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Glycolipid Antigens for Treating Hepatic Colorectal Cancer Metastases and Their Effect on the Therapeutic Efficacy of Live Attenuated Listeria monocytogenes

Kelly Olino, MD; Barish H. Edil, MD; Kristen F. Meckel, MS; Xiaoyu Pan, MS; Avesh Thuluvath; Drew M. Pardoll, MD, PhD; Richard D. Schulick, MD; Kiyoshi Yoshimura, MD, PhD; Walter P. Weber, MD
Arch Surg. 2012;147(5):480-482. doi:10.1001/archsurg.2011.2206.
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Previous work demonstrated that a subset of natural killer T cells in mice decreased the antitumor efficacy of live attenuated Listeria monocytogenes where the actin A and internalin B genes were genetically deleted (LMD) against murine hepatic colorectal cancer metastases. Therefore, we hypothesized that the use of specific glycolipids known to selectively stimulate natural killer T-cell subsets used alone or co-administered with LMD would increase survival. We found that early or multiple administrations of glycolipids after tumor challenge had a strong impact on survival with or without LMD. Solitary administration or treatment given later was less efficacious but still showed a strong trend toward enhancing the antitumor activity of LMD. These results underscore the potential of glycolipids in the treatment of hepatic metastases and encourage further investigations into the immunomodulation of natural killer T cells to enhance the antitumor activity of LMD.

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Figure 1. α-Galactosylceramide (α-GalCer) treatment improves survival. Survival of mice after tumor challenge on day 0 (1 × 105 colon tumor 26 cells) followed by either no treatment (NT), treatment with a single dose of 1 ug of α-GalCer on day 3 (α-GalCer d3), or 3 treatments of 1 ug of α-GalCer on days 3, 6, and 9 (α-GalCer d3, 6, 9; n = 5-7 per group). P = .006 for α-GalCer on day 3 vs no treatment. P = .002 for α-GalCer on days 3, 6, and 9 vs no treatment. P value is not significant for α-GalCer on days 3, 6, and 9 vs α-GalCer on day 3.

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Figure 2. α-Galactosylceramide (α-GalCer) and sulfatide enhance the impact of Listeria monocytogenes (LMD) on survival. Survival of mice after tumor challenge on day 0 (1 × 105 colon tumor 26 cells) followed by either no treatment (NT), 3 treatments of LMD on days 3, 6, and 9 (LMD), both LMD on days 3, 6, 9 and 1 ug of α-GalCer on day 3 (LMD α-GalCer), or both LMD on days 3, 6, and 9 and 25 ug of sulfatide on day 3 (LMD sulfatide; n = 6-7 per group). P = .04 for LMD vs no treatment. P = .004 for LMD α-GalCer vs no treatment. P = .005 for LMD sulfatide vs no treatment. P = .07 for LMD α-GalCer vs LMD. P = .02 for LMD sulfatide vs LMD. P value is not significant for LMD α-GalCer vs LMD sulfatide.

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