC tumors with increasing stromal content. The efficacy of antibody-targeted PDT (photoimmunotherapy; PIT) using cetuximab (a clinically approved anti-EGFR antibody) photoimmunoconjugates (PICs) of a benzoporphyrin derivative (BPD) is contrasted with that of liposomal BPD (Visudyne), which is currently in clinical trials for PDT of PDAC. We demonstrate that both Visudyne-PDT and PIT were effective in heterotypic PDAC 3D spheroids with a low stromal content. However, as the stromal content increases above 50% in the 3D spheroids, the efficacy of Visudyne-PDT is reduced by up to 10-fold, while PIT retains its efficacy. PIT was found to be 10-, 19-, and 14-fold more phototoxic in spheroids with 50, 75, and 90% PCAFs, respectively, as compared to Visudyne-PDT. This marked difference in efficacy is attributed to the ability of PICs to penetrate and distribute homogeneously within spheroids with a higher stromal content and the mechanistically different modes of action of the two formulations. This study thus demonstrates how the stromal content in PDAC spheroids directly impacts their responsiveness to PDT and proposes PIT to be a highly suited treatment option for desmoplastic tumors with particularly high degrees of stromal content.

Dataset Information

Photoimmunotherapy targeting biliary-pancreatic cancer with humanized anti-TROP2 antibody.

Publications

Photoimmunotherapy targeting biliary-pancreatic cancer with humanized anti-TROP2 antibody.

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