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Nishinakamura H, Shinya S, Irie T, Sakihama S, Naito T, Watanabe K, Sugiyama D, Tamiya M, Yoshida T, Hase T, Yoshida T, Karube K, Koyama S, Nishikawa H. Coactivation of innate immune suppressive cells induces acquired resistance against combined TLR agonism and PD-1 blockade. Sci Transl Med 2025; 17:eadk3160. [PMID: 39937883 DOI: 10.1126/scitranslmed.adk3160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Revised: 10/02/2024] [Accepted: 01/03/2025] [Indexed: 02/14/2025]
Abstract
Immune checkpoint blockade therapy has been successfully applied in clinical settings as a standard therapy for many cancer types, but its clinical efficacy is restricted to patients with immunologically hot tumors. Various strategies to modify the tumor microenvironment (TME), such as Toll-like receptor (TLR) agonists that can stimulate innate immunity, have been explored but have not been successful. Here, we show a mechanism of acquired resistance to combination treatment consisting of an agonist for multiple TLRs, OK-432 (Picibanil), and programmed cell death protein 1 (PD-1) blockade. Adding the TLR agonist failed to convert the TME from immunogenically cold to hot and did not augment antitumor immunity, particularly CD8+ T cell responses, in multiple animal models. The failure was attributed to the coactivation of innate suppressive cells, such as polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) expressing CXCR2, through high CXCL1 production by macrophages in the TME upon OK-432 treatment. A triple combination treatment with OK-432, PD-1 blockade, and a CXCR2 neutralizing antibody overcame the resistance induced by PMN-MDSCs, resulting in a stronger antitumor effect than that of any dual combinations or single treatments. The accumulation of PMN-MDSCs was similarly observed in the pleural effusions of patients with lung cancer after OK-432 administration. We propose that successful combination cancer immunotherapy intended to stimulate innate antitumor immunity requires modulation of unwanted activation of innate immune suppressive cells, including PMN-MDSCs.
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Affiliation(s)
- Hitomi Nishinakamura
- Division of Cancer Immunology, Research Institute/Exploratory Oncology Research and Clinical Trial Center (EPOC), National Cancer Center Japan, Tokyo, 104-0045/Chiba 277-8577, Japan
| | - Sayoko Shinya
- Division of Cancer Immunology, Research Institute/Exploratory Oncology Research and Clinical Trial Center (EPOC), National Cancer Center Japan, Tokyo, 104-0045/Chiba 277-8577, Japan
- Discovery and Research, Ono Pharmaceutical Co. Ltd., Osaka, 618-8585, Japan
| | - Takuma Irie
- Division of Cancer Immunology, Research Institute/Exploratory Oncology Research and Clinical Trial Center (EPOC), National Cancer Center Japan, Tokyo, 104-0045/Chiba 277-8577, Japan
| | - Shugo Sakihama
- Laboratory of Hemato-Immunology, Graduate School of Health Sciences, University of the Ryukyus, Nishihara, 903-0125, Japan
| | - Takeo Naito
- Division of Cancer Immunology, Research Institute/Exploratory Oncology Research and Clinical Trial Center (EPOC), National Cancer Center Japan, Tokyo, 104-0045/Chiba 277-8577, Japan
| | - Keisuke Watanabe
- Division of Cancer Immunology, Research Institute/Exploratory Oncology Research and Clinical Trial Center (EPOC), National Cancer Center Japan, Tokyo, 104-0045/Chiba 277-8577, Japan
| | - Daisuke Sugiyama
- Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
| | - Motohiro Tamiya
- Respiratory Medicine, Osaka International Cancer Institute, Osaka 541-8567, Japan
| | - Tatsuya Yoshida
- Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo 104-0045, Japan
| | - Tetsunari Hase
- Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
| | - Takao Yoshida
- Discovery and Research, Ono Pharmaceutical Co. Ltd., Osaka, 618-8585, Japan
| | - Kennosuke Karube
- Department of Pathology and Laboratory Medicine, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
| | - Shohei Koyama
- Division of Cancer Immunology, Research Institute/Exploratory Oncology Research and Clinical Trial Center (EPOC), National Cancer Center Japan, Tokyo, 104-0045/Chiba 277-8577, Japan
- Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita, 565-0871, Japan
| | - Hiroyoshi Nishikawa
- Division of Cancer Immunology, Research Institute/Exploratory Oncology Research and Clinical Trial Center (EPOC), National Cancer Center Japan, Tokyo, 104-0045/Chiba 277-8577, Japan
- Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
- Division of Cancer Immune Multicellular System Regulation, Center for Cancer Immunotherapy and Immunobiology (CCII), Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
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Li W, Zheng Z, Ma K, Zhang C, Li K, Tayier P, Yao Y. Preliminary Exploration of a New Therapy for Interstitial Cystitis/Bladder Pain Syndrome: Botulinum Toxin A Combined with Sapylin. Toxins (Basel) 2022; 14:toxins14120832. [PMID: 36548729 PMCID: PMC9783506 DOI: 10.3390/toxins14120832] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 11/23/2022] [Accepted: 11/28/2022] [Indexed: 12/05/2022] Open
Abstract
Interstitial cystitis/bladder pain syndrome (IC/BPS) is an intractable disease without long-term effective therapy. This study aims to evaluate the efficacy and safety of botulinum toxin A (BoNT/A) plus Sapylin, which might modulate the immune response of the bladder in the treatment of IC/BPS patients. We retrospectively investigated the clinical outcomes among 34 patients who accepted repeated Sapylin instillations after 200 U of BoNT/A submucosally injected into bladder walls (Mix group) and 28 patients who received BoNT/A alone (Control group). Each of the bladder walls (left, right, anterior and posterior) was injected six times with 8 U of BoNT/A per injection. The primary outcome measure was the global response assessment. The results showed that at 6 months post-injection, the response rate in the Mix group was remarkably higher than that in the Control group (58.8% vs. 28.6%, p < 0.05). The mean effective duration of the responders in the Mix group was apparently better than that in the Control group (27.5 (range 0-89) vs. 4.9 (range 0-11) months, p < 0.05). None of the patients experienced serious adverse events. In conclusion, repeated intravesical instillations of Sapylin after BoNT/A injection can produce significantly better clinical outcomes than BoNT/A alone in IC/PBS patients.
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Affiliation(s)
- Wenshuang Li
- Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
- Guangdong Provincial Clinical Research Center for Urological Diseases, Guangzhou 510120, China
- Department of Urology, The Eighth Affiliated Hospital of Sun Yat-Sen University, Shenzhen 518033, China
| | - Zhenming Zheng
- Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
- Guangdong Provincial Clinical Research Center for Urological Diseases, Guangzhou 510120, China
| | - Kaiqun Ma
- Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
- Guangdong Provincial Clinical Research Center for Urological Diseases, Guangzhou 510120, China
- Department of Urology, Shantou Central Hospital, Shantou 515031, China
| | - Caixia Zhang
- Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
- Guangdong Provincial Clinical Research Center for Urological Diseases, Guangzhou 510120, China
| | - Kuiqing Li
- Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
- Guangdong Provincial Clinical Research Center for Urological Diseases, Guangzhou 510120, China
| | - Paierhati Tayier
- Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
- Guangdong Provincial Clinical Research Center for Urological Diseases, Guangzhou 510120, China
| | - Yousheng Yao
- Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
- Guangdong Provincial Clinical Research Center for Urological Diseases, Guangzhou 510120, China
- Correspondence: ; Tel.: +86-1382-2213-262; Fax: +86-20-813-32505
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Afroz R, Tanvir EM, Tania M, Fu J, Kamal MA, Khan MA. LPS/TLR4 Pathways in Breast Cancer: Insights into Cell Signalling. Curr Med Chem 2022; 29:2274-2289. [PMID: 34382520 DOI: 10.2174/0929867328666210811145043] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 07/01/2021] [Accepted: 07/10/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND Cancer cells are usually recognized as foreign particles by the immune cells. Mounting evidence suggest an important link between toll-like receptors (TLRs) and carcinogenesis. This review article focused on the role of TLRs, especially TLR4, in breast cancer. METHODS Research data on TLRs and cancer was explored in PubMed, Scopus, Google Scholar and reviewed. Although some pioneer works are referenced, papers published in the last ten years were mostly cited. RESULTS TLRs are widely investigated pattern recognition receptors (PRR), and TLR4 is the most studied TLRs, implicated with the occurrence of several types of cancers, including breast cancer. TLR4 activation occurs via the binding of its ligand lipopolysaccharide (LPS), a component of the outer membrane of gram-negative bacteria. Upon LPS binding, TLR4 dimerizes and recruits downstream signalling and/or adapter molecules, leading to gene expression related to cancer cell proliferation, survival, invasion, and metastasis. Although LPS/TLR4 signalling seems a single signal transduction pathway, the TLR4 activation results in the activation of multiple diverse intracellular networks with huge cellular responses in both immune and cancer cells. The role of TLR4 in the growth, invasion, and metastasis of breast cancer is attracting huge attention in oncology research. Several clinical and preclinical studies utilize both TLR4 agonists and antagonists as a treatment option for cancer therapy, either as monotherapy or adjuvants for vaccine development. CONCLUSION This review narrates the role of LPS/TLR4 signalling in breast cancer development and future prospects for targeting LPS/TLR4 axis in the treatment of breast cancer.
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Affiliation(s)
- Rizwana Afroz
- School of Pharmacy, Pharmacy Australia Centre of Excellence, The University of Queensland, Woolloongabba, Queensland, Australia
| | - E M Tanvir
- School of Pharmacy, Pharmacy Australia Centre of Excellence, The University of Queensland, Woolloongabba, Queensland, Australia
- Veterinary Drug Residue Analysis Division, Institute of Food and Radiation Biology, Atomic Energy Research Establishment, Bangladesh Atomic Energy Commission, Dhaka, Bangladesh
| | - Mousumi Tania
- Research Division, Nature Study Society of Bangladesh, Dhaka, Bangladesh
- Division of Molecular Cancer, Red Green Research Center, Dhaka, Bangladesh
| | - Junjiang Fu
- Key Laboratory of Epigenetics and Oncology, The Research Center for Preclinical Medicine, Southwest Medical University, Luzhou, Sichuan, China
| | - Mohammad Amjad Kamal
- King Fahd Medical Research Center, King Abdulaziz University, Jaddah, Saudi Arabia
| | - Md Asaduzzaman Khan
- Key Laboratory of Epigenetics and Oncology, The Research Center for Preclinical Medicine, Southwest Medical University, Luzhou, Sichuan, China
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Ohe G, Kudo Y, Kamada K, Mouri Y, Takamaru N, Kudoh K, Kurio N, Miyamoto Y. The Soluble Factor from Oral Cancer Cell Lines Inhibits Interferon-γ Production by OK-432 via the CD40/CD40 Ligand Pathway. Cancers (Basel) 2021; 13:cancers13133301. [PMID: 34209347 PMCID: PMC8269085 DOI: 10.3390/cancers13133301] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 06/20/2021] [Accepted: 06/28/2021] [Indexed: 11/16/2022] Open
Abstract
(1) Background: OK-432 is a penicillin-killed, lyophilized formulation of a low-toxicity strain (Su) of Streptococcus pyogenes (Group A). It is a potent immunotherapy agent for several types of cancer, including oral cancer. We previously showed that (i) OK-432 treatment induces a high amount of IFN-? production from peripheral blood mononuclear cells (PBMCs), and (ii) conditioned medium (CM) from oral cancer cells suppresses both the IFN-? production and cytotoxic activity of PBMCs driven by OK-432. The aim of this study was to determine the inhibitory mechanism of OK-432-induced IFN-? production from PBMCs by CM. (2) Methods: We performed cDNA microarray analysis, quantitative RT-PCR, and ELISA to reveal the inhibitory mechanism of CM. (3) Results: We found that CD40 plays a key role in IFN-? production via IL-12 production. Although OK-432 treatment upregulated the expression levels of the IL-12p40, p35, and CD40 genes, CM from oral cancer cells downregulate these genes. The amount of IFN-? production by OK-432 treatment was decreased by an anti-CD40 neutralizing antibody. (4) Conclusions: Our study suggests that uncertain soluble factor(s) produced from oral cancer cells may inhibit IFN-? production from PBMCs via suppressing the CD40/CD40L-IL-12 axis.
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Affiliation(s)
- Go Ohe
- Department of Oral Surgery, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8504, Japan; (K.K.); (N.T.); (K.K.); (N.K.); (Y.M.)
- Dentistry and Oral Surgery, Takamatsu Municipal Hospital, 847-1 Ko Busshozan-cho, Takamatsu 761-8538, Japan
- Correspondence:
| | - Yasusei Kudo
- Department of Oral Bioscience, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8504, Japan; (Y.K.); (Y.M.)
| | - Kumiko Kamada
- Department of Oral Surgery, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8504, Japan; (K.K.); (N.T.); (K.K.); (N.K.); (Y.M.)
| | - Yasuhiro Mouri
- Department of Oral Bioscience, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8504, Japan; (Y.K.); (Y.M.)
| | - Natsumi Takamaru
- Department of Oral Surgery, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8504, Japan; (K.K.); (N.T.); (K.K.); (N.K.); (Y.M.)
| | - Keiko Kudoh
- Department of Oral Surgery, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8504, Japan; (K.K.); (N.T.); (K.K.); (N.K.); (Y.M.)
| | - Naito Kurio
- Department of Oral Surgery, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8504, Japan; (K.K.); (N.T.); (K.K.); (N.K.); (Y.M.)
| | - Youji Miyamoto
- Department of Oral Surgery, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8504, Japan; (K.K.); (N.T.); (K.K.); (N.K.); (Y.M.)
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Galluzzi L, Vacchelli E, Eggermont A, Fridman WH, Galon J, Sautès-Fridman C, Tartour E, Zitvogel L, Kroemer G. Trial Watch: Experimental Toll-like receptor agonists for cancer therapy. Oncoimmunology 2021; 1:699-716. [PMID: 22934262 PMCID: PMC3429574 DOI: 10.4161/onci.20696] [Citation(s) in RCA: 170] [Impact Index Per Article: 42.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Toll-like receptors (TLRs) are prototypic pattern recognition receptors (PRRs) best known for their ability to activate the innate immune system in response to conserved microbial components such as lipopolysaccharide and double-stranded RNA. Accumulating evidence indicates that the function of TLRs is not restricted to the elicitation of innate immune responses against invading pathogens. TLRs have indeed been shown to participate in tissue repair and injury-induced regeneration as well as in adaptive immune responses against cancer. In particular, TLR4 signaling appears to be required for the efficient processing and cross-presentation of cell-associated tumor antigens by dendritic cells, which de facto underlie optimal therapeutic responses to some anticancer drugs. Thus, TLRs constitute prominent therapeutic targets for the activation/intensification of anticancer immune responses. In line with this notion, long-used preparations such as the Coley toxin (a mixture of killed Streptococcus pyogenes and Serratia marcescens bacteria) and the bacillus Calmette-Guérin (BCG, an attenuated strain of Mycobacterium bovis originally developed as a vaccine against tuberculosis), both of which have been associated with consistent anticancer responses, potently activate TLR2 and TLR4 signaling. Today, besides BCG, only one TLR agonist is FDA-approved for therapeutic use in cancer patients: imiquimod. In this Trial Watch, we will briefly present the role of TLRs in innate and cognate immunity and discuss the progress of clinical studies evaluating the safety and efficacy of experimental TLR agonists as immunostimulatory agents for oncological indications.
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Affiliation(s)
- Lorenzo Galluzzi
- Université Paris Descartes/Paris V; Sorbonne Paris Cité; Paris, France ; Institut Gustave Roussy; Villejuif, France
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Combination Therapy of Pulsed-Wave Ultrasound Hyperthermia and Immunostimulant OK-432 Enhances Systemic Antitumor Immunity for Cancer Treatment. Int J Radiat Oncol Biol Phys 2020; 108:140-149. [PMID: 32339644 DOI: 10.1016/j.ijrobp.2020.04.021] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Revised: 02/26/2020] [Accepted: 04/13/2020] [Indexed: 11/20/2022]
Abstract
PURPOSE In this study, we hypothesized that systemic antitumor immunity might be enhanced by combining pulsed-wave ultrasound hyperthermia (pUSHT) with OK-432 and that the induced antitumor immunity could confer protection against tumorigenesis. These hypotheses were tested in bilateral and rechallenged tumor models. METHODS AND MATERIALS Bilateral and rechallenged tumor models were applied in the studies. In the bilateral tumor model, BALB/c mice were inoculated in both flanks with CT26-luc tumor cells. The tumors in the right flank were treated with 4 courses of pUSHT with or without OK-432. In the rechallenged tumor model, tumor cells were implanted into the right flank. Once formed, the tumors were treated with pUSHT with OK-432, followed by surgical resection. New tumor cells were then implanted into the contralateral flank. The antitumor response was evaluated via infiltrated immune cells and the severity of necrosis/apoptosis in tumors. RESULTS In the bilateral tumor model, the tumor growth rate and growth activity of both treated (100% reduction) and untreated tumors (90.5% reduction) were significantly inhibited with the combination treatment compared with the sham control group, and the systemic antitumor effect was prolonged. The survival rate was significantly enhanced (sham control, 8 days; OK plus pUSHT, >20 days). IFNγ+ CD4 (treated tumor, 8.6-fold; untreated tumor, 4-fold), IFNγ+ CD8 (treated tumor, 6.7-fold; untreated tumor, 2.6-fold), and T cell and NK cell (treated tumor, 4-fold; untreated tumor, 2.5-fold) infiltration was increased in the combination group compared with the control group. In the rechallenged tumor model, new tumors failed to form with the combination treatment. CONCLUSION This experimental study combining pUSHT and OK-432 explored a new therapeutic strategy for controlling colon cancer metastasis. The results show that the combination treatment may produce an effective antitumor immune response.
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Iwai T, Oebisu N, Hoshi M, Orita K, Yamamoto A, Hamamoto S, Kageyama K, Nakamura H. Promising abscopal effect of combination therapy with thermal tumour ablation and intratumoural OK-432 injection in the rat osteosarcoma model. Sci Rep 2020; 10:9679. [PMID: 32541941 PMCID: PMC7296025 DOI: 10.1038/s41598-020-66934-6] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Accepted: 06/01/2020] [Indexed: 02/06/2023] Open
Abstract
Treatment options for metastatic osteosarcoma are limited. The present study aimed to evaluate whether radiofrequency ablation (RFA) combined with intratumoural OK-432 injection induces systemic anti-tumour immunity in rat osteosarcoma model. Eighty of 145 rats were assigned to four groups to evaluate overall survival and tumour size: control (no treatment), RFA-only, OK-432, and RFA-OK-432. The remaining 65 were assigned for histological examination. Maximum diameters of tibial and lung tumours were determined. Tumour samples were histologically examined using haematoxylin-eosin and immunohistochemical staining. Overall survival was significantly prolonged in the RFA-OK-432 group compared to the RFA-only and OK-432 groups. Only rats in the RFA-OK-432 group exhibited significant decreases in maximum tumour diameter after treatment. Ki-67-positive tumour cells in the RFA-OK-432 group were significantly stained negative on immunohistochemical analysis as opposed to those in the RFA-only and OK-432 groups. The number of CD11c+, OX-62+, CD4+, and CD8 + cells significantly increased in the RFA-OK-432 group compared to the RFA-only group. RFA with intratumoural OK-432 injection resulted in distant tumour suppression, prolonged survival, and increased dendritic cells, cytotoxic T cells, IFN-γ, and TNF-α, whereas RFA or OK-432 alone did not produce this effect. This combination may induce an abscopal effect in human osteosarcoma.
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Affiliation(s)
- Tadashi Iwai
- Department of Orthopedic Surgery, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-Machi, Abeno-Ku, Osaka, 545-8585, Japan.
| | - Naoto Oebisu
- Department of Orthopedic Surgery, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-Machi, Abeno-Ku, Osaka, 545-8585, Japan
| | - Manabu Hoshi
- Department of Orthopedic Surgery, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-Machi, Abeno-Ku, Osaka, 545-8585, Japan
| | - Kumi Orita
- Department of Orthopedic Surgery, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-Machi, Abeno-Ku, Osaka, 545-8585, Japan
| | - Akira Yamamoto
- Department of Radiology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-Machi, Abeno-Ku, Osaka, 545-8585, Japan
| | - Shinichi Hamamoto
- Department of Radiology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-Machi, Abeno-Ku, Osaka, 545-8585, Japan
| | - Ken Kageyama
- Department of Radiology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-Machi, Abeno-Ku, Osaka, 545-8585, Japan
| | - Hiroaki Nakamura
- Department of Orthopedic Surgery, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-Machi, Abeno-Ku, Osaka, 545-8585, Japan
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OK-432 Administration Inhibits Murine Allergic Rhinitis at the Induction Phase, through the Macrophage Activation with TLR2 Signaling Pathway. Med Sci (Basel) 2018; 6:medsci6040107. [PMID: 30486312 PMCID: PMC6313634 DOI: 10.3390/medsci6040107] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Revised: 11/05/2018] [Accepted: 11/05/2018] [Indexed: 11/16/2022] Open
Abstract
OK-432, a preparation of a low-virulence strain (Su) of Streptococcus pyogenes (Group A) killed by a penicillin and lyophilized, is a stiff inducer of Th1 cytokines, and exerts anti-cancer effects in tumor-bearing mice. OK-432 has been reported to consist of many bacterial components, such as peptidoglycan, M-protein, etc. However, it is yet to be ascertained which bacterial component induces T helper 1 (Th1) responses. For the last decade, Toll-like receptor (TLR) family proteins are well elucidated to play a role in recognizing bacterial components and inducing interleukin (IL)-12 from macrophages. Above all, peptidoglycan seems to be the agonist of TLR2 rather than the obverse. In our present study, the role of TLR2 for the recognition of OK-432 by macrophages and the effects of OK-432 are examined on murine allergic rhinitis model. Interestingly, results show IL-12 production by macrophages derived from TLR2 knock-out (ko) mice was significantly decreased, in comparison with that of macrophages derived from wild-type mice. Moreover, in TLR2 ko mice, no regulatory effect of OK-432 was observed on an allergic rhinitis model. These data indicate that TLR2 signaling is involved in regulating OK-432-induced anti-T helper 2 (Th2) immunity, and may offer a new prophylactic and therapeutic approach using OK-432 to downregulate allergic disorders, such as allergic rhinitis.
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Toll-like receptors in immunity and inflammatory diseases: Past, present, and future. Int Immunopharmacol 2018; 59:391-412. [PMID: 29730580 PMCID: PMC7106078 DOI: 10.1016/j.intimp.2018.03.002] [Citation(s) in RCA: 454] [Impact Index Per Article: 64.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2017] [Revised: 02/28/2018] [Accepted: 03/01/2018] [Indexed: 02/07/2023]
Abstract
The immune system is a very diverse system of the host that evolved during evolution to cope with various pathogens present in the vicinity of environmental surroundings inhabited by multicellular organisms ranging from achordates to chordates (including humans). For example, cells of immune system express various pattern recognition receptors (PRRs) that detect danger via recognizing specific pathogen-associated molecular patterns (PAMPs) and mount a specific immune response. Toll-like receptors (TLRs) are one of these PRRs expressed by various immune cells. However, they were first discovered in the Drosophila melanogaster (common fruit fly) as genes/proteins important in embryonic development and dorso-ventral body patterning/polarity. Till date, 13 different types of TLRs (TLR1-TLR13) have been discovered and described in mammals since the first discovery of TLR4 in humans in late 1997. This discovery of TLR4 in humans revolutionized the field of innate immunity and thus the immunology and host-pathogen interaction. Since then TLRs are found to be expressed on various immune cells and have been targeted for therapeutic drug development for various infectious and inflammatory diseases including cancer. Even, Single nucleotide polymorphisms (SNPs) among various TLR genes have been identified among the different human population and their association with susceptibility/resistance to certain infections and other inflammatory diseases. Thus, in the present review the current and future importance of TLRs in immunity, their pattern of expression among various immune cells along with TLR based therapeutic approach is reviewed.
TLRs are first described PRRs that revolutionized the biology of host-pathogen interaction and immune response The discovery of different TLRs in humans proved milestone in the field of innate immunity and inflammation The pattern of expression of all the TLRs expressed by human immune cells An association of various TLR SNPs with different inflammatory diseases Currently available drugs or vaccines based on TLRs and their future in drug targeting along with the role in reproduction, and regeneration
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Hasan HYA, Rizwan MA. Efficacy of OK-432 Therapy for the Incisionless Treatment of Head and Neck Cystic Masses: Case series. Sultan Qaboos Univ Med J 2018; 18:e88-e92. [PMID: 29666687 DOI: 10.18295/squmj.2018.18.01.014] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2017] [Revised: 11/26/2017] [Accepted: 12/21/2017] [Indexed: 11/16/2022] Open
Abstract
Head and neck masses can present in different pathologies that usually vary according to the age of the patient. We report five cases of benign head or neck masses occurring among patients of different ages who were managed at the Bahrain Defence Force Royal Medical Services Hospital, Ar-Rifaa, Bahrain, between 2005-2014. All of the patients were treated using the sclerotherapeutic agent OK-432. Although surgical removal is usually considered optimal treatment in the management of such cases, OK-432 appears to be a promising alternative.
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Affiliation(s)
- Hesham Y A Hasan
- Department of Otorhinolaryngology, Bahrain Defence Force Hospital, Ar-Rifaa, Bahrain
| | - Muhammad A Rizwan
- Department of Otorhinolaryngology, Bahrain Defence Force Hospital, Ar-Rifaa, Bahrain
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11
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Vu A, Calzadilla A, Gidfar S, Calderon-Candelario R, Mirsaeidi M. Toll-like receptors in mycobacterial infection. Eur J Pharmacol 2016; 808:1-7. [PMID: 27756604 DOI: 10.1016/j.ejphar.2016.10.018] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2016] [Revised: 10/04/2016] [Accepted: 10/14/2016] [Indexed: 10/20/2022]
Abstract
Toll-like receptors are transmembrane glycoproteins predominantly expressed in tissues with immune function. They are considered one of the most important pattern recognition receptor families discovered at the end of 20th century and a key aspect of the innate immune system response to infectious disease. Here we present a review of the current knowledge of individual Toll-like receptors, 1 through 13, with a focus on their role in the immune system response to mycobacterial infection. We present literature to date about the Toll-like receptors structure, localization and expression, signaling pathways, and function. The Toll-like receptor family may have proven an important role in the immune system response to mycobacterial infections, including M. tuberculosis and non-tuberculous (NTM) organisms.
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Affiliation(s)
- Ann Vu
- Department of Medicine, University of Miami, 1600 NW, Miami, FL 33136, USA.
| | - Andrew Calzadilla
- Department of Medicine, University of Miami, 1600 NW, Miami, FL 33136, USA.
| | - Sanaz Gidfar
- Department of Medicine, University of Miami, 1600 NW, Miami, FL 33136, USA.
| | - Rafael Calderon-Candelario
- Division of Pulmonary and Critical Care, University of Miami, 1600 NW, Miami, FL 33136, USA; Miami VA Medical Center, 1201 N.W. 16th St., Miami, FL 33125, USA.
| | - Mehdi Mirsaeidi
- Division of Pulmonary and Critical Care, University of Miami, 1600 NW, Miami, FL 33136, USA; Miami VA Medical Center, 1201 N.W. 16th St., Miami, FL 33125, USA.
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12
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Iwasaki Y, Takamori S, Mitsuoka M, Kashihara M, Nishi T, Murakami D, Matsumoto R, Mifune H, Tajiri Y, Akagi Y. Experimental validation of talc pleurodesis for carcinomatous pleuritis in an animal model. Gen Thorac Cardiovasc Surg 2016; 64:409-13. [PMID: 27169846 DOI: 10.1007/s11748-016-0653-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2016] [Accepted: 04/26/2016] [Indexed: 01/17/2023]
Abstract
OBJECTIVE This study was performed to evaluate the change of pleural cavity by talc pleurodesis for carcinomatous pleuritis in an animal model. METHODS Models of malignant pleuritis were produced by an intra-venous injection of lung adenocarcinoma cells to male BALB/c nude mice at 6 weeks of age. Two weeks after the injection, either talc or saline was injected into the left thoracic cavity and the mice were further observed for 4 weeks. Six weeks after the injection, they were killed and the occurrence of lung cancer, amount of pleural effusion, and histological change of the pleural cavity were examined and compared between the two groups with or without talc administration. RESULTS Talc administration caused a significant reduction in pleural effusion with no increase of pleural adhesion. Talc administration resulted in marked pleural thickening compared to saline treatment. The vascular architecture and its area did not differ between the two groups. CONCLUSION Talc pleurodesis to reduce pleural effusion is valid for carcinomatous pleuritis, potentially through an acceleration of pleural thickening.
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Affiliation(s)
- Yasunori Iwasaki
- Department of Surgery, Kurume University School of Medicine, 67 Asahi-machi, Kurume, 830-0011, Japan
| | - Shinzo Takamori
- Department of Surgery, Kurume University School of Medicine, 67 Asahi-machi, Kurume, 830-0011, Japan.
| | - Masahiro Mitsuoka
- Department of Surgery, Kurume University School of Medicine, 67 Asahi-machi, Kurume, 830-0011, Japan
| | - Masaki Kashihara
- Department of Surgery, Kurume University School of Medicine, 67 Asahi-machi, Kurume, 830-0011, Japan
| | - Tatsuya Nishi
- Department of Surgery, Kurume University School of Medicine, 67 Asahi-machi, Kurume, 830-0011, Japan
| | - Daigo Murakami
- Department of Surgery, Kurume University School of Medicine, 67 Asahi-machi, Kurume, 830-0011, Japan
| | - Ryoichi Matsumoto
- Department of Surgery, Kurume University School of Medicine, 67 Asahi-machi, Kurume, 830-0011, Japan
| | - Hiroharu Mifune
- Institute of Animal Experimentation, Kurume University School of Medicine, 67 Asahi-machi, Kurume, 830-0011, Japan
| | - Yuji Tajiri
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume, 830-0011, Japan
| | - Yoshito Akagi
- Department of Surgery, Kurume University School of Medicine, 67 Asahi-machi, Kurume, 830-0011, Japan
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13
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Kenjo A, Sato T, Marubashi S, Saito T, Tsuchiya T, Kimura T, Sato N, Takahashi A, Ohira H, Gotoh M. Role of intratumoral infiltrating macrophages after transarterial immunoembolization for hepatocellular carcinoma. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2016; 23:298-304. [DOI: 10.1002/jhbp.342] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/18/2016] [Accepted: 03/01/2016] [Indexed: 01/13/2023]
Affiliation(s)
- Akira Kenjo
- Department of Regenerative Surgery; Fukushima Medical University, 1 Hikariga-oka; Fukushima 960-1295 Japan
| | - Tetsu Sato
- Department of Regenerative Surgery; Fukushima Medical University, 1 Hikariga-oka; Fukushima 960-1295 Japan
| | - Shigeru Marubashi
- Department of Regenerative Surgery; Fukushima Medical University, 1 Hikariga-oka; Fukushima 960-1295 Japan
| | - Takuro Saito
- Department of Regenerative Surgery; Fukushima Medical University, 1 Hikariga-oka; Fukushima 960-1295 Japan
| | - Takao Tsuchiya
- Department of Regenerative Surgery; Fukushima Medical University, 1 Hikariga-oka; Fukushima 960-1295 Japan
| | - Takashi Kimura
- Department of Regenerative Surgery; Fukushima Medical University, 1 Hikariga-oka; Fukushima 960-1295 Japan
| | - Naoya Sato
- Department of Regenerative Surgery; Fukushima Medical University, 1 Hikariga-oka; Fukushima 960-1295 Japan
| | - Atsushi Takahashi
- Department of Gastroenterology; Fukushima Medical University; Fukushima Japan
| | - Hiromasa Ohira
- Department of Gastroenterology; Fukushima Medical University; Fukushima Japan
| | - Mitsukazu Gotoh
- Department of Regenerative Surgery; Fukushima Medical University, 1 Hikariga-oka; Fukushima 960-1295 Japan
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14
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Oba MS, Teramukai S, Ohashi Y, Ogawa K, Maehara Y, Sakamoto J. The efficacy of adjuvant immunochemotherapy with OK-432 after curative resection of gastric cancer: an individual patient data meta-analysis of randomized controlled trials. Gastric Cancer 2016; 19:616-624. [PMID: 25804300 DOI: 10.1007/s10120-015-0489-9] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2014] [Accepted: 03/13/2015] [Indexed: 02/07/2023]
Abstract
BACKGROUND OK-432 has been used as a cancer treatment for 40 years, and the immunostimulatory effects of OK-432 therapy have been intensely investigated in Japan. Recently, it has received attention as a possible booster for cancer vaccine treatments. Our previous meta-analysis based on summary measures revealed a significant improvement in the survival of patients with curatively resected gastric cancer. However, it is impossible to exclude the possibility of bias due to several prognostic factors. METHODS We collected individual data for patients with stage III or stage IV gastric cancer after curative resection from 14 trials that were identified in a previous meta-analysis. Immunochemotherapy with OK-432 was compared with treatment with standard chemotherapy on an intention-to-treat basis. The primary end point was overall survival. Stratified survival analyses were performed with the trial as the stratification factor. Subgroup analyses were also performed according to the potential prognostic factors, which included pathological factors, splenectomy, and delayed-type hypersensitivity. RESULTS There were 796 and 726 patients in the OK-432 and control groups, respectively. The median overall survival was 42.6 months for the OK-432 group and 32.3 months for the control group. The overall hazard ratio was 0.88 (95 % confidence interval 0.77-1.00, p = 0.050). No factor showed a statistically significant interaction in the subgroup analyses. CONCLUSIONS The results suggest that immunochemotherapy treatment with OK-432 could have a borderline significant effect for patients with stage III or stage IV gastric cancer after curative resection.
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Affiliation(s)
- Mari S Oba
- Department of Biostatistics and Epidemiology, Yokohama City University, Yokohama, Japan. .,, 4-57 Urafune-cho, Minami-ku, Yokohama, 232-0024, Japan.
| | - Satoshi Teramukai
- Department of Biostatistics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Yasuo Ohashi
- Department of Integrated Science and Engineering for Sustainable Society, Chuo University, Tokyo, Japan
| | - Kenji Ogawa
- Department of Surgery, Tokyo Women's Medical University Medical Center East, Tokyo, Japan
| | - Yoshihiko Maehara
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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15
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Okamoto M, Kobayashi M, Yonemitsu Y, Koido S, Homma S. Dendritic cell-based vaccine for pancreatic cancer in Japan. World J Gastrointest Pharmacol Ther 2016; 7:133-138. [PMID: 26855819 PMCID: PMC4734946 DOI: 10.4292/wjgpt.v7.i1.133] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2015] [Revised: 08/28/2015] [Accepted: 11/17/2015] [Indexed: 02/06/2023] Open
Abstract
“Vaccell” is a dendritic cell (DC)-based cancer vaccine which has been established in Japan. The DCs play central roles in deciding the direction of host immune reactions as well as antigen presentation. We have demonstrated that DCs treated with a streptococcal immune adjuvant OK-432, produce interleukin-12, induce Th1-dominant state, and elicit anti-tumor effects, more powerful than those treated with the known DC-maturating factors. We therefore decided to mature DCs by the OK-432 for making an effective DC vaccine, Vaccell. The 255 patients with inoperable pancreatic cancer who received standard chemotherapy combined with DC vaccines, were analyzed retrospectively. Survival time of the patients with positive delayed type hypersensitivity (DTH) skin reaction was significantly prolonged as compared with that of the patients with negative DTH. The findings strongly suggest that there may be “Responders” for the DC vaccine in advanced pancreatic cancer patients. We next conducted a small-scale prospective clinical study. In this trial, we pulsed HLA class II-restricted WT1 peptide (WT1-II) in addition to HLA class I-restricted peptide (WT1-I) into the DCs. Survival of the patients received WT1-I and -II pulsed DC vaccine was significantly extended as compared to that of the patients received DCs pulsed with WT1-I or WT1-II alone. Furthermore, WT1-specific DTH positive patients showed significantly improved the overall survival as well as progression-free survival as compared to the DTH negative patients. The activation of antigen-specific immune responses by DC vaccine in combination with standard chemotherapy may be associated with a good clinical outcome in advanced pancreatic cancer. We are now planning a pivotal study of the Vaccell in appropriate protocols in Japan.
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16
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Iribarren K, Bloy N, Buqué A, Cremer I, Eggermont A, Fridman WH, Fucikova J, Galon J, Špíšek R, Zitvogel L, Kroemer G, Galluzzi L. Trial Watch: Immunostimulation with Toll-like receptor agonists in cancer therapy. Oncoimmunology 2015; 5:e1088631. [PMID: 27141345 DOI: 10.1080/2162402x.2015.1088631] [Citation(s) in RCA: 99] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2015] [Accepted: 08/25/2015] [Indexed: 12/19/2022] Open
Abstract
Accumulating preclinical evidence indicates that Toll-like receptor (TLR) agonists efficiently boost tumor-targeting immune responses (re)initiated by most, if not all, paradigms of anticancer immunotherapy. Moreover, TLR agonists have been successfully employed to ameliorate the efficacy of various chemotherapeutics and targeted anticancer agents, at least in rodent tumor models. So far, only three TLR agonists have been approved by regulatory agencies for use in cancer patients. Moreover, over the past decade, the interest of scientists and clinicians in these immunostimulatory agents has been fluctuating. Here, we summarize recent advances in the preclinical and clinical development of TLR agonists for cancer therapy.
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Affiliation(s)
- Kristina Iribarren
- INSERM, U1138, Paris, France; Equipe 13, Center de Recherche des Cordeliers, Paris, France; Université Pierre et Marie Curie/Paris VI, Paris, France
| | - Norma Bloy
- INSERM, U1138, Paris, France; Gustave Roussy Cancer Campus, Villejuif, France; Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Center de Recherche des Cordeliers, Paris, France
| | - Aitziber Buqué
- INSERM, U1138, Paris, France; Gustave Roussy Cancer Campus, Villejuif, France; Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Center de Recherche des Cordeliers, Paris, France
| | - Isabelle Cremer
- INSERM, U1138, Paris, France; Equipe 13, Center de Recherche des Cordeliers, Paris, France; Université Pierre et Marie Curie/Paris VI, Paris, France
| | | | - Wolf Hervé Fridman
- INSERM, U1138, Paris, France; Equipe 13, Center de Recherche des Cordeliers, Paris, France; Université Pierre et Marie Curie/Paris VI, Paris, France
| | - Jitka Fucikova
- Sotio, Prague, Czech Republic; Dept. of Immunology, 2nd Faculty of Medicine and University Hospital Motol, Charles University, Prague, Czech Republic
| | - Jérôme Galon
- INSERM, U1138, Paris, France; Université Pierre et Marie Curie/Paris VI, Paris, France; Laboratory of Integrative Cancer Immunology, Center de Recherche des Cordeliers, Paris, France; Université Paris Descartes/Paris V, Sorbonne Paris Cité, Paris, France
| | - Radek Špíšek
- Sotio, Prague, Czech Republic; Dept. of Immunology, 2nd Faculty of Medicine and University Hospital Motol, Charles University, Prague, Czech Republic
| | - Laurence Zitvogel
- Gustave Roussy Cancer Campus, Villejuif, France; INSERM, U1015, CICBT507, Villejuif, France
| | - Guido Kroemer
- INSERM, U1138, Paris, France; Université Pierre et Marie Curie/Paris VI, Paris, France; Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Center de Recherche des Cordeliers, Paris, France; Université Paris Descartes/Paris V, Sorbonne Paris Cité, Paris, France; Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France; Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France; Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden
| | - Lorenzo Galluzzi
- INSERM, U1138, Paris, France; Université Pierre et Marie Curie/Paris VI, Paris, France; Gustave Roussy Cancer Campus, Villejuif, France; Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Center de Recherche des Cordeliers, Paris, France; Université Paris Descartes/Paris V, Sorbonne Paris Cité, Paris, France
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17
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Harnessing the Microbiome to Enhance Cancer Immunotherapy. J Immunol Res 2015; 2015:368736. [PMID: 26101781 PMCID: PMC4458560 DOI: 10.1155/2015/368736] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2015] [Accepted: 05/10/2015] [Indexed: 12/20/2022] Open
Abstract
The microbiota plays a key role in regulating the innate and adaptive immune system. Herein, we review the immunological aspects of the microbiota in tumor immunity in mice and man, with a focus on toll-like receptor (TLR) agonists, vaccines, checkpoint modulators, chemotherapy, and adoptive T cell transfer (ACT) therapies. We propose innovative treatments that may safely harness the microbiota to enhance T cell-based therapies in cancer patients. Finally, we highlight recent developments in tumor immunotherapy, particularly novel ways to modulate the microbiome and memory T cell responses to human malignancies.
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18
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Yang Y, Chen Y, Qu J, Zhang X, Pan Y. The use of OK-432 to prevent seroma in extended latissimus dorsi flap donor site after breast reconstruction. J Surg Res 2015; 193:492-6. [DOI: 10.1016/j.jss.2014.08.010] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2014] [Revised: 06/17/2014] [Accepted: 08/05/2014] [Indexed: 11/29/2022]
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19
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Galluzzi L, Vacchelli E, Pedro JMBS, Buqué A, Senovilla L, Baracco EE, Bloy N, Castoldi F, Abastado JP, Agostinis P, Apte RN, Aranda F, Ayyoub M, Beckhove P, Blay JY, Bracci L, Caignard A, Castelli C, Cavallo F, Celis E, Cerundolo V, Clayton A, Colombo MP, Coussens L, Dhodapkar MV, Eggermont AM, Fearon DT, Fridman WH, Fučíková J, Gabrilovich DI, Galon J, Garg A, Ghiringhelli F, Giaccone G, Gilboa E, Gnjatic S, Hoos A, Hosmalin A, Jäger D, Kalinski P, Kärre K, Kepp O, Kiessling R, Kirkwood JM, Klein E, Knuth A, Lewis CE, Liblau R, Lotze MT, Lugli E, Mach JP, Mattei F, Mavilio D, Melero I, Melief CJ, Mittendorf EA, Moretta L, Odunsi A, Okada H, Palucka AK, Peter ME, Pienta KJ, Porgador A, Prendergast GC, Rabinovich GA, Restifo NP, Rizvi N, Sautès-Fridman C, Schreiber H, Seliger B, Shiku H, Silva-Santos B, Smyth MJ, Speiser DE, Spisek R, Srivastava PK, Talmadge JE, Tartour E, Van Der Burg SH, Van Den Eynde BJ, Vile R, Wagner H, Weber JS, Whiteside TL, Wolchok JD, Zitvogel L, Zou W, Kroemer G. Classification of current anticancer immunotherapies. Oncotarget 2014; 5:12472-508. [PMID: 25537519 PMCID: PMC4350348 DOI: 10.18632/oncotarget.2998] [Citation(s) in RCA: 339] [Impact Index Per Article: 30.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2014] [Accepted: 12/15/2014] [Indexed: 11/25/2022] Open
Abstract
During the past decades, anticancer immunotherapy has evolved from a promising therapeutic option to a robust clinical reality. Many immunotherapeutic regimens are now approved by the US Food and Drug Administration and the European Medicines Agency for use in cancer patients, and many others are being investigated as standalone therapeutic interventions or combined with conventional treatments in clinical studies. Immunotherapies may be subdivided into "passive" and "active" based on their ability to engage the host immune system against cancer. Since the anticancer activity of most passive immunotherapeutics (including tumor-targeting monoclonal antibodies) also relies on the host immune system, this classification does not properly reflect the complexity of the drug-host-tumor interaction. Alternatively, anticancer immunotherapeutics can be classified according to their antigen specificity. While some immunotherapies specifically target one (or a few) defined tumor-associated antigen(s), others operate in a relatively non-specific manner and boost natural or therapy-elicited anticancer immune responses of unknown and often broad specificity. Here, we propose a critical, integrated classification of anticancer immunotherapies and discuss the clinical relevance of these approaches.
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Affiliation(s)
- Lorenzo Galluzzi
- Equipe 11 labellisée pas la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France
- INSERM, U1138, Paris, France
- Gustave Roussy Cancer Campus, Villejuif, France
- Université Paris Descartes/Paris V, Sorbonne Paris Cité, Paris, France
| | - Erika Vacchelli
- Equipe 11 labellisée pas la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France
- INSERM, U1138, Paris, France
- Gustave Roussy Cancer Campus, Villejuif, France
| | - José-Manuel Bravo-San Pedro
- Equipe 11 labellisée pas la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France
- INSERM, U1138, Paris, France
- Gustave Roussy Cancer Campus, Villejuif, France
| | - Aitziber Buqué
- Equipe 11 labellisée pas la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France
- INSERM, U1138, Paris, France
- Gustave Roussy Cancer Campus, Villejuif, France
| | - Laura Senovilla
- Equipe 11 labellisée pas la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France
- INSERM, U1138, Paris, France
- Gustave Roussy Cancer Campus, Villejuif, France
| | - Elisa Elena Baracco
- Equipe 11 labellisée pas la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France
- INSERM, U1138, Paris, France
- Gustave Roussy Cancer Campus, Villejuif, France
- Faculté de Medicine, Université Paris Sud/Paris XI, Le Kremlin-Bicêtre, France
| | - Norma Bloy
- Equipe 11 labellisée pas la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France
- INSERM, U1138, Paris, France
- Gustave Roussy Cancer Campus, Villejuif, France
- Faculté de Medicine, Université Paris Sud/Paris XI, Le Kremlin-Bicêtre, France
| | - Francesca Castoldi
- Equipe 11 labellisée pas la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France
- INSERM, U1138, Paris, France
- Gustave Roussy Cancer Campus, Villejuif, France
- Faculté de Medicine, Université Paris Sud/Paris XI, Le Kremlin-Bicêtre, France
- Sotio a.c., Prague, Czech Republic
| | - Jean-Pierre Abastado
- Pole d'innovation thérapeutique en oncologie, Institut de Recherches Internationales Servier, Suresnes, France
| | - Patrizia Agostinis
- Cell Death Research and Therapy (CDRT) Laboratory, Dept. of Cellular and Molecular Medicine, University of Leuven, Leuven, Belgium
| | - Ron N. Apte
- The Shraga Segal Dept. of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Fernando Aranda
- Equipe 11 labellisée pas la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France
- INSERM, U1138, Paris, France
- Gustave Roussy Cancer Campus, Villejuif, France
- Group of Immune receptors of the Innate and Adaptive System, Institut d'Investigacions Biomédiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Maha Ayyoub
- INSERM, U1102, Saint Herblain, France
- Institut de Cancérologie de l'Ouest, Saint Herblain, France
| | - Philipp Beckhove
- Translational Immunology Division, German Cancer Research Center, Heidelberg, Germany
| | - Jean-Yves Blay
- Equipe 11, Centre Léon Bérard (CLR), Lyon, France
- Centre de Recherche en Cancérologie de Lyon (CRCL), Lyon, France
| | - Laura Bracci
- Dept. of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Anne Caignard
- INSERM, U1160, Paris, France
- Groupe Hospitalier Saint Louis-Lariboisière - F. Vidal, Paris, France
| | - Chiara Castelli
- Unit of Immunotherapy of Human Tumors, Dept. of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy
| | - Federica Cavallo
- Molecular Biotechnology Center, Dept. of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy
| | - Estaban Celis
- Cancer Immunology, Inflammation and Tolerance Program, Georgia Regents University Cancer Center, Augusta, GA, USA
| | - Vincenzo Cerundolo
- MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
| | - Aled Clayton
- Institute of Cancer & Genetics, School of Medicine, Cardiff University, Cardiff, UK
- Velindre Cancer Centre, Cardiff, UK
| | - Mario P. Colombo
- Unit of Immunotherapy of Human Tumors, Dept. of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy
| | - Lisa Coussens
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA
| | - Madhav V. Dhodapkar
- Sect. of Hematology and Immunobiology, Yale Cancer Center, Yale University, New Haven, CT, USA
| | | | | | - Wolf H. Fridman
- INSERM, U1138, Paris, France
- Université Paris Descartes/Paris V, Sorbonne Paris Cité, Paris, France
- Université Pierre et Marie Curie/Paris VI, Paris, France
- Equipe 13, Centre de Recherche des Cordeliers, Paris, France
| | - Jitka Fučíková
- Sotio a.c., Prague, Czech Republic
- Dept. of Immunology, 2nd Faculty of Medicine and University Hospital Motol, Charles University, Prague, Czech Republic
| | - Dmitry I. Gabrilovich
- Dept. of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Jérôme Galon
- INSERM, U1138, Paris, France
- Université Paris Descartes/Paris V, Sorbonne Paris Cité, Paris, France
- Université Pierre et Marie Curie/Paris VI, Paris, France
- Laboratory of Integrative Cancer Immunology, Centre de Recherche des Cordeliers, Paris, France
| | - Abhishek Garg
- Cell Death Research and Therapy (CDRT) Laboratory, Dept. of Cellular and Molecular Medicine, University of Leuven, Leuven, Belgium
| | - François Ghiringhelli
- INSERM, UMR866, Dijon, France
- Centre Georges François Leclerc, Dijon, France
- Université de Bourgogne, Dijon, France
| | - Giuseppe Giaccone
- Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, USA
- Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA
| | - Eli Gilboa
- Dept. of Microbiology and Immunology, Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, FL, USA
| | - Sacha Gnjatic
- Sect. of Hematology/Oncology, Immunology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Axel Hoos
- Glaxo Smith Kline, Cancer Immunotherapy Consortium, Collegeville, PA, USA
| | - Anne Hosmalin
- Université Paris Descartes/Paris V, Sorbonne Paris Cité, Paris, France
- INSERM, U1016, Paris, France
- CNRS, UMR8104, Paris, France
- Hôpital Cochin, AP-HP, Paris, France
| | - Dirk Jäger
- National Center for Tumor Diseases, University Medical Center Heidelberg, Heidelberg, Germany
| | - Pawel Kalinski
- Dept. of Surgery, University of Pittsburgh, Pittsburgh, PA, USA
- University of Pittsburgh Cancer Institute, Hillman Cancer Center, Pittsburgh, PA, USA
- Dept. of Immunology and Infectious Diseases and Microbiology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Klas Kärre
- Dept. of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden
| | - Oliver Kepp
- Equipe 11 labellisée pas la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France
- INSERM, U1138, Paris, France
- Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France
| | - Rolf Kiessling
- Dept. of Oncology, Karolinska Institute Hospital, Stockholm, Sweden
| | - John M. Kirkwood
- University of Pittsburgh Cancer Institute Laboratory, Pittsburgh, PA, USA
| | - Eva Klein
- Dept. of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden
| | - Alexander Knuth
- National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar
| | - Claire E. Lewis
- Academic Unit of Inflammation and Tumour Targeting, Dept. of Oncology, University of Sheffield Medical School, Sheffield, UK
| | - Roland Liblau
- INSERM, UMR1043, Toulouse, France
- CNRS, UMR5282, Toulouse, France
- Laboratoire d'Immunologie, CHU Toulouse, Université Toulouse II, Toulouse, France
| | - Michael T. Lotze
- Dept. of Surgery, University of Pittsburgh, Pittsburgh, PA, USA
- University of Pittsburgh Cancer Institute, Hillman Cancer Center, Pittsburgh, PA, USA
| | - Enrico Lugli
- Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Institute, Rozzano, Italy
| | - Jean-Pierre Mach
- Dept. of Biochemistry, University of Lausanne, Epalinges, Switzerland
| | - Fabrizio Mattei
- Dept. of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Domenico Mavilio
- Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Institute, Rozzano, Italy
- Dept. of Medical Biotechnologies and Translational Medicine, University of Milan, Rozzano, Italy
| | - Ignacio Melero
- Dept. of Immunology, Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Pamplona, Spain
- Dept. of Oncology, Clínica Universidad de Navarra, Pamplona, Spain
| | - Cornelis J. Melief
- ISA Therapeutics, Leiden, The Netherlands
- Dept. of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands
| | - Elizabeth A. Mittendorf
- Research Dept. of Surgical Oncology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | | | - Adekunke Odunsi
- Center for Immunotherapy, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Hideho Okada
- Dept. of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA
| | | | - Marcus E. Peter
- Div. of Hematology/Oncology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA
| | - Kenneth J. Pienta
- The James Buchanan Brady Urological Institute, The Johns Hopkins Medical Institutions, Baltimore, MD, USA
| | - Angel Porgador
- The Shraga Segal Dept. of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - George C. Prendergast
- Lankenau Institute for Medical Research, Wynnewood, PA, USA
- Dept. of Pathology, Anatomy and Cell Biology, Sidney Kimmel Medical College, Philadelphia, PA, USA
- Cell Biology and Signaling Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
| | - Gabriel A. Rabinovich
- Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental (IBYME), Buenos Aires, Argentina
| | - Nicholas P. Restifo
- National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, USA
| | - Naiyer Rizvi
- Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY, USA
| | - Catherine Sautès-Fridman
- INSERM, U1138, Paris, France
- Université Paris Descartes/Paris V, Sorbonne Paris Cité, Paris, France
- Université Pierre et Marie Curie/Paris VI, Paris, France
- Equipe 13, Centre de Recherche des Cordeliers, Paris, France
| | - Hans Schreiber
- Dept. of Pathology, The Cancer Research Center, The University of Chicago, Chicago, IL, USA
| | - Barbara Seliger
- Institute of Medical Immunology, Martin Luther University Halle-Wittenberg, Halle, Germany
| | - Hiroshi Shiku
- Dept. of Immuno-GeneTherapy, Mie University Graduate School of Medicine, Tsu, Japan
| | - Bruno Silva-Santos
- Instituto de Medicina Molecular, Universidade de Lisboa, Lisboa, Portugal
| | - Mark J. Smyth
- Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
- School of Medicine, University of Queensland, Herston, Queensland, Australia
| | - Daniel E. Speiser
- Dept. of Oncology, University of Lausanne, Lausanne, Switzerland
- Ludwig Cancer Research Center, Lausanne, Switzerland
| | - Radek Spisek
- Sotio a.c., Prague, Czech Republic
- Dept. of Immunology, 2nd Faculty of Medicine and University Hospital Motol, Charles University, Prague, Czech Republic
| | - Pramod K. Srivastava
- Dept. of Immunology, University of Connecticut School of Medicine, Farmington, CT, USA
- Carole and Ray Neag Comprehensive Cancer Center, Farmington, CT, USA
| | - James E. Talmadge
- Laboratory of Transplantation Immunology, Dept. of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Eric Tartour
- Université Paris Descartes/Paris V, Sorbonne Paris Cité, Paris, France
- INSERM, U970, Paris, France
- Paris-Cardiovascular Research Center (PARCC), Paris, France
- Service d'Immunologie Biologique, Hôpital Européen Georges Pompidou (HEGP), AP-HP, Paris, France
| | | | - Benoît J. Van Den Eynde
- Ludwig Institute for Cancer Research, Brussels, Belgium
- de Duve Institute, Brussels, Belgium
- Université Catholique de Louvain, Brussels, Belgium
| | - Richard Vile
- Dept. of Molecular Medicine and Immunology, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Hermann Wagner
- Institute of Medical Microbiology, Immunology and Hygiene, Technical University Munich, Munich, Germany
| | - Jeffrey S. Weber
- Donald A. Adam Comprehensive Melanoma Research Center, Moffitt Cancer Center, Tampa, FL, USA
| | - Theresa L. Whiteside
- University of Pittsburgh Cancer Institute, Hillman Cancer Center, Pittsburgh, PA, USA
- University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Jedd D. Wolchok
- Dept. of Medicine and Ludwig Center, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY, USA
- Weill Cornell Medical College, New York, NY, USA
| | - Laurence Zitvogel
- Gustave Roussy Cancer Campus, Villejuif, France
- INSERM, U1015, Villejuif, France
- Centre d'Investigation Clinique Biothérapie 507 (CICBT507), Gustave Roussy Cancer Campus, Villejuif, France
| | - Weiping Zou
- University of Michigan, School of Medicine, Ann Arbor, MI, USA
| | - Guido Kroemer
- Equipe 11 labellisée pas la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France
- INSERM, U1138, Paris, France
- Université Paris Descartes/Paris V, Sorbonne Paris Cité, Paris, France
- Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France
- Pôle de Biologie, Hôpital Européen Georges Pompidou (HEGP), AP-HP, Paris, France
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Abstract
Toll-like receptors (TLRs) have generated an extraordinary amount of interest in cancer research since the last decade. TLRs are a family of pattern recognition receptors that is involved in the host defense against microbial infections. It is well known that the activation of TLRs leads to the production of biological factors that drive inflammatory responses and activate the adaptive immune system. More recently, TLR-mediated signaling pathways have been shown to support tumor cell growth in vitro and in vivo. In this review, we describe recently emerged links between TLR4 and breast cancer oncogenesis, and future perspectives for the targeting of TLR4 in breast cancer therapy.
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Affiliation(s)
- Abubakr Ahmed
- Department of Academic Surgery; University College Cork (UCC); Cork University Hospital; Cork, Ireland
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21
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Aranda F, Vacchelli E, Obrist F, Eggermont A, Galon J, Sautès-Fridman C, Cremer I, Henrik ter Meulen J, Zitvogel L, Kroemer G, Galluzzi L. Trial Watch: Toll-like receptor agonists in oncological indications. Oncoimmunology 2014; 3:e29179. [PMID: 25083332 PMCID: PMC4091055 DOI: 10.4161/onci.29179] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2014] [Accepted: 05/09/2014] [Indexed: 12/20/2022] Open
Abstract
Toll-like receptors (TLRs) are an evolutionarily conserved group of enzymatically inactive, single membrane-spanning proteins that recognize a wide panel of exogenous and endogenous danger signals. Besides constituting a crucial component of the innate immune response to bacterial and viral pathogens, TLRs appear to play a major role in anticancer immunosurveillance. In line with this notion, several natural and synthetic TLR ligands have been intensively investigated for their ability to boost tumor-targeting immune responses elicited by a variety of immunotherapeutic and chemotherapeutic interventions. Three of these agents are currently approved by the US Food and Drug Administration (FDA) or equivalent regulatory agencies for use in cancer patients: the so-called bacillus Calmette-Guérin, monophosphoryl lipid A, and imiquimod. However, the number of clinical trials testing the therapeutic potential of both FDA-approved and experimental TLR agonists in cancer patients is stably decreasing, suggesting that drug developers and oncologists are refocusing their interest on alternative immunostimulatory agents. Here, we summarize recent findings on the use of TLR agonists in cancer patients and discuss how the clinical evaluation of FDA-approved and experimental TLR ligands has evolved since the publication of our first Trial Watch dealing with this topic.
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Affiliation(s)
- Fernando Aranda
- Gustave Roussy; Villejuif, France
- INSERM, UMRS1138; Paris, France
- Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers; Paris, France
- Université Paris-Sud/Paris XI; Paris, France
| | - Erika Vacchelli
- Gustave Roussy; Villejuif, France
- INSERM, UMRS1138; Paris, France
- Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers; Paris, France
- Université Paris-Sud/Paris XI; Paris, France
| | - Florine Obrist
- Gustave Roussy; Villejuif, France
- INSERM, UMRS1138; Paris, France
- Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers; Paris, France
- Université Paris-Sud/Paris XI; Paris, France
| | | | - Jérôme Galon
- INSERM, UMRS1138; Paris, France
- Université Paris Descartes/Paris V, Sorbonne Paris Cité; Paris, France
- Laboratory of Integrative Cancer Immunology, Centre de Recherche des Cordeliers; Paris, France
| | - Catherine Sautès-Fridman
- INSERM, UMRS1138; Paris, France
- Université Paris Descartes/Paris V, Sorbonne Paris Cité; Paris, France
- Université Pierre et Marie Curie/Paris VI; Paris, France
- Equipe 13, Centre de Recherche des Cordeliers; Paris, France
| | - Isabelle Cremer
- INSERM, UMRS1138; Paris, France
- Université Paris Descartes/Paris V, Sorbonne Paris Cité; Paris, France
- Université Pierre et Marie Curie/Paris VI; Paris, France
- Equipe 13, Centre de Recherche des Cordeliers; Paris, France
| | | | - Laurence Zitvogel
- Gustave Roussy; Villejuif, France
- INSERM, U1015; CICBT507; Villejuif, France
| | - Guido Kroemer
- INSERM, UMRS1138; Paris, France
- Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers; Paris, France
- Université Paris Descartes/Paris V, Sorbonne Paris Cité; Paris, France
- Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP; Villejuif, France
- Metabolomics and Cell Biology Platforms, Gustave Roussy; Villejuif, France
| | - Lorenzo Galluzzi
- Gustave Roussy; Villejuif, France
- Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers; Paris, France
- Université Paris Descartes/Paris V, Sorbonne Paris Cité; Paris, France
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Taniguchi T, Motomura H, Ohba N, Harada T, Muraoka M, Ishii M. Clinical Results of OK-432 Injection Therapy for Ganglions. J Dermatol 2014; 32:262-5. [PMID: 15863847 DOI: 10.1111/j.1346-8138.2005.tb00759.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2004] [Accepted: 12/14/2004] [Indexed: 11/27/2022]
Abstract
We performed a study of intralesional OK-432 injection therapy for the non-surgical treatment of ganglions. OK-432 is an agent made from penicillin-killed and lyophilized preparations of a low-virulence strain of group A streptococcus pyogenes, which has been developed as an immune-augmentation agent for cancer therapy. Derived from an extract of bacterial culture it, induces an immunological response and causes local inflammation and subsequent tissue shrinkage following intralesional injection. After skin anesthesia and aspiration of the ganglion contents, OK-432 was injected into the ganglion cavity. When the ganglion recurred, this procedure was repeated usually up to a total of three times. Clinical evaluations six months after the last injection were: 56.6% complete cure, 35.3% incomplete cure with size reduced, 7.5% no change. Complications were as follows. There were no cases of shock. High fever was seen in five patients (9.4%); two patients suffered a high fever up to 39.0 degrees C for one day, and the others had fevers from 1 to 3 days. Thirty-two patients (60.4%) complained of local swelling that persisted for 1 to 7 days, and 11 (20.8%) complained of continuous pain for 1 to 3 days. Intralesional OK-432 injection therapy is thought to be a safe and convenient alternative to surgical treatment.
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Affiliation(s)
- Toshiko Taniguchi
- Department of Plastic and Reconstructive Surgery, Osaka City University Medical School, Osaka 545-8585, Japan
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Immunochemoradiotherapy for patients with oral squamous cell carcinoma: augmentation of OK-432-induced helper T cell 1 response by 5-FU and X-ray irradiation. Neoplasia 2014; 15:805-14. [PMID: 23814492 DOI: 10.1593/neo.13488] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2013] [Revised: 02/18/2013] [Accepted: 04/10/2013] [Indexed: 12/26/2022] Open
Abstract
Eighty-one patients with oral squamous cell carcinoma (OSCC) received oral fluoropyrimidine UFT and radiotherapy (RT) with or without an immunotherapeutic agent OK-432. Both overall survival and progression-free survival of patients who received RT + UFT + OK-432 were significantly longer than those of patients who received RT + UFT (P = .0075 and P = .0175, respectively). Clinical response was also more favorable in RT + UFT + OK-432 group than in RT + UFT group (P = .0066). Next, in vitro experiments were conducted to examine the effect of 5-fluorouracil (5-FU) and X-ray irradiation in OK-432-induced immunity. Human peripheral blood mononuclear cells stimulated with OK-432 produced helper T cell 1 (Th1)-type cytokines as well as interleukin-10 (IL-10) and transforming growth factor-β (TGF-β), which are produced by Th2 and regulatory T cells (Tregs), respectively, and are inhibitory in antitumor immunity. OK-432-induced IL-10 and TGF-β but not Th1 cytokines were significantly inhibited by 5-FU and/or X-ray. 5-FU and X-ray also inhibited the expression of mRNAs for GATA-3 and Foxp3, which are transcription factors for Th2 and Tregs, respectively, but not for T-bet, a transcription factor for Th1. In addition, 5-FU and X-ray decreased the expression of mRNAs for suppressor of cytokine signaling 1 (SOCS1) and SOCS3. Antisense oligonucleotides for SOCS1 and SOCS3 markedly reduced OK-432-induced IL-10 and TGF-β. This is the first report clearly demonstrating that OK-432-based immunotherapy significantly enhanced the therapeutic effects of chemoradiotherapy in patients with OSCC as well as elucidating the mechanism of the synergistic effect of immunochemoradiotherapy in which 5-FU and radiation enhanced OK-432-induced Th1 response mediated by the inhibition of SOCS1 and SOCS3 gene expression.
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Pan K, Lv L, Zheng HX, Zhao JJ, Pan QZ, Li JJ, Weng DS, Wang DD, Jiang SS, Chang AE, Li Q, Xia JC. OK-432 synergizes with IFN-γ to confer dendritic cells with enhanced antitumor immunity. Immunol Cell Biol 2013; 92:263-74. [PMID: 24296809 DOI: 10.1038/icb.2013.87] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2013] [Revised: 10/30/2013] [Accepted: 10/31/2013] [Indexed: 11/09/2022]
Abstract
Generation of functional dendritic cells (DCs) with boosted immunity after the withdrawal of initial activation/maturation conditions remains a significant challenge. In this study, we investigated the impact of a newly developed maturation cocktail consisting of OK-432 and interferon-gamma (IFN-γ) on the function of human monocyte-derived DCs (MoDCs). We found that OK-432 plus IFN-γ stimulation could induce significantly stronger expression of surface molecules, production of cytokines, as well as migration of DCs compared with OK-432 stimulation alone. Most importantly, DCs matured with OK-432 plus IFN-γ-induced maintained secretion of interleukin-12 (IL-12)p70 in secondary culture after stimulus withdrawal. Functionally, OK-432 plus IFN-γ-conditioned DCs induce remarkable Th1 and Tc1 responses more effectively than OK-432 alone, even more than the use of α-type-1 cytokine cocktail. As a result, DCs matured with OK-432 plus IFN-γ can prime stronger cytotoxic lymphocyte (CTL) and natural killer (NK) cell response against tumor cells in vitro. Peripheral blood mononuclear cells activated by DCs matured with OK-432 plus IFN-γ also showed greater tumor growth inhibition in vivo in null mice. Molecular mechanistic analysis showed that DC maturation using IFN-γ in concert with OK-432 involves the activation of p38 and nuclear factor-kappa B (NF-κB) pathways. This study provided a novel strategy to generate more potent immune segments in DC vaccine.
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Affiliation(s)
- Ke Pan
- State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Lin Lv
- 1] State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China [2] Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Hai-xia Zheng
- State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Jing-jing Zhao
- State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Qiu-zhong Pan
- State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Jian-jun Li
- State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - De-sheng Weng
- State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Dan-dan Wang
- State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Shan-shan Jiang
- State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Alfred E Chang
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Qiao Li
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Jian-chuan Xia
- State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
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Vacchelli E, Eggermont A, Sautès-Fridman C, Galon J, Zitvogel L, Kroemer G, Galluzzi L. Trial Watch: Toll-like receptor agonists for cancer therapy. Oncoimmunology 2013; 2:e25238. [PMID: 24083080 PMCID: PMC3782517 DOI: 10.4161/onci.25238] [Citation(s) in RCA: 120] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2013] [Accepted: 05/31/2013] [Indexed: 12/19/2022] Open
Abstract
Toll-like receptors (TLRs) have long been known for their ability to initiate innate immune responses upon exposure to conserved microbial components such as lipopolysaccharide (LPS) and double-stranded RNA. More recently, this family of pattern recognition receptors has been attributed a critical role in the elicitation of anticancer immune responses, raising interest in the development of immunochemotherapeutic regimens based on natural or synthetic TLR agonists. In spite of such an intense wave of preclinical and clinical investigation, only three TLR agonists are currently licensed by FDA for use in cancer patients: bacillus Calmette-Guérin (BCG), an attenuated strain of Mycobacterium bovis that operates as a mixed TLR2/TLR4 agonist; monophosphoryl lipid A (MPL), a derivative of Salmonella minnesota that functions as a potent agonist of TLR4; and imiquimod, a synthetic imidazoquinoline that activates TLR7. One year ago, in the August and September issues of OncoImmunology, we described the main biological features of TLRs and discussed the progress of clinical studies evaluating the safety and therapeutic potential of TLR agonists in cancer patients. Here, we summarize the latest developments in this exciting area of research, focusing on preclinical studies that have been published during the last 13 mo and clinical trials launched in the same period to investigate the antineoplastic activity of TLR agonists.
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Affiliation(s)
- Erika Vacchelli
- Institut Gustave Roussy; Villejuif, France
- Université Paris-Sud/Paris XI; Le Kremlin-Bicêtre; Paris, France
- INSERM, U848; Villejuif, France
| | | | - Catherine Sautès-Fridman
- Université Paris Descartes/Paris V; Sorbonne Paris Cité; Paris, France
- Equipe 13, Centre de Recherche des Cordeliers; Paris, France
- Pôle de Biologie, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris; Paris, France
| | - Jérôme Galon
- Université Paris Descartes/Paris V; Sorbonne Paris Cité; Paris, France
- Equipe 15, Centre de Recherche des Cordeliers; Paris, France
- INSERM, U872; Paris, France
- Université Pierre et Marie Curie/Paris VI; Paris, France
| | - Laurence Zitvogel
- Université Paris-Sud/Paris XI; Le Kremlin-Bicêtre; Paris, France
- INSERM, U1015; Villejuif, France
| | - Guido Kroemer
- INSERM, U848; Villejuif, France
- Université Paris Descartes/Paris V; Sorbonne Paris Cité; Paris, France
- Pôle de Biologie, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris; Paris, France
- Equipe 11 labelisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers; Paris, France
- Metabolomics and Cell Biology Platform; Institut Gustave Roussy; Villejuif, France
| | - Lorenzo Galluzzi
- Institut Gustave Roussy; Villejuif, France
- Université Paris Descartes/Paris V; Sorbonne Paris Cité; Paris, France
- Equipe 11 labelisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers; Paris, France
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Radiofrequency Ablation of Liver Tumors in Combination with Local OK-432 Injection Prolongs Survival and Suppresses Distant Tumor Growth in the Rabbit Model with Intra- and Extrahepatic VX2 Tumors. Cardiovasc Intervent Radiol 2013; 36:1383-92. [DOI: 10.1007/s00270-013-0650-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2012] [Accepted: 05/01/2013] [Indexed: 12/21/2022]
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27
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Ohe G, Sasai A, Uchida D, Tamatani T, Nagai H, Miyamoto Y. Effect of soluble factors derived from oral cancer cells on the production of interferon-γ from peripheral blood mononuclear cells following stimulation with OK-432. Oncol Rep 2013; 30:945-51. [PMID: 23685791 DOI: 10.3892/or.2013.2480] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2012] [Accepted: 03/14/2013] [Indexed: 11/05/2022] Open
Abstract
The streptococcal antitumor agent OK-432 is commonly used as an immunopotentiator for immunotherapy in various types of malignant tumors including oral cancer. It has been demonstrated that OK-432 elicits an antitumor effect by stimulating immunocompetent cells, thereby inducing multiple cytokines including interferon (IFN)-γ, interleukin (IL)-2 and IL-12. Serum concentrations of IFN-γ in patients with oral cancer were examined 24 h after administration of OK-432. Serum concentrations of IFN-γ in patients with advanced cancer were significantly lower than those in patients with early cancer. These results suggested that some soluble factors produced by cancer cells may inhibit IFN-γ production with OK-432. Thus, in the present study, an in vitro simulation model was established for the immune status of patients with oral cancer by adding conditioned medium (CM) derived from oral cancer cell lines into a culture of peripheral blood mononuclear cells (PBMCs) derived from a healthy volunteer. We investigated whether soluble factors derived from oral cancer cells affected IFN-γ production from PBMCs following stimulation with OK-432. PBMCs stimulated with OK-432 produced a large amount of IFN-γ; however, both IFN-γ production and cytotoxic activity from PBMCs induced by OK-432 were inhibited by the addition of CM in a dose-dependent manner. In order to examine these inhibitory effects against IFN-γ production, the contribution of inhibitory cytokines such as IL-4, IL-6, IL-10, transforming growth factor-β and vascular endothelial growth factor was investigated. However, neutralization of these inhibitory cytokines did not recover IFN-γ production inhibited by CM. These results indicated that unknown molecules may inhibit IFN-γ production from PBMCs following stimulation with OK-432.
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Affiliation(s)
- Go Ohe
- Department of Oral Surgery, Subdivision of Molecular Oral Medicine, Division of Integrated Sciences of Translational Research, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8504, Japan.
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Liu J, Liu X, Cui F, Chen G, Guan Y, He J. The efficacy of the inhalation of an aerosolized Group A streptococcal preparation in the treatment of lung cancer. Chin J Cancer Res 2013; 24:346-52. [PMID: 23359778 DOI: 10.3978/j.issn.1000-9604.2012.10.08] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2012] [Accepted: 10/09/2012] [Indexed: 01/17/2023] Open
Abstract
OBJECTIVE To observe the efficacy of the inhalation of an aerosolized group A streptococcal (GAS) preparation in treating orthotopic lung cancer in mouse models and assess the feasibility, safety, and effectiveness of this administration mode for lung cancer. METHODS Lewis lung carcinoma (LLC) cell strains were administered via intrathoracic injection to establish orthotopic lung cancer mouse models. After the tumor-bearing models were successfully established, as confirmed by computed tomography, the mice were administered by inhalation with an aerosolized GAS preparation (GAS group) or aerosolized normal saline (control group). The anti-tumor effect of the aerosolized GAS preparation was evaluated histologically; meanwhile, the survival and quality of life were compared between these two groups. RESULTS The aerosolized GAS preparation showed remarkably anti-tumor effect, causing the necrosis of the orthotopic lung cancer cells in tumor-bearing mice. Furthermore, mice in the GAS group had significantly better quality of life and longer survival than those in control group. CONCLUSIONS The inhalation of aerosolized GAS preparation may be a feasible, safe and effective solution for lung cancer.
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Affiliation(s)
- Jun Liu
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of Guangzhou Medical College, Guangzhou, China; ; Guangzhou Institute of Respiratory Disease & China State Key Laboratory of Respiratory Disease, Guangzhou, China
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Miwa S, Nishida H, Tanzawa Y, Takata M, Takeuchi A, Yamamoto N, Shirai T, Hayashi K, Kimura H, Igarashi K, Mizukoshi E, Nakamoto Y, Kaneko S, Tsuchiya H. TNF-α and tumor lysate promote the maturation of dendritic cells for immunotherapy for advanced malignant bone and soft tissue tumors. PLoS One 2012; 7:e52926. [PMID: 23300824 PMCID: PMC3533902 DOI: 10.1371/journal.pone.0052926] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2012] [Accepted: 11/22/2012] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Dendritic cells (DCs) play a pivotal role in the immune system. There are many reports concerning DC-based immunotherapy. The differentiation and maturation of DCs is a critical part of DC-based immunotherapy. We investigated the differentiation and maturation of DCs in response to various stimuli. METHODS Thirty-one patients with malignant bone and soft tissue tumors were enrolled in this study. All the patients had metastatic tumors and/or recurrent tumors. Peripheral blood mononuclear cells (PBMCs) were suspended in media containing interleukin-4 (IL-4) and granulocyte-macrophage colony stimulating factor (GM-CSF). These cells were then treated with or without 1) tumor lysate (TL), 2) TL + TNF-α, 3) OK-432. The generated DCs were mixed and injected in the inguinal or axillary region. Treatment courses were performed every week and repeated 6 times. A portion of the cells were analyzed by flow cytometry to determine the degree of differentiation and maturation of the DCs. Serum IFN-γ and serum IL-12 were measured in order to determine the immune response following the DC-based immunotherapy. RESULTS Approximately 50% of PBMCs differentiated into DCs. Maturation of the lysate-pulsed DCs was slightly increased. Maturation of the TL/TNF-α-pulsed DCs was increased, commensurate with OK-432-pulsed DCs. Serum IFN-γ and serum IL-12 showed significant elevation at one and three months after DC-based immunotherapy. CONCLUSIONS Although TL-pulsed DCs exhibit tumor specific immunity, TL-pulsed cells showed low levels of maturation. Conversely, the TL/TNF-α-pulsed DCs showed remarkable maturation. The combination of IL-4/GM-CSF/TL/TNF-α resulted in the greatest differentiation and maturation for DC-based immunotherapy for patients with bone and soft tissue tumors.
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Affiliation(s)
- Shinji Miwa
- Department of Orthopaedic Surgery, Kanazawa University School of Medicine, Kanazawa, Japan
| | - Hideji Nishida
- Department of Orthopaedic Surgery, Kanazawa University School of Medicine, Kanazawa, Japan
| | - Yoshikazu Tanzawa
- Department of Orthopaedic Surgery, Kanazawa University School of Medicine, Kanazawa, Japan
| | - Munetomo Takata
- Department of Orthopaedic Surgery, Kanazawa University School of Medicine, Kanazawa, Japan
| | - Akihiko Takeuchi
- Department of Orthopaedic Surgery, Kanazawa University School of Medicine, Kanazawa, Japan
| | - Norio Yamamoto
- Department of Orthopaedic Surgery, Kanazawa University School of Medicine, Kanazawa, Japan
| | - Toshiharu Shirai
- Department of Orthopaedic Surgery, Kanazawa University School of Medicine, Kanazawa, Japan
| | - Katsuhiro Hayashi
- Department of Orthopaedic Surgery, Kanazawa University School of Medicine, Kanazawa, Japan
| | - Hiroaki Kimura
- Department of Orthopaedic Surgery, Kanazawa University School of Medicine, Kanazawa, Japan
| | - Kentaro Igarashi
- Department of Orthopaedic Surgery, Kanazawa University School of Medicine, Kanazawa, Japan
| | - Eishiro Mizukoshi
- Department of Disease Control and Homeostasis, Kanazawa University School of Medicine, Kanazawa, Japan
| | - Yasunari Nakamoto
- Department of Disease Control and Homeostasis, Kanazawa University School of Medicine, Kanazawa, Japan
| | - Shuichi Kaneko
- Department of Disease Control and Homeostasis, Kanazawa University School of Medicine, Kanazawa, Japan
| | - Hiroyuki Tsuchiya
- Department of Orthopaedic Surgery, Kanazawa University School of Medicine, Kanazawa, Japan
- * E-mail:
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The efficacy of the inhalation of an aerosolized Group A streptococcal preparation in the treatment of lung cancer. Chin J Cancer Res 2012. [DOI: 10.1007/s11670-012-0274-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022] Open
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Yang Y, Gao E, Liu X, Ye Z, Chen Y, Li Q, Qu J, Dai X, Wang O, Pan Y, Zhang X. Effectiveness of OK-432 (Sapylin) to reduce seroma formation after axillary lymphadenectomy for breast cancer. Ann Surg Oncol 2012; 20:1500-4. [PMID: 23104710 DOI: 10.1245/s10434-012-2728-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2012] [Indexed: 11/18/2022]
Abstract
BACKGROUND The occurrence of seroma formation after axillary lymphadenectomy for breast cancer cannot be ignored. Various approaches have been used in an effort to reduce it, but these results are still controversial. We aimed to describe a new method of application of OK-432 (Sapylin, heat-treated Su strain of Streptococcus) to reduce seroma formation after axillary lymphadenectomy for breast cancer and to verify the safety and efficacy of it as a beneficial supplement for conventional surgery. METHODS A prospective, randomized analysis of consecutive quadrantectomy or mastectomy plus axillary lymphadenectomy using or not using OK-432 was designed. From July 2010 to November 2011, a total of 111 patients were enrolled in this prospective, randomized study and completed the follow-up. OK-432 applied to the axillary fossa plus placement of closed suction drainage was used in 54 patients (the experimental group); placement of closed suction drainage was used in 57 patients (the control group). RESULTS There were no statistical significance between the two groups in terms of age, body mass index, treatment received, tumor size, number of removed lymph nodes, and lymph node status. Postoperative drainage magnitude and duration were significantly reduced in the experimental group (P = 0.008 and 0.003, respectively). One week after hospital discharge, fewer patients developed a palpable seroma in the experimental group: 10 in the experimental group versus 28 in the control group (P = 0.001). Fewer seromas needed aspiration (mean 1 [range 0-3] in the experimental group vs. mean 4 [range 1-5] in the control group; P < 0.001). There were no significant differences in terms of the incidence of complications associated with axillary lymphadenectomy (P = 0.941). CONCLUSIONS OK-432 is a feasible and safe option for axillary lymphadenectomy for breast cancer. The use of it does not always prevent seroma formation, but it can reduce drainage magnitude and duration, as well as decrease the incidence of seroma after the removal of drainage. It may be increasingly conducted in day surgery clinics.
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Affiliation(s)
- Yinlong Yang
- Department of Surgical Oncology, The First Affiliated Hospital of Wenzhou Medical College, Wenzhou, Zhejiang, People's Republic of China
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Basith S, Manavalan B, Yoo TH, Kim SG, Choi S. Roles of toll-like receptors in cancer: a double-edged sword for defense and offense. Arch Pharm Res 2012; 35:1297-316. [PMID: 22941474 DOI: 10.1007/s12272-012-0802-7] [Citation(s) in RCA: 148] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2012] [Revised: 06/21/2012] [Accepted: 06/25/2012] [Indexed: 12/18/2022]
Abstract
Toll-like receptors (TLRs) belong to a class of pattern-recognition receptors that play an important role in host defense against pathogens by recognizing a wide variety of pathogen-associated molecular patterns (PAMPs). Besides driving inflammatory responses, TLRs also regulate cell proliferation and survival by expanding useful immune cells and integrating inflammatory responses and tissue repair processes. TLR signaling, which is centrally involved in the initiation of both innate and adaptive immune responses, has been thought to be restricted to immune cells. However, recent studies have shown that functional TLRs are expressed not only on immune cells, but also on cancer cells, thus implicating a role of TLRs in tumor biology. Increasing bodies of evidence have suggested that TLRs act as a double-edged sword in cancer cells because uncontrolled TLR signaling provides a microenvironment that is necessary for tumor cells to proliferate and evade the immune response. Alternatively, TLRs can induce an antitumor immune response in order to inhibit tumor progression. In this review, we summarize the dual roles of TLRs in tumor cells and, more importantly, delve into the therapeutic potential of TLRs in the context of tumorigenesis.
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Affiliation(s)
- Shaherin Basith
- Department of Molecular Science and Technology, Ajou University, Suwon, 443-749, Korea
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Growth inhibition and apoptosis by an active component of OK-432, a streptococcal agent, via Toll-like receptor 4 in human head and neck cancer cell lines. Oral Oncol 2012; 48:678-85. [PMID: 22387210 DOI: 10.1016/j.oraloncology.2012.02.005] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2011] [Revised: 02/01/2012] [Accepted: 02/02/2012] [Indexed: 11/21/2022]
Abstract
Toll-like receptor 4 (TLR4) plays a significant role in cancer therapy as receptors of bacteria-derived immunotherapeutic agents such as OK-432, a streptococcal immunotherapeutic agent. In addition, recent reports demonstrated that TLRs, including TLR4, are also expressed in cancer cells as well as in immunocompetent cells. It is a problem in cancer therapy that the immunoadjuvant may activate survival signals such as nuclear factor (NF)-κB or mitogen-activated protein kinases (MAPKs) in cancer cells via TLRs. In the current study, we investigated responsiveness of human head and neck cancer cell lines against TLR4 ligands, OK-PSA, an active component of OK-432, and a lipopolysaccharide (LPS). Stimulation with LPS or OK-PSA resulted in the activation of NF-κB in these cell lines expressing TLR4 and MD-2 that is a significant coreceptor for TLR4 signaling. Interestingly, OK-PSA induced cell-growth inhibition, while LPS enhanced the proliferation of the cancer cells. OK-PSA induced NF-κB activation more slowly than that induced by LPS. In addition, phosphorylation of p38 MAPK by OK-PSA was only slight compared with that by LPS. OK-PSA also induced apoptosis of the cancer cells mediated by the activation of caspase 1, 3 and 8 in a p53-independent manner. These findings strongly suggest that active components of OK-432 may elicit anti-cancer effects via enhancing host immunity as well as via directly inducing the growth inhibition and apoptosis of head and neck cancer cells through TLR4 signal.
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Hovden AO, Karlsen M, Jonsson R, Appel S. The bacterial preparation OK432 induces IL-12p70 secretion in human dendritic cells in a TLR3 dependent manner. PLoS One 2012; 7:e31217. [PMID: 22363584 PMCID: PMC3283639 DOI: 10.1371/journal.pone.0031217] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2011] [Accepted: 01/04/2012] [Indexed: 01/12/2023] Open
Abstract
Dendritic cells (DC) used in therapeutic cancer immunotherapy have to be able to stimulate T cells resulting in an immune response that can efficiently target the cancer cells. One of the critical hurdles has been the lack of IL-12p70 production when maturating the DC, which is rectified by using the bacterial preparation OK432 (trade name Picibanil) to mature the cells. In order to identify the mechanism behind OK432 stimulation of DC, we investigated the contribution of different TLR to examine their involvement in IL-12p70 production. By combining different inhibitors of TLR signaling, we demonstrate here that TLR3 is responsible for the IL-12p70 production of DC induced by OK432. Moreover, our data suggest that the ligand triggering IL-12p70 secretion upon TLR3 stimulation is sensitive to proteinase and partly also RNAse treatment. The fact that a bacterial compound like OK432 can activate the TLR3 pathway in human DC is a novel finding. OK432 demonstrates a critical ability to induce IL-12p70 production, which is of great relevance in DC based cancer immunotherapy.
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Affiliation(s)
- Arnt-Ove Hovden
- Broegelmann Research Laboratory, The Gade Institute, University of Bergen, Bergen, Norway
| | - Marie Karlsen
- Broegelmann Research Laboratory, The Gade Institute, University of Bergen, Bergen, Norway
| | - Roland Jonsson
- Broegelmann Research Laboratory, The Gade Institute, University of Bergen, Bergen, Norway
| | - Silke Appel
- Broegelmann Research Laboratory, The Gade Institute, University of Bergen, Bergen, Norway
- * E-mail:
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Matsubara N, Itoh K, Mukai H, Nagai S. Long-term outcome of pleurodesis with OK-432 in metastatic breast cancer: a new risk model for success from an analysis of 75 cases. Int J Clin Oncol 2011; 17:470-6. [PMID: 21979749 DOI: 10.1007/s10147-011-0312-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2011] [Accepted: 08/18/2011] [Indexed: 01/03/2023]
Abstract
BACKGROUND Malignant pleural effusion is a common and devastating complication of metastatic breast cancer. This occurs in about 30% of patients with metastatic breast cancer during the clinical course, and chemical pleurodesis is sometimes performed to relieve dyspnea. However, the long-term outcome of pleurodesis and factors affecting successful pleurodesis have not been clarified. OBJECTIVES The aim of this analysis is to evaluate the long-term outcome of pleurodesis and to identify risk factors associated with success. METHODS Data on 75 patients who had undergone chemical pleurodesis with OK-432 for pleural effusion due to metastatic breast cancer were reviewed retrospectively. The primary outcomes were success rate and pleural progression-free survival (PPFS) rate. RESULTS The median duration of follow-up was 134 days (range 8-975 days). During this period, 22 patients re-accumulated pleural fluid. The overall success rate was 70.5%. The 4-, 8- and 12-week PPFS rates were 88.0, 84.0 and 78.7% respectively. Multivariate analysis identified three unfavorable factors that were independently associated with unsuccessful pleurodesis, including estrogen-receptor negative status, a 24-h drainage volume of more than 100 mL before extubation and NSAID use. The PPFS rate at median follow-up was 93.5% in the low-risk group (n = 41, 0 or 1 unfavorable factor) and 55.1% in the high-risk group (n = 34, 2 or 3 unfavorable factors). The difference between the PPFS curves of the two risk groups was statistically significant (P < 0.001). CONCLUSIONS Pleurodesis for metastatic breast cancer was efficacious in controlling malignant pleural effusion. Our simple new risk model warrants further studies.
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Affiliation(s)
- Nobuaki Matsubara
- Division of Oncology and Hematology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, Japan.
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St Denis TG, Aziz K, Waheed AA, Huang YY, Sharma SK, Mroz P, Hamblin MR. Combination approaches to potentiate immune response after photodynamic therapy for cancer. Photochem Photobiol Sci 2011; 10:792-801. [PMID: 21479313 PMCID: PMC3449163 DOI: 10.1039/c0pp00326c] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2010] [Accepted: 03/08/2011] [Indexed: 01/23/2023]
Abstract
Photodynamic therapy (PDT) has been used as a cancer therapy for forty years but has not advanced to a mainstream cancer treatment. Although it has been shown to be an efficient way to destroy local tumors by a combination of non-toxic dyes and harmless visible light, it is its additional effects in mediating the stimulation of the host immune system that gives PDT great potential to become more widely used. Although the stimulation of tumor-specific cytotoxic T-cells that can destroy distant tumor deposits after PDT has been reported in some animal models, it remains the exception rather than the rule. This realization has prompted several investigators to test various combination approaches that could potentiate the immune recognition of tumor antigens that have been released after PDT. This review will cover these combination approaches using immunostimulants including various microbial preparations that activate Toll-like receptors and other receptors for pathogen-associated molecular patterns, cytokines growth factors, and approaches that target regulatory T-cells. We believe that by understanding the methods employed by tumors to evade immune response and neutralizing them, more precise ways of potentiating PDT-induced immunity can be devised.
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Affiliation(s)
- Tyler G. St Denis
- Wellman Center for Photomedicine, Massachusetts General Hospital, 40 Blossom Street, Boston, MA, 02114, USA; Fax: +1 617-726-8566; Tel: +1 617-726-6182
- John Jay High School, Cross River, NY, 10518, USA
| | - Kanza Aziz
- Wellman Center for Photomedicine, Massachusetts General Hospital, 40 Blossom Street, Boston, MA, 02114, USA; Fax: +1 617-726-8566; Tel: +1 617-726-6182
- Aga Khan University Medical College, Stadium Road, Karachi, 75950, Pakistan
| | - Anam A. Waheed
- Wellman Center for Photomedicine, Massachusetts General Hospital, 40 Blossom Street, Boston, MA, 02114, USA; Fax: +1 617-726-8566; Tel: +1 617-726-6182
- Aga Khan University Medical College, Stadium Road, Karachi, 75950, Pakistan
| | - Ying-Ying Huang
- Wellman Center for Photomedicine, Massachusetts General Hospital, 40 Blossom Street, Boston, MA, 02114, USA; Fax: +1 617-726-8566; Tel: +1 617-726-6182
- Department of Dermatology, Harvard Medical School, Boston, MA, 02115, USA
- Aesthetic and Plastic Center of Guangxi Medical University, Nanning, PR China
| | - Sulbha K. Sharma
- Wellman Center for Photomedicine, Massachusetts General Hospital, 40 Blossom Street, Boston, MA, 02114, USA; Fax: +1 617-726-8566; Tel: +1 617-726-6182
| | - Pawel Mroz
- Wellman Center for Photomedicine, Massachusetts General Hospital, 40 Blossom Street, Boston, MA, 02114, USA; Fax: +1 617-726-8566; Tel: +1 617-726-6182
- Department of Dermatology, Harvard Medical School, Boston, MA, 02115, USA
| | - Michael R. Hamblin
- Wellman Center for Photomedicine, Massachusetts General Hospital, 40 Blossom Street, Boston, MA, 02114, USA; Fax: +1 617-726-8566; Tel: +1 617-726-6182
- Department of Dermatology, Harvard Medical School, Boston, MA, 02115, USA
- Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA, 02139, USA
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Tabu M, Imai K, Ogawa JI, Minamiya Y, Yoshida S, Hirayama K, Sawano T, Matsuzaki I. Late-onset chylothorax after pulmonary resection for lung cancer. Gen Thorac Cardiovasc Surg 2011; 59:205-8. [PMID: 21448802 DOI: 10.1007/s11748-010-0635-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2010] [Accepted: 04/22/2010] [Indexed: 01/11/2023]
Abstract
Chylothorax is a relatively rare complication of thoracic surgery. Most instances of chylothorax after pulmonary resection are diagnosed within 3 days after surgery. Hence, late-onset chylothorax is rare. A 68-year-old woman underwent right lower lobectomy and mediastinal dissection for lung cancer. After discharge, the patient developed a dry cough, and chest radiography more than 3 months after surgery revealed a right-sided pleural effusion occupying more than half of the right hemithorax, which we diagnosed as late-onset chylothorax. Treatment comprised chest drainage, subcutaneous octreotide, and pleurodesis by injecting a preparation of OK-432. Follow-up chest radiography confirmed no reaccumulation of fluid. Three months later no recurrence of pleural effusion was detected. We report a rare case of postoperative late-onset chylothorax that proved difficult to treat.
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Affiliation(s)
- Maiko Tabu
- Department of General Thoracic Surgery, Hachinohe City Hospital, 1 Tamukai aza Bishamontaira, Hachinohe, Aomori 031-8555, Japan
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Hovden AO, Karlsen M, Jonsson R, Aarstad HJ, Appel S. Maturation of monocyte derived dendritic cells with OK432 boosts IL-12p70 secretion and conveys strong T-cell responses. BMC Immunol 2011; 12:2. [PMID: 21208424 PMCID: PMC3023782 DOI: 10.1186/1471-2172-12-2] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2010] [Accepted: 01/05/2011] [Indexed: 12/21/2022] Open
Abstract
Background Design of tumour specific immunotherapies using the patients' own dendritic cells (DC) is a fast advancing scientific field. The functional qualities of the DC generated in vitro are critical, and today's gold standard for maturation is a cytokine cocktail consisting of IL-1β, IL-6, TNF-α and PGE2 generating cells lacking IL-12p70 production. OK432 is an immunotherapeutic agent derived from killed Streptococcus pyogenes that has been used clinically to treat malignant and benign neoplasms for decades. Methods In this study, we analysed the effects of OK432 on DC maturation, DC migration, cytokine and chemokine secretion as well as T-cell stimulatory capacity, and compared it to the cytokine cocktail alone and combinations of OK432 with the cytokine cocktail. Results OK432 induced a marked up-regulation of CD40 on the cell surface as well as a strong inflammatory response from the DC with significantly more secretion of 19 different cytokines and chemokines compared to the cytokine cocktail. Interestingly, secretion of IL-15 and IL-12p70 was detected at high concentrations after maturation of DC with OK432. However, the OK432 treated DC did not migrate as well as DC treated with cytokine cocktail in a transwell migration assay. During allogeneic T-cell stimulation OK432 treated DC induced proliferation of over 50 percent of CD4 and 30 percent of CD8 T-cells for more than two cell divisions, whereas cytokine cocktail treated DC induced proliferation of 12 and 11 percent of CD4 and CD8 T-cells, respectively. Conclusions The clinically approved compound OK432 has interesting properties that warrants its use in DC immunotherapy and should be considered as a potential immunomodulating agent in cancer immunotherapy.
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Saito T, Tsuchiya T, Sato Y, Kenjo A, Kimura T, Anazawa T, Terashima M, Takahashi A, Ohira H, Gotoh M. Effect of Transarterial Immunoembolization as Preoperative Treatment for Hepatocellular Carcinoma. ACTA ACUST UNITED AC 2011. [DOI: 10.4993/acrt.19.26] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
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Muta F, Takamori S, Matsuo T, Iwasaki Y, Yoshiyama K, Shirouzu K. Changes in the pleural cavity by pleurodesis using talc or OK-432: an experimental study. Surg Today 2010; 41:111-4. [PMID: 21191701 DOI: 10.1007/s00595-010-4275-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2009] [Accepted: 01/14/2010] [Indexed: 12/15/2022]
Abstract
PURPOSE To define the changes in the pleural cavity after pleurodesis induced by talc or OK-432. METHODS A total of 30 rats were divided into three groups: a normal saline group (control group, n = 10), a group administered 400 mg/kg talc (talc group, n = 10), and a group administered 0.3 KE/kg OK-432 (OK-432 group, n = 10). Pleural cavities were examined and scored on the 30th day after the intrapleural administration of each agent. RESULTS Both the talc group and OK-432 group showed significantly higher macroscopic or microscopic pleurodesis scores than the control group (P < 0.05). Upon microscopic evaluation, the pleurodesis scores in the talc group were significantly higher than those in the OK-432 group (P < 0.01).The majority of the pleural thickness was found on the visceral pleura, and the parietal pleura was very thin. The thickness of the visceral pleura in the talc group was significantly higher than that in the OK-432 group (P < 0.005). Pathologically, the pleural thickening in the talc group consisted of fibrous tissue with injury of the pleural mesothelium, and talc particles were seen in the submesothelial fibrotic tissue and inside the alveoli. CONCLUSIONS Talc pleurodesis induces more marked changes in the pleural cavity than OK-432-induced pleurodesis.
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Affiliation(s)
- Fumihiko Muta
- Department of Surgery, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan
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Mizukoshi E, Nakamoto Y, Arai K, Yamashita T, Mukaida N, Matsushima K, Matsui O, Kaneko S. Enhancement of tumor-specific T-cell responses by transcatheter arterial embolization with dendritic cell infusion for hepatocellular carcinoma. Int J Cancer 2010; 126:2164-2174. [PMID: 19739081 DOI: 10.1002/ijc.24882] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Transcatheter arterial embolization (TAE) destroys a tumor by the induction of necrosis and/or apoptosis and causes inflammation with cytokine production, which may favor immune activation and presentation of tumor-specific antigens. In the current study, we attempted to identify the effect of TAE on tumor-specific T-cell responses and the additional effect of dendritic cell (DC) infusion performed during TAE. The prevalence of tumor antigen-specific T cells was determined by interferon-gamma enzyme-linked immunospot analysis using alpha-fetoprotein (AFP) and tumor antigen-derived peptides in 20 and 13 patients with hepatocellular carcinoma (HCC) who received TAE and TAE with DC infusion, respectively. The increased frequency of AFP-specific T cells was observed in 6 of 20 patients after TAE. It was observed more frequently in patients with DC infusion than in those with TAE alone. However, tumor recurrence was not completely prevented in patients albeit displayed enhanced immune responses. The evidence that the enhanced immune responses were transient and attenuated within 3 months was provided in time-course analysis. In conclusion, TAE with DC infusion enhances the tumor-specific immune responses more effectively than TAE alone. Although the effect is not sufficient to prevent HCC recurrence, these results may contribute to the development of novel immunotherapeutic approach for HCC.
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Affiliation(s)
- Eishiro Mizukoshi
- Department of Disease Control and Homeostasis, Graduate School of Medicine, Kanazawa University, Kanazawa, Japan
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Umemura M. Reconsidering Japan's underperformance in pharmaceuticals: evidence from Japan's anticancer drug sector. ENTERPRISE & SOCIETY 2010; 11:560-593. [PMID: 20821877 DOI: 10.1093/es/khq063] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/29/2023]
Abstract
Unlike its automobile or electronics industries, Japan's pharmaceutical industry did not become a global leader. Japan remains a net importer of pharmaceuticals and has introduced few global blockbuster drugs. Alfred Chandler argued that Japan's pharmaceutical firms remained relatively weak because Western firms enjoyed an insurmountable first first-mover advantage. However, this case study of the anticancer drug sector illustrates that Chandler's explanation is incomplete. Japanese medical culture, government policy, and research environment also played a substantial role in shaping the industry. In the 1970s and 1980s, these factors encouraged firms to develop little few effective drugs with low side effects, and profit from Japan's domestic market. But, these drugs were unsuitable to foreign markets with more demanding efficacy standards. As a result, Japan not only lost more than a decade in developing ineffective drugs, but also neglected to create the infrastructure necessary to develop innovative drugs and build a stronger pharmaceutical industry.
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Pan K, Wang H, Liu WL, Zhang HK, Zhou J, Li JJ, Weng DS, Huang W, Sun JC, Liang XT, Xia JC. The pivotal role of p38 and NF-κB signal pathways in the maturation of human monocyte-derived dendritic cells stimulated by streptococcal agent OK-432. Immunobiology 2009; 214:350-8. [DOI: 10.1016/j.imbio.2008.10.008] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2008] [Accepted: 10/28/2008] [Indexed: 10/21/2022]
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Matsukuma E, Aoki Y, Sakai M, Kawamoto N, Watanabe H, Iwagaki S, Takahashi Y, Kawabata I, Kondo N, Uchida Y. Treatment with OK-432 for persistent congenital chylothorax in newborn infants resistant to octreotide. J Pediatr Surg 2009; 44:e37-9. [PMID: 19302843 DOI: 10.1016/j.jpedsurg.2008.12.008] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2008] [Revised: 12/04/2008] [Accepted: 12/05/2008] [Indexed: 11/19/2022]
Abstract
Chylothorax is a relatively uncommon condition defined as an abnormal collection of lymphatic fluid within the pleural space. We are reporting the use of OK-432 for treatment of prolonged idiopathic congenital chylothorax in 2 newborn infants who failed to respond to conservative medical therapy, including octreotide injection.
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Affiliation(s)
- Eiji Matsukuma
- The Department of Pediatrics, Nagara Medical Center, Gifu 502-8558, Japan
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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.
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Affiliation(s)
- Seth Rakoff-Nahoum
- Howard Hughes Medical Institute and Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
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Rakoff-Nahoum S, Medzhitov R. Role of toll-like receptors in tissue repair and tumorigenesis. BIOCHEMISTRY (MOSCOW) 2008; 73:555-61. [PMID: 18605980 DOI: 10.1134/s0006297908050088] [Citation(s) in RCA: 61] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Toll-like receptors (TLRs) play a critical role in host defense from microbial infection. TLRs recognize conserved molecular structures produced by microorganisms and induce activation of innate and adaptive immune responses. The inflammatory responses induced by TLRs play an important role TLRs not only in host defense from infection, but also in tissue repair and regeneration. This latter function of TLRs can also contribute to tumorigenesis. Here we review recent progress in understanding the role of TLRs in cancer development.
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Affiliation(s)
- S Rakoff-Nahoum
- Howard Hughes Memorial Institute and Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06510, USA
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Bahrun U, Kimoto M, Tsukamoto H, Tsuneyoshi N, Kohara J, Fukudome K. Preparation and characterization of agonistic monoclonal antibodies against Toll-like receptor 4-MD-2 complex. Hybridoma (Larchmt) 2008; 26:393-9. [PMID: 18158784 DOI: 10.1089/hyb.2007.0523] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Ligands for toll-like receptors (TLR) are known to induce a variety of immune responses. Selective induction of desirable responses would be important for the treatment of individual diseases with various pathogenesis. For this purpose, we established six MAbs against the TLR4/MD-2 complex (UT MAbs) from TLR4(-/-) mice or MD-2(-/-) mice. Three MAbs (UT12, 18, and 22) induced NF-kappaB activation and production of pro-inflammatory cytokines, but the other three (UT15, 41, and 49) did not induce such cell responses. Unlike lipopolysaccharide (LPS), agonistic UT MAbs did not require serum components for the functions. UT41 and UT49 recognized TLR4 in the absence of MD-2. On the other hand, the other four MAbs reacted to the TLR4/MD-2 complex, but not to solo TLR4. Agonistic UT MAbs shared the epitopes, but non-agonistic UT15 reacted to distinct epitope on the complex. UT MAbs appear to be useful analyzing the molecular mechanism of TLR signaling and will contribute to the development of novel immunotherapies.
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Affiliation(s)
- Uleng Bahrun
- Department of Immunology, Saga Medical School, Saga, Japan
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Mol W, Furukawa H, Sasaki S, Tomaru U, Hayashi T, Saito A, Nagao M, Saito N, Hata S, Yamamoto Y. Evaluation of the sclerotherapeutic efficacy of ethanol, polidocanol, and OK-432 using an in vitro model. Dermatol Surg 2007; 33:1452-9. [PMID: 18076610 DOI: 10.1111/j.1524-4725.2007.33315.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
BACKGROUND Sclerosants are used to treat vascular malformations. Owing to variations in the flow, the injected concentrations and the duration of exposure of these sclerosants are altered. Therefore, the clinical effectiveness of sclerotherapy is variable. OBJECTIVE The objective was to evaluate the differences in clinical response, usually observed among ethanol, polidocanol, and OK-432, using an in vitro sclerotherapy model. METHODS Endothelial cells were cultured and exposed to different concentrations of the sclerosants for 5 seconds and the remaining viable cells were counted using a MTT assay kit. Dyes were used to visualize the morphologic changes. Precipitant formation in blood was also evaluated. Finally, the degree of ICAM-1 expression, after exposure to lower concentrations of these sclerosants, was studied using immunocytochemistry. RESULTS Only ethanol causes precipitant formation and kills almost all cells from 30% concentration. Polidocanol begins to disrupt the cell membrane from 0.0125% onward. Only OK-432 induces ICAM-1 expression. CONCLUSION Ethanol's strong precipitant-forming effect may induce thromboembolism, thus enhancing sclerosis. Polidocanol's endothelial cell-lysing effect was clearly documented. OK-432 may mediate its effect by inducing inflammatory response of the endothelium via ICAM-1 expression. This in vitro model may be useful in evaluating other sclerosants as well.
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Affiliation(s)
- William Mol
- Department of Plastic and Reconstructive Surgery, University of Hokkaido at Sapporo, Graduate School of Medicine, Sapporo, Japan
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Hashimoto M, Takashige K, Furuyashiki M, Yoshidome K, Sano R, Kawamura Y, Ijichi S, Morioka H, Koide H, Oku N, Moriya Y, Kusumoto S, Suda Y. Enhancement of antitumor activity of OK-432 (picibanil) by Triton X-114 phase partitioning. Int Immunopharmacol 2007; 8:12-9. [PMID: 18068095 DOI: 10.1016/j.intimp.2007.09.021] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2007] [Revised: 09/27/2007] [Accepted: 09/27/2007] [Indexed: 11/28/2022]
Abstract
OK-432 (Picibanil), a Streptococcal immunotherapeutic agent, has been used for immunotherapy of various cancers as a biological response modifier (BRM). However, OK-432 contains multiple components consisting of immunotherapeutic ones and contaminants which may weaken the effects or exert side-effects. In this study, we investigated extraction of contaminants from OK-432 using Triton X-114 (TX-114)-water phase partitioning and examined an antitumor effect of the resulting preparation. OK-432 was subjected to TX-114 partitioning to give residual precipitate designated as OK-TX-ppt. OK-TX-ppt exerted no TLR2-mediated activity, but induced interleukin (IL)-6 in human PBMC. OK-TX-ppt also induced tumor necrosis factor (TNF)-alpha, IL-10, IL-12, and interferon (IFN)-gamma in PBMC. Moreover, IFN-gamma-inducing activity of OK-TX-ppt was significantly higher and IL-10 production was lower than that of OK-432. In tumor-bearing mice model, administration of OK-TX-ppt i.p. extended the survival time of Meth-A-bearing mice compared to OK-432. OK-TX-ppt also increased the levels of IL-12 and IFN-gamma in mouse spleen cells in vitro. These results indicated that TX-114 partitioning removed some contaminants, which attenuates the antitumor effect, from OK-432 and increase the immunotherapeutic effects of OK-432.
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Affiliation(s)
- Masahito Hashimoto
- Department of Nanostructure and Advanced Materials, Graduate School of Science and Engineering, Kagoshima University, 1-21-40 Korimoto, Kagoshima 890-0065, Japan
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Evaluation of the Sclerotherapeutic Efficacy of Ethanol, Polidocanol, and OK-432 Using an In Vitro Model. Dermatol Surg 2007. [DOI: 10.1097/00042728-200712000-00006] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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