Advances in targeted therapeutics, such as the anti-Epidermal Growth Factor Receptor (EGFR) MAb, cetuximab (Erbitux®), have dramatically changed treatment options for many cancers. Disappointingly, cetuximab administered with standard-of-care gemcitabine, failed to improve survival in pancreatic cancer (PC), a fatal disease with very few treatment options. About 90% of PCs that express EGFR also contain activating KRAS mutations making it resistant to anti-EGFR therapies. Imprime PGG®, a yeast-derived pathogen-associated molecular pattern, is a soluble β-1,3/1,6 glucan that primes innate immune cells to recognize and kill MAb targeted tumor cells.

Objective: To determine the anti-tumor potential of Imprime PGG® in combination with cetuximab +/- gemcitabine in a standard pancreatic cancer xenograft model.

Method: Briefly, Balb/c nude mice were inoculated s.c. with 3 x 106 EGFR+, KRAS-mutant, MiaPaCa-2 tumor cells. When tumors reached ~50-70 mm3, mice were randomized into different treatment groups and administered Imprime PGG®, cetuximab, or gemcitabine, or combinations thereof, 3x/ week for 4 weeks. Tumor measurements were performed twice per week until the tumor volume reached 3000 mm3, after which the mice were euthanized. Study endpoints were change in tumor volume and overall survival.

Results: Tumor growth data on day +38 demonstrated gemcitabine alone to have significant inhibitory effects (47%; p=0.027) compared to placebo treated mice. The addition of Imprime PGG® or cetuximab to gemcitabine therapy further enhanced tumor inhibition (64% and 88% respectively; p<0.01). Combining all three agents demonstrated the greatest tumor inhibition of 98% (p<0.001), which was also significantly better than the cetuximab plus gemcitabine treatment group (p=0.002). When the various treatment groups were followed for overall survival through day +80, mice treated with the triple-combination of Imprime PGG®, cetuximab, and gemcitabine continued to demonstrate enhanced anti-tumor activity and superior overall survival (p=0.001; with a median survival time of >80 days).

Conclusion: In summary, Imprime PGG® combination treatment with cetuximab and gemcitabine induced significant anti-tumor activity, with delay in tumor growth and prolongation of survival in immunodeficient mice with KRAS-mutant pancreatic tumors. Based on these observations, we propose the novel combination treatment with Imprime PGG®, cetuximab, and gemcitabine as a promising new strategy in PC treatment for humans.

Work supported by funds from the NCI (Contract # HHSN261201000118C). In vivo work performed at CrownBio.

Citation Format: Mary A. Antonysamy, Yumi Yokoyama, Arkadiusz Z. Dudek, Nadine Ottoson, William Grossman. Imprime PGG®, a soluble β-1,3/1,6 immunomodulatory glucan, induces enhanced antitumor activity in an in vivo pancreatic tumor model when combined with cetuximab and gemcitabine. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Progress and Challenges; Jun 18-21, 2012; Lake Tahoe, NV. Philadelphia (PA): AACR; Cancer Res 2012;72(12 Suppl):Abstract nr A19.