Combination therapy of a PI3K p110α-isoform-selective inhibitor and anti-HER2/neu antibody enhances the anti-tumor immunity in breast cancer mouse model

Autor: Jae Hyeog Choi, Ki Hyang Kim, Kug Hwan Roh, Hana Jung, Su Kil Seo, Il Whan Choi, Sung Su Yea, SaeGwang Park
Rok vydání: 2017
Předmět:
Zdroj: The Journal of Immunology. 198:204.9-204.9
ISSN: 1550-6606
0022-1767
DOI: 10.4049/jimmunol.198.supp.204.9
Popis: Trastuzumab (Herceptin) is a humanized recombinant monoclonal antibody against HER2 that has shown the clinical benefit in HER2+ breast cancer patients. Because non-responders to trastuzumab have been observed, one strategy to overcome the resistance is combination therapy. Combination therapies with phosphoinositide 3-kinase (PI3K) inhibitors and trastuzumab (anti-HER2/neu antibody) are effective against HER2+ breast cancer mouse model. The therapeutic effect and anti-tumor immunity of combination therapy with an anti-HER2/neu antibody and a pan-PI3K inhibitor (GDC-0941) or a p110a isoform-selective inhibitor (A66) was evaluated in vivo breast cancer models. Combined the anti-neu and PI3Ki treatment synergistically occurred in anti-tumor immunity and HER2/neu-mediated memory T cell responses. In the presence of the anti-neu antibody, A66 was more effective in increasing the T cells and IFN-γ+ CD8+ T cells in TILs. IFN-γ ELISPOT data showed that tumor-specific T cells against neu and non-neu tumor antigens increased synergistically after combination PI3Ki and anti-neu treatment, and A66 was more potent. In a TUBO (neu+) and TUBO-P2J (neu-) mixed model representing IHC2+ tumors, A66 showed greater tumor mass control and survival prolongation than GDC-0941, when combined with the anti-neu antibody. Combined with the anti-neu antibody, A66 was more effective than GDC-0941, and A66 synergized with the anti-neu antibody in terms of anti-tumor immunity. We propose A66 plus anti-HER2/neu antibody as an effective strategy in trastuzumab-resistant breast cancers.
Databáze: OpenAIRE
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