Masato Okamoto

Bio: Masato Okamoto is an academic researcher from Osaka University. The author has contributed to research in topics: Immunotherapy & Cancer. The author has an hindex of 27, co-authored 111 publications receiving 2333 citations. Previous affiliations of Masato Okamoto include Musashino University & Keio University.

Clinical and immunologic evaluation of dendritic cell-based immunotherapy in combination with gemcitabine and/or S-1 in patients with advanced pancreatic carcinoma.

Abstract: ObjectivesIn the current study, we have evaluated the clinical and immunological responses in patients with advanced pancreatic carcinoma who received dendritic cell (DC)–based immunotherapy in combination with gemcitabine and/or S-1.MethodsDendritic cell–based immunotherapy (DC vaccine alone or DC

Expression of Toll-Like Receptor 4 on Dendritic Cells Is Significant for Anticancer Effect of Dendritic Cell-Based Immunotherapy in Combination with an Active Component of OK-432, a Streptococcal Preparation

Abstract: A lipoteichoic acid-related molecule OK-PSA is an active component of OK-432, a Streptococcus -derived anticancer immunotherapeutic agent. In the present study, we first examined the effect of OK-PSA on the maturation of dendritic cells (DCs) in vitro by using the DCs derived from 5 healthy donors and 10 patients with head and neck cancer with or without expression of toll-like receptor 4 ( TLR4 ) or MD-2 mRNA. OK-PSA treatment effectively increased the surface expression of MHC class II, CD80, CD83, and CD86. OK-PSA-stimulated DCs secreted the cytokines that can induce helper T-cell 1 (Th1)-type T-cell response, and stimulated allogeneic T cells to produce IFN-γ and to elicit an allogeneic antigen-specific cytotoxicity. These activities almost depended on expression of TLR4 and MD-2 genes. We next investigated the in vivo anticancer effect of intratumoral administration of syngeneic DCs followed by OK-PSA against established tumors in mice. C57BL/6 mice, which express wild-type TLR4, and C57BL/6-derived TLR4-knockout (TLR4−/−) mice were used. Although OK-PSA accelerated the antitumor effect of intratumoral DC administration in wild-type mice bearing syngeneic tumors, the antitumor effect of OK-PSA as well as of the combination therapy with DCs and OK-PSA was not significant in TLR4−/− mice. Interestingly, an administration of wild-type-mouse-derived DCs followed by OK-PSA exhibited a marked antitumor effect even in the TLR4−/− mice. These findings suggest that OK-PSA may be a potent adjuvant for local DC therapy, and that DC therapy followed by OK-PSA is able to elicit anticancer activity even in a TLR4-deficient host when TLR4 is expressed only in DCs injected intratumorally.

Treatment with Chemotherapy and Dendritic Cells Pulsed with Multiple Wilms' Tumor 1 (WT1)–Specific MHC Class I/II–Restricted Epitopes for Pancreatic Cancer

Abstract: Purpose: We performed a phase I trial to investigate the safety, clinical responses, and Wilms9 tumor 1 (WT1)-specific immune responses following treatment with dendritic cells (DC) pulsed with a mixture of three types of WT1 peptides, including both MHC class I and II–restricted epitopes, in combination with chemotherapy. Experimental Design: Ten stage IV patients with pancreatic ductal adenocarcinoma (PDA) and 1 patient with intrahepatic cholangiocarcinoma (ICC) who were HLA-positive for A*02:01, A*02:06, A*24:02, DRB1*04:05, DRB1*08:03, DRB1*15:01, DRB1*15:02, DPB1*05:01, or DPB1*09:01 were enrolled. The patients received one course of gemcitabine followed by biweekly intradermal vaccinations with mature DCs pulsed with MHC class I (DC/WT1-I; 2 PDA and 1 ICC), II (DC/WT1-II; 1 PDA), or I/II–restricted WT1 peptides (DC/WT1-I/II; 7 PDA), and gemcitabine. Results: The combination therapy was well tolerated. WT1-specific IFNγ-producing CD4 + T cells were significantly increased following treatment with DC/WT1-I/II. WT1 peptide-specific delayed-type hypersensitivity (DTH) was detected in 4 of the 7 patients with PDA vaccinated with DC/WT1-I/II and in 0 of the 3 patients with PDA vaccinated with DC/WT1-I or DC/WT1-II. The WT1-specific DTH-positive patients showed significantly improved overall survival (OS) and progression-free survival (PFS) compared with the negative control patients. In particular, all 3 patients with PDA with strong DTH reactions had a median OS of 717 days. Conclusions: The activation of WT1-specific immune responses by DC/WT1-I/II combined with chemotherapy may be associated with disease stability in advanced pancreatic cancer. Clin Cancer Res; 20(16); 4228–39. ©2014 AACR .

Toll-like receptor signaling in anti-cancer immunity.

Abstract: It is important to augment the anti-cancer host response in cancer treatment. Recent studies suggested that the signaling via Toll-like receptors (TLRs) which are new- ly identified receptor molecules recognizing many pathogens, are involved in the induction of anti-cancer immunity. Seyaet al. demonstrated that maturation of dendritic cells (DCs) and cytokine induction by the cell wall skeleton of Mycobacterium bovis bacillus Calmette-Guerin (BCG-CWS) are induced via both TLR2 and TLR4. Akira et al. discovered a new molecule of TLR family, TLR9, recognizing unmethylated bacterial CpG-DNA, whose clinical use is expected for cancer therapy as a potent inducer of a helper T cell 1 (Th1)-type T-cell response. TLR9-deficient mice did not show any responses to CpG-DNA, including Th 1 cytokine production and maturation of DCs. We have obtained two molecules, a lipoteichoic acid-related molecule isolated from streptococcal agent OK-432, and a plant-derived 55-kDa protein that can induce Th1 response and elicit a strong anti-cancer effect in vivo and in vitro. Our basic experiments demonstrate that TLR4 signaling is intimately involved in anti-cancer immunity induced by these immunopotentiators. Our clinical examination in oral cancer patients also suggests the requirement of both TLR4 and MD-2 in the OK-432-induced anti-cancer host response. Establishment and clinical use of the methodology for human cancer therapy by utilizing TLR signaling is greatly expected. J. Med. Invest. 50 : 9-24, 2003

Involvement of Toll-Like Receptor 4 Signaling in Interferon-γ Production and Antitumor Effect by Streptococcal Agent OK-432

Abstract: Background: The streptococcal agent OK-432 has been used for immunotherapy of head and neck cancer, among other malignancies, but its mechanism of action is unknown. Because the Toll-like receptor 4 (TLR4)/MD-2 complex is important in enabling the mammalian immune system to recognize bacterial components, we investigated whether expression of the TLR4 and MD-2 genes is associated with OK-432-induced anticancer immunity. Methods: Peripheral blood mononuclear cells (PBMCs) from 28 patients with head and neck cancer were analyzed for TLR4 and MD-2 mRNA expression by reverse transcription–polymerase chain reaction (RT–PCR) analysis. PBMCs were treated in vitro with OK-432 or with OK-PSA (a lipoteichoic-acidrelated molecule that is an active component of OK-432), and interferon-gamma (IFN-) mRNA expression, an immune response measure, was analyzed by RT–PCR. Patient sera collected 24 hours after OK-432 administration were examined for IFN- protein using an enzyme-linked immunosorbent assay. Lewis lung carcinoma-bearing wild-type C57BL/6 and TLR4-deficient mice (four mice per group) received intraperitoneal injections of OK-432, and tumor volumes and sera IFN- levels were measured over time. All statistical tests were two-sided. Results: Twenty patients expressed both TLR4 and MD-2. Expression of TLR4 and MD-2 genes was associated with the in vivo IFN- induction in 19 patients administered OK-432 (Fisher’s exact test P<.001). Although both OK-432 and OK-PSA induced IFN- expression from PBMCs in vitro, expression of TLR4 and MD-2 was associated only with IFN- expression induced by OK-PSA (P<.001). In vivo intraperitoneal administration of OK-432 resulted in an increase of IFN- in sera from wild-type mice but not in sera from TLR4-deficient mice. Tumors in wild-type mice treated with OK-432 were statistically significantly smaller than those in mice treated with saline (P = .007). By contrast, in TLR4-deficient mice, there was no difference in tumor volume between the two treatment groups. Conclusions: TLR4 and MD-2 may mediate OK-432-induced anticancer immunity. [J Natl Cancer Inst 2003;95:316–26]

Combining immunotherapy and targeted therapies in cancer treatment

Abstract: During the past two decades, the paradigm for cancer treatment has evolved from relatively nonspecific cytotoxic agents to selective, mechanism-based therapeutics. Cancer chemotherapies were initially identified through screens for compounds that killed rapidly dividing cells. These drugs remain the backbone of current treatment, but they are limited by a narrow therapeutic index, significant toxicities and frequently acquired resistance. More recently, an improved understanding of cancer pathogenesis has given rise to new treatment options, including targeted agents and cancer immunotherapy. Targeted approaches aim to inhibit molecular pathways that are crucial for tumour growth and maintenance; whereas, immunotherapy endeavours to stimulate a host immune response that effectuates long-lived tumour destruction. Targeted therapies and cytotoxic agents also modulate immune responses, which raises the possibility that these treatment strategies might be effectively combined with immunotherapy to improve clinical outcomes.

Toll-like receptors and cancer.

Abstract: Toll-like receptors (TLRs) are a family of pattern recognition receptors that are best-known for their role in host defence from infection. Emerging evidence also suggests that TLRs have an important role in maintaining tissue homeostasis by regulating the inflammatory and tissue repair responses to injury. The development of cancer has been associated with microbial infection, injury, inflammation and tissue repair. Here we discuss how the function of TLRs may relate to these processes in the context of carcinogenesis.

Cancer Immunosurveillance and Immunoediting: The Roles of Immunity in Suppressing Tumor Development and Shaping Tumor Immunogenicity

Abstract: Cellular transformation and tumor development result from an accumulation of mutational and epigenetic changes that alter normal cell growth and survival pathways. For the last 100 years, there has been a vigorous debate as to whether the unmanipulated immune system can detect and eliminate such altered host derived cells despite the fact that cancer cells frequently express either abnormal proteins or abnormal levels of normal cellular proteins that function as tumor antigens. In this review, we discuss the current state of this argument and point out some of the recent key experiments demonstrating that immunity not only protects the host from cancer development (i.e., provides a cancer immunosurveillance function) but also can promote tumor growth, sometimes by generating more aggressive tumors. The terminology "cancer immunoediting" has been used to describe this dual host protective and tumor promoting action of immunity, and herein we summarize the ever-increasing experimental and clinical data that support the validity of this concept.

Head and Neck Cancer

Abstract: Head and Neck Cancer Most head and neck cancers (73% in the United States) are now related to human papillomavirus infection rather than tobacco and alcohol. Primary cancers are largely squamous-ce...