研究者詳細 - 河上　裕

論文 - 河上　裕

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A randomized phase II study comparing nivolumab with carboplatin-pemetrexed for patients with EGFR mutation-positive nonsquamous non-small cell lung cancer who acquire resistance to tyrosine kinase inhibitors not due to a secondary T790M mutation

Hayashi H, Chiba Y, Sakai K, Fujita T, Yoshioka H, Sakai D, Kitagawa C, Naito T, Takeda K, Okamoto I, Mitsudomi T, Kawakami Y, Nishio K, Nakamura S, Yamamoto N, Nakagawa K.

Clinical Lung Cancer. 18 719 - 723 2017年05月

研究論文（学術雑誌）, 共著

Inter-patient and Intra-tumor Heterogeneity in the Sensitivity to Tumor-targeted Immunity in Colorectal Cancer.

Miyauchi T, Yaguchi T, Kawakami Y.

Jpn J Clin Immunol. 40 （ 1 ） 54 - 59 2017年05月

研究論文（学術雑誌）, 共著

Prospects for personalized combination immunotherapy for solid tumors based on adoptive cell therapies and immune checkpoint blockade therapies.

Kato D, Yaguchi T, Iwata T, Morii K, Nakagawa T, Nishimura R, Kawakami Y.

Jpn J Clin Immunol. 40 （ 1 ） 68 - 77 2017年05月

研究論文（学術雑誌）, 共著

Novel Treatment of Chronic Graft-Versus-Host Disease in Mice Using the ER Stress Reducer 4-Phenylbutyric Acid

Mukai Shin, Ogawa Yoko, Urano Fumihiko, Kudo-Saito Chie, Kawakami Yutaka, Tsubota Kazuo

Scientific Reports 7 2017年02月

研究論文（学術雑誌）, 共著, ISSN 2045-2322

Chronic graft-versus-host disease (cGVHD) is a notorious complication of allogeneic hematopoietic stem cell transplantation and causes disabling systemic inflammation and fibrosis. In this novel study, we focused on a relationship between endoplasmic reticulum (ER) stress and cGVHD, and aimed to create effective treatment of cGVHD. A series of experiments were conducted using a mouse model of cGVHD. Our data suggested (1) that ER stress was elevated in organs affected by cGVHD and (2) that 4-phenylbutyric acid (PBA) could reduce cGVHD-induced ER stress and thereby alleviate systemic inflammation and fibrosis. Because fibroblasts are thought to be implicated in cGVHD-elicited fibrosis and because macrophages are reported to play a role in the development of cGVHD, we investigated cGVHD-triggered ER stress in fibroblasts and macrophages. Our investigation demonstrated (1) that indicators for ER stress and activation markers for fibroblasts were elevated in cGVHD-affected lacrimal gland fibroblasts and (2) that they could be reduced by PBA. Our work also indicated that splenic macrophages from PBA-dosed mice exhibited the lower levels of ER stress and M2 macrophage markers than those from cGVHD-affected mice. Collectively, this study suggests that the reduction of ER stress utilizing PBA can be a clinically translatable method to treat systemic cGVHD.

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Predictive biomarkers for the efficacy of peptide vaccine treatment: based on the results of a phase II study on advanced pancreatic cancer.

Shindo Y, Hazama S, Suzuki N, Iguchi H, Uesugi K, Tanaka H, Aruga A, Hatori T, Ishizaki H, Umeda Y, Fujiwara T, Ikemoto T, Shimada M, Yoshimatsu K, Takenouchi H, Matsui H, Kanekiyo S, Iida M, Koki Y, Arima H, Furukawa H, Ueno T, Yoshino S, Fujita T, Kawakami Y, Nakamura Y, Oka M, Nagano H.

Journal of Experimental & Clinical Cnacer Research 36 （ 1 ） 36 2017年02月

研究論文（学術雑誌）, 共著

Functional analysis of KIF20A, a potential immunotherapeutic target for glioma

Saito Katsuya, Ohta Shigeki, Kawakami Yutaka, Yoshida Kazunari, Toda Masahiro

Journal of Neuro-Oncology 132 （ 1 ） 63 - 74 2017年01月

研究論文（学術雑誌）, 共著, ISSN 0167-594X

Kinesin family member 20A (KIF20A), an ideal cancer-testis antigen, was reported to be a promising immunotherapeutic target for pancreatic cancers. Clinical trials of KIF20A peptide vaccine immunotherapy have been conducted against pancreatic cancers. To demonstrate the efficacy of KIF20A as a candidate molecular target for gliomas, we analyzed the expression and function of KIF20A in gliomas. Western blot and quantitative PCR analyses showed that KIF20A expression in glioma cell lines and glioma tissues was high compared with that found in a normal brain. KIF20A immunostaining of glioma cells and glioma tissues demonstrated that KIF20A was involved in spindle formation and cytokinesis, and that KIF20A was highly expressed, especially in glioma cells undergoing mitosis. In silico analysis of a cancer microarray database revealed that KIF20A was highly expressed in gliomas depending on the pathological grade, and glioma patients with higher expression of KIF20A showed poorer prognosis. Down-regulating KIF20A reduced cell proliferation in glioma cells due to the failure of cytokinesis and generation of binucleated cells. Additionally, KIF20A inhibition induced significant apoptosis in SF126 glioma cells. Taken together, KIF20A is a tumor-associated antigen involved in the glioma cell growth and cell survival, suggesting that KIF20A is an oncoantigen of gliomas. Thus, KIF20A is a candidate novel immunotherapeutic target for gliomas.

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Progression of Human Renal Cell Carcinoma via Inhibition of RhoA-ROCK Axis by PARG1.

Miyazaki J, Ito K, Fujita T, Matsuzaki Y, Asano T, Hayakawa M, Asano T, Kawakami Y.

Transl Oncol. 10 （ 2 ） 142 - 152 2017年01月

研究論文（学術雑誌）, 共著

CHD7 promotes proliferation of neural stem cells mediated by MIF

Ohta Shigeki, Yaguchi Tomonori, Okuno Hironobu, Chneiweiss Hervé, Kawakami Yutaka, Okano Hideyuki

Molecular Brain 9 （ 1 ） 1 - 12 2016年12月

研究論文（学術雑誌）, 共著, ISSN 1756-6606

Macrophage migration inhibitory factor (MIF) plays an important role in supporting the proliferation and/or survival of murine neural stem/progenitor cells (NSPCs); however, the downstream effectors of this factor remain unknown. Here, we show that MIF increases the expression of Pax6 and Chd7 in NSPCs in vitro. During neural development, the chromatin remodeling factor Chd7 (chromatin helicase-DNA-binding protein 7) is expressed in the ventricular zone of the telencephalon of mouse brain at embryonic day 14.5, as well as in cultured NSPCs. Retroviral overexpression of Pax6 in NSPCs increased Chd7 gene expression. Lentivirally-expressed Chd7 shRNA suppressed cell proliferation and neurosphere formation, and inhibited neurogenesis in vitro, while decreasing gene expression of Hes5 and N-myc. In addition, CHD7 overexpression increased cell proliferation in human embryonic stem cell-derived NSPCs (ES-NSPCs). In Chd7 mutant fetal mouse brains, there were fewer intermediate progenitor cells (IPCs) compared to wildtype littermates, indicating that Chd7 contributes to neurogenesis in the early developmental mouse brain. Furthermore, in silico database analysis showed that, among members of the CHD family, CHD7 is highly expressed in human gliomas. Interestingly, high levels of CHD7 gene expression in human glioma initiating cells (GICs) compared to normal astrocytes were revealed and gene silencing of CHD7 decreased GIC proliferation. Collectively, our data demonstrate that CHD7 is an important factor in the proliferation and stemness maintenance of NSPCs, and CHD7 is a promising therapeutic target for the treatment of gliomas.

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Prognostic value of tumor-infiltrating lymphocytes differs depending on histological type and smoking habit in completely resected non-small-cell lung cancer.

Kinoshita T, Muramatsu R, Fujita T, Nagumo H, Sakurai T, Noji S, Takahata E, Yaguchi T, Tsukamoto N, Kudo-Saito C, Hayashi Y, Kamiyama I, Ohtsuka T, Asamura H, Kawakami Y.　

Annals Of Oncology. 27 （ 11 ） 2117 - 2123 2016年11月

研究論文（学術雑誌）, 共著

Targeting ALCAM in the cryo-treated tumour microenvironment successfully induces systemic anti-tumour immunity

Kudo-Saito Chie, Fuwa Takafumi, Kawakami Yutaka

European Journal of Cancer 62 54 - 61 2016年07月

研究論文（学術雑誌）, 共著, ISSN 0959-8049

Cryoablative treatment has been widely used for treating cancer. However, the therapeutic efficacies are still controversial. The molecular mechanisms of the cryo-induced immune responses, particularly underlying the ineffectiveness, remain to be fully elucidated. In this study, we identified a new molecular mechanism involved in the cryo failure. We used cryo-ineffective metastatic tumour models that murine melanoma B16-F10 cells were subcutaneously and intravenously implanted into C57BL/6 mice. When the subcutaneous tumours were treated cryoablation on day 7 after tumour implantation, cells expressing activated leucocyte cell adhesion molecule (ALCAM/CD166) were significantly expanded not only locally in the treated tumours but also systemically in spleen and bone marrow of the mice. The cryo-induced ALCAM⁺ cells including CD45^- mesenchymal stem/stromal cells, CD11b⁺Gr1⁺ myeloid-derived suppressor cells, and CD4⁺Foxp3⁺ regulatory T cells significantly suppressed interferon γ production and cytotoxicity of tumour-specific CD8⁺ T cells via ALCAM expressed in these cells. This suggests that systemic expansion of the ALCAM⁺ cells negatively switches host-immune directivity to the tumour-supportive mode. Intratumoural injection with anti-ALCAM blocking monoclonal antibody (mAb) following the cryo treatment systemically induced tumour-specific CD8⁺ T cells with higher cytotoxic activities, resulting in suppression of tumour growth and metastasis in the cryo-resistant tumour models. These suggest that expansion of ALCAM⁺ cells is a determinant of limiting the cryo efficacy. Further combination with an immune checkpoint inhibitor anti-CTLA4 mAb optimized the anti-tumour efficacy of the dual-combination therapy. Targeting ALCAM may be a promising strategy for overcoming the cryo ineffectiveness leading to the better practical use of cryoablation in clinical treatment of cancer.

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MIF maintains the tumorigenic capacity of brain tumor-initiating cells by directly inhibiting p53

Fukaya Raita, Ohta Shigeki, Yaguchi Tomonori, Matsuzaki Yumi, Sugihara Eiji, Okano Hideyuki, Saya Hideyuki, Kawakami Yutaka, Kawase Takeshi, Yoshida Kazunari, Toda Masahiro

Cancer Research 76 （ 9 ） 2813 - 2823 2016年05月

研究論文（学術雑誌）, 共著, ISSN 0008-5472

Tumor-initiating cells thought to drive brain cancer are embedded in a complex heterogeneous histology. In this study, we isolated primary cells from 21 human brain tumor specimens to establish cell lines with high tumorigenic potential and to identify the molecules enabling this capability. The morphology, sphereforming ability upon expansion, and differentiation potential of all cell lines were indistinguishable in vitro. However, testing for tumorigenicity revealed two distinct cell types, brain tumor-initiating cells (BTIC) and non-BTIC. We found that macrophage migration inhibitory factor (MIF) was highly expressed in BTIC compared with non-BTIC. MIF bound directly to both wild-type and mutant p53 but regulated p53-dependent cell growth by different mechanisms, depending on glioma cell line and p53 status. MIF physically interacted with wild-type p53 in the nucleus and inhibited its transcription-dependent functions. In contrast, MIF bound to mutant p53 in the cytoplasm and abrogated transcription-independent induction of apoptosis. Furthermore, MIF knockdown inhibited BTIC-induced tumor formation in a mouse xenograft model, leading to increased overall survival. Collectively, our findings suggest that MIF regulates BTIC function through direct, intracellular inhibition of p53, shedding light on the molecular mechanisms underlying the tumorigenicity of certain malignant brain cells.

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MHC-compatible bone marrow stromal/stem cells trigger fibrosis by activating host T cells in a scleroderma mouse model

Ogawa Yoko, Morikawa Satoru, Okano Hideyuki, Mabuchi Yo, Suzuki Sadafumi, Yaguchi Tomonori, Sato Yukio, Mukai Shin, Yaguchi Saori, Inaba Takaaki, Okamoto Shinichiro, Kawakami Yutaka, Tsubota Kazuo, Matsuzaki Yumi, Shimmura Shigeto

eLife 5 e09394 2016年01月

研究論文（学術雑誌）, 共著

Fibrosis of organs is observed in systemic autoimmune disease. Using a scleroderma mouse, we show that transplantation of MHC compatible, minor antigen mismatched bone marrow stromal/stem cells (BMSCs) play a role in the pathogenesis of fibrosis. Removal of donor BMSCs rescued mice from disease. Freshly isolated PDGFRα⁺ Sca-1⁺ BMSCs expressed MHC class II following transplantation and activated host T cells. A decrease in FOXP3⁺ CD25⁺ Treg population was observed. T cells proliferated and secreted IL-6 when stimulated with mismatched BMSCs in vitro. Donor T cells were not involved in fibrosis because transplanting T cell-deficient RAG2 knock out mice bone marrow still caused disease. Once initially triggered by mismatched BMSCs, the autoimmune phenotype was not donor BMSC dependent as the phenotype was observed after effector T cells were adoptively transferred into naïve syngeneic mice. Our data suggest that minor antigen mismatched BMSCs trigger systemic fibrosis in this autoimmune scleroderma model.

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Melanoma cells control antimelanoma CTL responses via interaction between TIGIT and CD155 in the effector phase

Inozume Takashi, Yaguchi Tomonori, Furuta Junpei, Harada Kazutoshi, Kawakami Yutaka, Shimada Shinji

Journal of Investigative Dermatology 136 （ 1 ） 255 - 263 2016年01月

研究論文（学術雑誌）, 共著, ISSN 0022-202X

Recently, T-cell immunoreceptor with Ig and ITIM domains (TIGIT) was reported as a candidate for novel immune checkpoints. However, the impact of TIGIT on melanoma-specific cytotoxic T lymphocytes in the effector phase remains unclear. In this study, we demonstrated that melanoma cells control antimelanoma cytotoxic T lymphocyte responses via the TIGIT-CD155 interaction in the effector phase. TIGIT is an inhibitory receptor expressed on T cells, and CD155 is one of the cognate ligands expressed on the tumor cells or antigen presenting cells. First, we confirmed that CD155 was constitutively expressed on melanoma cells. We then demonstrated that CD155 on melanoma cells suppressed cytokine release from melanoma-specific cytotoxic T lymphocytes via interaction with TIGIT. Overexpression of CD155 enhanced and its downregulation attenuated the suppressive effect. This suggested that antimelanoma cytotoxic T lymphocyte responses are controlled not only by an imbalance in CD226 (an activating molecule that binds to CD155) and TIGIT expression on T cells but also by the expression levels of CD155 on melanoma cells. In addition, the co-blockade of TIGIT and PD-1 signals synergistically elicited a response of tumor-infiltrating lymphocytes on autologous melanoma cells. These results suggest that the CD155-TIGIT interaction should be blocked for enhancement of antimelanoma immune responses.

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Identification of novel HLA-A*24:02-restricted epitope derived from a homeobox protein expressed in hematological malignancies.

Matsushita Maiko, Otsuka Yohei, Tsutsumida Naoya, Tanaka Chiaki, Uchiumi Akane, Ozawa Koji, Suzuki Takuma, Ichikawa Daiju, Aburatani Hiroyuki, Okamoto Shinichiro, Kawakami Yutaka, Hattori Yutaka

PLoS One 11 （ 1 ） e0146371 2016年01月

研究論文（学術雑誌）, 共著

The homeobox protein, PEPP2 (RHOXF2), has been suggested as a cancer/testis (CT) antigen based on its expression pattern. However, the peptide epitope of PEPP2 that is recognized by cytotoxic T cells (CTLs) is unknown. In this study, we revealed that PEPP2 gene was highly expressed in myeloid leukemia cells and some other hematological malignancies. This gene was also expressed in leukemic stem-like cells. We next identified the first reported epitope peptide (PEPP2^271-279). The CTLs induced by PEPP2^271-279 recognized PEPP2-positive target cells in an HLA-A∗24:02-restricted manner. We also found that a demethylating agent, 5-aza-2′-deoxycytidine, could enhance PEPP2 expression in leukemia cells but not in blood mononuclear cells from healthy donors. The cytotoxic activity of anti-PEPP2 CTL against leukemic cells treated with 5-aza-2′-deoxycytidine was higher than that directed against untreated cells. These results suggest a clinical rationale that combined treatment with this novel antigen-specific immunotherapy together with demethylating agents might be effective in therapy-resistant myeloid leukemia patients.

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Cancer-induced heterogeneous immunosuppressive tumor microenvironments and their personalized modulation

Yaguchi Tomonori, Kawakami Yutaka

International Immunology 28 （ 8 ） 393 - 399 2016年

研究論文（学術雑誌）, 共著, ISSN 0953-8178

Although recent cancer immunotherapy strategies, including immune-checkpoint blockade (i.e. blocking PD-1, PD-L1 or CTLA-4), have shown durable clinical effects in some (but not all) patients with various advanced cancers, further understanding of human immunopathology, particularly in tumor microenvironments, is essential to improve this type of therapy. The major hurdle for immunotherapy is the immunosuppression that is found in cancer patients. There are two types of immunosuppression: one is induced by gene alterations in cancer; the other is local adaptive immunosuppression, triggered by tumor-specific T cells in tumors. The former is caused by multiple mechanisms via various immunosuppressive molecules and via cells triggered by gene alterations, including activated oncogenes, in cancer cells. The various immunosuppressive mechanisms involve signaling cascades that vary among cancer types, subsets within cancer types and individual cancers. Therefore, personalized immune-interventions are necessary to appropriately target oncogene-induced signaling that modulates anti-cancer immune responses, on the basis of genetic and immunological analysis of each patient. Further understanding of human cancer immunopathology may lead to real improvement of current cancer immunotherapies.

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2015 Guidance on cancer immunotherapy development in early-phase clinical studies

Arato Teruyo, Yamaguchi Yoshiyuki, Daimon Takashi, Heike Yuji, Ishii Ken, Kobiyama Kouji, Itho Kyogo, Kageyama Shinichi, Shiku Hiroshi, Miyahara Yoshihiro, Ikeda Hiroaki, Harada Naozumi, Muraoka Daisuke, Kawakami Yutaka, Nakayama Eiichi, Ozawa Keiya, Sato Noriyuki, Takeuchi Masahiro, Tani Kenzaburo, Tamada Koji, Ueda Ryuzo, Yamanaka Takeharu, Yamaue Hiroki, Yasukawa Masaki, Iguchi Toyotaka, Terashima Takeshi, Amakasu Kohei, Kitano Shigehisa, Nagata Yasuhiro, Noguchi Masanori, Asano Takeo, Asonuma Motohiro, Kakimi Kazuhiro, Takesako Kazutoh, Tanaka Masanori, Yamada Akira, Aoshi Taiki, Kuroda Etsushi, Yamazaki Naoya, Kuchiba Aya, Tanaka Shiro, Michimae Hirofumi, Yamada Tomomi, Hanada Kenichi, Okada Hideho, Takebe Naoko, Hirano Naoto, Okumura Satoshi, Shibatsuji Masayoshi, Sato Daisaku, Yamaguchi Teruhide

Cancer Science 106 （ 12 ） 1761 - 1771 2015年12月

研究論文（学術雑誌）, 共著, ISSN 1347-9032

The development of cancer immunotherapies is progressing rapidly with a variety of technological approaches. They consist of "cancer vaccines", which are based on the idea of vaccination, "effector cell therapy", classified as passive immunotherapy, and "inhibition of immunosuppression", which intends to break immunological tolerance to autoantigens or immunosuppressive environments characterizing antitumor immune responses. Recent reports showing clinical evidence of efficacy of immune checkpoint inhibitors and adoptive immunotherapies with tumor-infiltrating lymphocytes and tumor-specific receptor gene-modified T cells indicate the beginning of a new era for cancer immunotherapy. This guidance summarizes ideas that will be helpful to those who plan to develop cancer immunotherapy. The aims of this guidance are to discuss and offer important points in early phase clinical studies of innovative cancer immunotherapy, with future progress in this field, and to contribute to the effective development of cancer immunotherapy aligned with the scope of regulatory science. This guidance covers cancer vaccines, effector cell therapy, and inhibition of immunosuppression, including immune checkpoint inhibitors.

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Cancer immunotherapy by immuno-checkpoint blockade

Kawakami Yutaka

[Rinshō ketsueki] The Japanese journal of clinical hematology 56 （ 10 ） 2186 - 2194 2015年10月

ISSN 0485-1439

As cancer immunotherapies utilizing anti-tumor T-cell responses, immuno-checkpoint blockade and adoptive T-cell immunotherapy have recently achieved durable responses even in advanced cancer patients with metastases. Administration of antibodies on the T-cell surface, CTLA-4 and PD-1 (or PD-1 ligand PD-L1), resulted in tumor regression of not only melanoma and renal cell cancer which were known to be relatively sensitive to immunotherapy, but also various malignancies including lung, bladder, ovarian, gastric, and head and neck cancers, as well as hematological malignancies such as Hodgkin and B-cell malignant lymphomas. These findings have changed the status of immunotherapy in the development of cancer treatments. Currently, development of combinations employing cancer immunotherapy with immuno-checkpoint blockade, as well as personalized cancer immunotherapy based on the evaluation of pretreatment immune status, are in progress.

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NUAK2 amplification coupled with PTEN deficiency promotes melanoma development via CDK Activation

Namiki Takeshi, Yaguchi Tomonori, Nakamura Kenta, Valencia Julio C., Coelho Sergio G., Yin Lanlan, Kawaguchi Masakazu, Vieira Wilfred D., Kaneko Yasuhiko, Tanemura Atsushi, Katayama Ichiro, Yokozeki Hiroo, Kawakami Yutaka, Hearing Vincent J.

Cancer Research 75 （ 13 ） 2708 - 2715 2015年07月

研究論文（学術雑誌）, 共著, ISSN 0008-5472

The AMPK-related kinase NUAK2 has been implicated in melanoma growth and survival outcomes, but its therapeutic utility has yet to be confirmed. In this study, we show how its genetic amplification in PTEN-deficient melanomas may rationalize the use of CDK2 inhibitors as a therapeutic strategy. Analysis of array-CGH data revealed that PTEN deficiency is coupled tightly with genomic amplification encompassing the NUAK2 locus, a finding strengthened by immunohistochemical evidence that phospho-Akt overexpression was correlated with NUAK2 expression in clinical specimens of acral melanoma. Functional studies in melanoma cells showed that inactivation of the PI3K pathway upregulatedp21 expression and reduced the number of cells in S phase. NUAK2 silencing and inactivation of the PI3K pathway efficiently controlled CDK2 expression, whereas CDK2 inactivation specifically abrogated the growth of NUAK2-amplified and PTEN-deficient melanoma cells. Immunohistochemical analyses confirmed an association of CDK2 expression with NUAK2 amplification and p-Akt expression in melanomas. Finally, pharmacologic inhibition of CDK2 was sufficient to suppress the growth of NUAK2-amplified and PTEN-deficient melanoma cells in vitro and in vivo. Overall, our results show how CDK2 blockade may offer a promising therapy for genetically defined melanomas, where NUAK2 is amplified and PTEN is deleted.

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Synergistic antiproliferative effect of imatinib and adriamycin in platelet-derived growth factor receptor-expressing osteosarcoma cells

Yamaguchi Sayaka I., Ueki Arisa, Sugihara Eiji, Onishi Nobuyuki, Yaguchi Tomonori, Kawakami Yutaka, Horiuchi Keisuke, Morioka Hideo, Matsumoto Morio, Nakamura Masaya, Muto Akihiro, Toyama Yoshiaki, Saya Hideyuki, Shimizu Takatsune

Cancer Science 106 （ 7 ） 875 - 882 2015年07月

研究論文（学術雑誌）, 共著, ISSN 1347-9032

Osteosarcoma (OS) is the most frequent primary solid malignant tumor of bone. Its prognosis remains poor in the substantial proportion of patients who do not respond to chemotherapy and novel therapeutic options are therefore needed. We previously established a mouse model that mimics the aggressive behavior of human OS. Enzyme-linked immunosorbent assay-based screening of such mouse tumor lysates identified platelet-derived growth factor-BB (PDGF-BB) as an abundant soluble factor, the gene for which was expressed dominantly in surrounding non-malignant cells of the tumor, whereas that for the cognate receptor (PDGF receptor β) was highly expressed in OS cells. Platelet-derived growth factor-BB induced activation of both MEK-ERK and phosphatidylinositol 3-kinase-protein kinase B signaling pathways and promoted survival in OS cells deprived of serum, and these effects were blocked by the PDGF receptor inhibitor imatinib. However, these actions of PDGF-BB and imatinib were mostly masked in the presence of serum. Whereas imatinib alone did not manifest an antitumor effect in mice harboring OS tumors, combined treatment with imatinib and adriamycin exerted a synergistic antiproliferative effect on OS cells in vivo. These results suggest that treatment of OS with imatinib is effective only when cell survival is dependent on PDGF signaling or when imatinib is combined with another therapeutic intervention that renders the tumor cells susceptible to imatinib action, such as by inducing cellular stress.

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Phase I pilot study of Wilms tumor gene 1 peptide-pulsed dendritic cell vaccination combined with gemcitabine in pancreatic cancer

Mayanagi Shuhei, Kitago Minoru, Sakurai Toshiharu, Matsuda Tatsuo, Fujita Tomonobu, Higuchi Hajime, Taguchi Junichi, Takeuchi Hiroya, Itano Osamu, Aiura Koichi, Hamamoto Yasuo, Takaishi Hiromasa, Okamoto Masato, Sunamura Makoto, Kawakami Yutaka, Kitagawa Yuko

Cancer Science 106 （ 4 ） 397 - 406 2015年04月

研究論文（学術雑誌）, 共著, ISSN 1347-9032

This study aimed to evaluate the feasibility of and immune response to Wilms tumor gene 1 (WT1) peptide-pulsed dendritic cell vaccination combined with gemcitabine (DCGEM) as a first-line therapy among patients with advanced pancreatic cancer. Ten HLA-A*2402 patients were treated with WT1 peptide-pulsed DC vaccination (1 × 107 cells) on days 8 and 22 and gemcitabine (1000 mg/m2) on days 1, 8 and 15. Induction of a WT1-specific immune response was evaluated using the delayed-type hypersensitivity (DTH) skin test, interferon-γ enzyme-linked immunospot and HLA tetramer assays, along with assays for various immunological factors. DCGEM was well-tolerated, and the relative dose intensity of gemcitabine was 87%. Disease control associated with a low neutrophil/lymphocyte ratio was observed in all three patients with DTH positivity; it was also correlated with a low percentage of granulocytic myeloid derived suppressor cells in the pretreatment peripheral blood (P = 0.017). Patients with liver metastases and high levels of inflammatory markers such as C-reactive protein and interleukin-8 (IL-8) showed poor survival even though a WT1-specific immune response was induced in them. WT1 peptide-pulsed DCGEM is feasible and effective for inducing anti-tumor T-cell responses. Our results support future investigations for pancreatic cancer patients with non-liver metastases and favorable immunological conditions. This trial was registered with the University hospital Medical Information Network (UMIN) Clinical Trials Registry (http://www.umin.ac.jp/ctr/ number: UMIN-000004855).

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