Abstract 2500: Identification of promiscuous oncofetal antigen (IMP-3)-derived long peptides, bearing both Th cell and CTL epitopes

Abstract

Abstract We recently identified CTL epitopes derived from an oncofetal antigen, insulin-like growth factor II mRNA-binding protein 3 (IMP-3) which was frequently overexpressed in head-and-neck cancers (HNCs) and lung cancers, but not in many normal adult organs, by using genome-wide cDNA microarray analyses. Several phase I/II clinical trials using IMP-3-derived short peptides (SPs) vaccination against several types of malignant tumor are ongoing. Recently we reported the phase I/II clinical trial of multiple tumor-associated-antigen (TAA)-derived SPs vaccinations including IMP-3-SP for advanced HNC patients. In this trial, we observed the vaccinated SPs-specific CTL responses and the prolongation of overall survival of HNC patients (Clin Cancer Res; Nov. 12, 2014 in press). In order to further develop peptides-based cancer immunotherapy, we attempted to identify IMP-3-derived long peptides (LPs) containing both CTL and Th cell epitopes in this study. We successfully identified two promiscuous IMP-3-derived LPs, and one of them encompasses two natural CTL epitopes, and these LPs can stimulate IMP-3-LP-specific Th1 cells restricted by 7 frequent HLA class II molecules. We confirmed that Th cells induced by two LPs responded to autologous dendritic cells (DCs) loaded with IMP-3 protein, suggesting that these IMP-3-derived LPs were possibly naturally processed from IMP-3 protein and presented by DCs. We also demonstrated that one of the IMP-3-derived LPs could cross-prime IMP-3-SP-specific CTLs in vitro in human and in vivo in HLA-A2 transgenic mice. The same LP encapsulated in newly developed pH-sensitive liposome, that can deliver LPs from endosome to cytoplasm, was also found to be efficiently cross presented in vitro to stimulate IMP-3-SP-specific human CTLs. Furthermore, we could induce IMP-3-LP-specific Th cells from a HNC patient vaccinated with an IMP3-derived SP. Immune response to these LPs in many other HNC patients is now under investigation. Taken together, IMP-3-derived LPs may be applicable to cancer immunotherapy. Citation Format: Masatoshi Hirayama, Akira Yuno, Yusuke Tomita, Mohammad Abu Sayem, Hirotake Tsukamoto, Atsushi Irie, Satoru Senju, Yoshihiro Yoshitake, Daiki Fukuma, Masanori Shinohara, Eiji Yuba, Kenji Kono, Koji Yoshida, Yusuke Nakamura, Hideki Nakayama, Yasuharu Nishimura. Identification of promiscuous oncofetal antigen (IMP-3)-derived long peptides, bearing both Th cell and CTL epitopes. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2500. doi:10.1158/1538-7445.AM2015-2500