Division of Molecular and Cellular Medicine (Aoki Group)

Kazunori Aoki, Chie Kudo, Kenta Narumi, Yoko Kobayashi, Yukihiro Mizoguchi, Akihisa Kondo, Osamu Mizumori, Ryousuke Ueda, Hisayoshi Hashimoto, Yuki Yamamoto, Aya Hirata, Yosei Rin, Masaki Nagasato, Chihiro Shibasaki, Marina Henmi, Yamato Ogiwara

Introduction

Research programs in the Division of Molecular and Cellular Medicine (Aoki group) consist of development of novel therapeutic strategies for solid cancers based on the analysis of host-immune response against cancer cells and the exploitation of cancer-targeting technologies. The specific activities in 2016 are as follows.

1)Clarification of antitumor mechanism induced by intratumoral administration of immune- stimulatory antibody

2)Development of inhibitory antibody specific for an immune exhaustion-inducible molecule

3)Development of cancer-targeting vector using the peptide-display adenovirus library

Research activities

1.Clarification of antitumor mechanism induced by intratumoral administration of immune- stimulatory antibody

An anti-glucocorticoid induced TNF receptor (GITR) agonistic antibody (Ab) induces antitumor immunity by activation of CD8+T cells and suppression of regulatory T cells. We found that intratumoral (i.t.) administration of GITR Ab increased the number of cancer-responsive immune cells and more suppressed tumor growth compared with intraperitoneal (i.p.) injection in a mouse colon cancer model. The peritumoral injection also induced antitumor immunity as the same level as i.t. injection did. Therefore, we hypothesized that locally administrated GITR Ab transferred into tumor-draining lymph nodes (TDLN) and activated cellular immunity there. To confirm this, GITR Ab was i.t. injected, and TDLN was resected. Resection of Ab-injected TDLN cancelled GITR-mediated antitumor immunity, whereas resection of Ab-uninjected TDLN didn't change the antitumor effect. We showed that the i.t. administration of GITR Ab is a promising strategy to induce effective antitumor immunity.

2.Development of inhibitory antibody specific for an immune exhaustion-inducible molecule

Immunological approaches, particularly blocking immunosuppression using immune checkpoint inhibitory antibody drugs, have been noticed in treatment of cancer in the world. However, immune exhaustion is another issue in cancer immunotherapy, since it is very hard to re-invigorate the dysfunctional immune status in cancer patients. For clearing such a hurdle, we have been developing an inhibitory antibody drug specific for an immune exhaustion-inducible molecule. We started a large-scale clinical study in order to statistically analyze the relationships between the target molecule expression in tumor tissues and the clinical data of patients by establishing the cooperative research network with researchers and clinicians at intra- and extramural institutions. We already found that it is a poor prognostic factor in patients with lung cancer. We have also been conducting in vivo study using various mouse tumor models, and have been accumulating many data that shows treatment with the antibody is significantly effective in suppressing tumor progression even with rare cancers including osteosarcoma, for which effective diagnostic and therapeutic methods are urgently needed.

3.Development of cancer-targeting vector using the peptide-display adenovirus library

Although oncolytic adenovirus is a promising therapeutic strategy for prostate cancer, the recent advance of clinical studies shows that cancer-targetability in a vector is necessary to enhance oncolytic activity and secure safety in a future clinical trial. We are developing cancer-targeted adenovirus vectors with our original system of adenovirus (Ad) library displaying random peptides on the fiber knob. We found that an Ad vector (Ad-S) newly selected from the Ad library showed enhanced transduction efficacy in several cancer cell lines but not in normal cells. Especially, the Ad-S showed a high gene transduction and strong cytotoxic potency in prostate cancer cells compared with an untargeted control vector. Therefore, the selected ligand displayed on fiber is useful to construct a prostate cancer-targeted oncolytic vector. Ad lib technology of a specific adenovirus vector selection may have broad implications for the development of targeted gene therapy.

Education

Two graduate students (doctoral course) linking with Keio University, one graduate student (doctoral course) linking with Kyorin University, four graduate students (doctoral course: one, master course: three) linking with Tokyo Medical and Dental University, one graduate student (master course) and one undergraduate student linking with Tokyo University of Pharmacy and Life Sciences studied about cancer immunology and cancer-targeted therapy in our laboratory.

Future prospects

We are investigating the molecular basis of immune-suppressive microenvironment and the interaction between cancer cells, stromal cells and immune cells in a tumor microenvironment, which may open a new perspective on immunotherapy of cancer. In addition, tumor-targeting vectors are also promising as a next-generation molecular targeting therapy.