Abstract C104: TAS-121, a highly potent and mutant-specific EGFR inhibitor, modulates the immune system, resulting in anti-tumor immune responses

Background: TAS-121 is one of the 3 rd generation EGFR TKI, which specifically inhibits mutant EGFRs, and it leads to high cellular selectivity and potent antitumor activity in various in vivo models. TAS-121 is being investigated in patients with non-small cell lung cancer (NSCLC) harboring not only active mutant EGFR, but also acquired resistance mutation T790M in phase I study. immune-related events observed during treatment with TAS-121 in preclinical and clinical studies suggested that TAS-121 could modulate the immune system and, consequently, might partially contribute to anti-tumor effect. To prove this hypothesis, we examined the immuno-modulating potential of TAS-121 using MLR assay, TCR stimulation assay and in vivo syngeneic tumor models. Material and methods: Immune cell proliferation and cytokine production were confirmed by the CFSE dilution using flow cytometry, and ELISA assay, respectively. Anti-tumor immune response was analyzed in syngeneic models bearing with MC38 murine colon carcinoma cell line. Results: TAS-121 strongly induced the proliferation of CD4 T cells and CD8 T cells as well as stimulating cytokine production. Other EGFR TKIs, including 1 st generation to 3 rd generation agents, didn9t show these effects. TAS-121 inhibited the growth of syngeneic tumor, MC38 in vivo , while no growth inhibition was observed in vitro . These data demonstrate that TAS-121 can induce anti-tumor immune responses. Conclusions: These findings suggest that TAS-121 could specifically modulate the immune system including T cells, leading to the anti-tumor immune responses. Therefore, TAS-121 has a unique profile among the 3 rd generation EGFR-TKI. Considering this immune-modulating profile, combination with immune checkpoint blockade agent such as anti-PD1 monoclonal antibody might be beneficial for NSCLC patients harboring mutant EGFR. Citation Format: Satoshi Fukaya, Yoshimi Aoyagi, Masanori Katoh, Kimihiro Itoh, Toshihiro Shibutani, Nozomu Tanaka, Tomonori Haruma, Akihiro Hashimoto, Kazutaka Miyadera, Kenichi Matsuo, Yoshikazu Iwasawa, Teruhiro Utsugi, Kazuhiko Yonekura. TAS-121, a highly potent and mutant-specific EGFR inhibitor, modulates the immune system, resulting in anti-tumor immune responses. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C104.