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Neoplasia (New York, N.Y.) Jul 2013Eighty-one patients with oral squamous cell carcinoma (OSCC) received oral fluoropyrimidine UFT and radiotherapy (RT) with or without an immunotherapeutic agent OK-432....
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.
Topics: Adult; Aged; Aged, 80 and over; Carcinoma, Squamous Cell; Cytokines; Dendritic Cells; Female; Fluorouracil; Gene Expression Regulation, Neoplastic; Humans; Immunotherapy; Leukocytes, Mononuclear; Male; Middle Aged; Mouth Neoplasms; Neoplasm Staging; Picibanil; Suppressor of Cytokine Signaling 1 Protein; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Th1 Cells; Th2 Cells; Transcription Factors
PubMed: 23814492
DOI: 10.1593/neo.13488 -
Korean Journal of Pediatrics May 2012OK-432 (picibanil) is an inactivated preparation of Streptococcus pyogenes that causes pleurodesis by inducing a strong inflammatory response. Intrapleural instillation...
OK-432 (picibanil) is an inactivated preparation of Streptococcus pyogenes that causes pleurodesis by inducing a strong inflammatory response. Intrapleural instillation of OK-432 has recently been used to successfully treat neonatal and fetal chylothorax. Here we report a trial of intrapleural instillation of OK-432 in two preterm infants who were born with hydrops fetalis and massive bilateral pleural effusion. Both cases showed persistent pleural effusion, refractory to conservative treatment, up to postnatal days 26 and 46, respectively. An average of 80 to 140 mL of pleural fluid was drained daily. In case 1, the infant was treated with OK-432 during the fetal period at gestation 28 weeks and 4 days of gestation, but showed recurrence of pleural effusion and progressed into hydrops. Within two to three days after OK-432 injection, the amount of pleural fluid drainage was dramatically decreased and there was no reaccumulation. We did not observe any side effects related to OK-432 injection. We suggest that OK-432 should be considered as a therapeutic option in infants who have persistent pleural effusion for more than four weeks, with the expectation of the early removal of the chest tube and a good outcome.
PubMed: 22670153
DOI: 10.3345/kjp.2012.55.5.177 -
Cureus Apr 2024We present a case of lung adenocarcinoma with malignant pleural effusion. Nineteen days after pleurodesis using minocycline and OK-432 (picibanil), pembrolizumab...
We present a case of lung adenocarcinoma with malignant pleural effusion. Nineteen days after pleurodesis using minocycline and OK-432 (picibanil), pembrolizumab monotherapy was initiated. Four days later, the patient experienced a persistent cough. Chest computed tomography showed that ground-glass opacity appeared on the same side as pleurodesis and spread bilaterally thereafter, which was diagnostic of immune checkpoint inhibitors (ICI)-related pneumonitis. As he presented a severe respiratory failure, corticosteroid therapy was administered. Two weeks later, respiratory failure completely resolved and the abnormal shadows dramatically improved. Our results indicate that severe ICI-related pneumonitis can develop within a short period after pleurodesis.
PubMed: 38784310
DOI: 10.7759/cureus.58798 -
Scientific Reports Feb 2017Active human dendritic cells (DCs), which efficiently induce immune responses through their functions as antigen-presenting cells, exhibit direct anti-tumour killing...
Active human dendritic cells (DCs), which efficiently induce immune responses through their functions as antigen-presenting cells, exhibit direct anti-tumour killing activity in response to some pathogens and cytokines. These antigen-presenting and tumour killing abilities may provide a breakthrough in cancer immunotherapy. However, the mechanisms underlying this killer DC activity have not been fully proven, despite the establishment of interferon-α (IFN-α)-generated killer DCs (IFN-DCs). Here mature IFN-DCs (mIFN-DCs), generated from IFN-DCs primed with OK-432 (streptococcal preparation), exhibited elevated expression of CD86 and human leukocyte antigen-DR (minimum criteria for DC vaccine clinical trials) as well as antigen-presenting abilities comparable with those of mature IL-4-DCs (mIL-4-DCs). Interestingly, the killing activity of mIFN-DCs, which correlated with the expression of CD56 (natural killer cell marker) and was activated via the tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) and Fas ligand pathway, was stronger than that of IFN-DCs and remarkably stronger than that of mIL-4-DCs. Therefore, mIFN-DCs exhibit great potential as an anti-cancer vaccine that would promote both acquired immunity and direct tumour killing.
Topics: Antigen Presentation; B7-2 Antigen; CD56 Antigen; Cancer Vaccines; Cell Differentiation; Cytotoxicity, Immunologic; Dendritic Cells; Dinoprostone; Fas Ligand Protein; Gene Expression Regulation; Granulocyte-Macrophage Colony-Stimulating Factor; HLA-DR Antigens; Humans; Immunophenotyping; Interferon-alpha; Interleukin-4; Monocytes; Picibanil; Primary Cell Culture; Signal Transduction; TNF-Related Apoptosis-Inducing Ligand
PubMed: 28191816
DOI: 10.1038/srep42145 -
BMC Immunology Jan 2009OK-432, penicillin-killed Streptococcus pyogenes, is used in treating lymphangiomas and carcinomas. We have studied in vitro the role of mononuclear phagocytes (MNPs),...
BACKGROUND
OK-432, penicillin-killed Streptococcus pyogenes, is used in treating lymphangiomas and carcinomas. We have studied in vitro the role of mononuclear phagocytes (MNPs), including purified monocytes (MOs), in the immune response to OK-432. MIP-1alpha/beta and MCP-1 secretions were assessed in whole blood (WB), peripheral blood mononuclear cells (PBMCs) and purified MOs, after in vitro stimulation with OK-432 with or without adherence for 24 hours.
RESULTS
OK-432 stimulated MNPs to secrete MCP-1 and MIP-1alpha/beta in healthy individuals and in head and neck squamous cell carcinoma (HNSCC) patients, except for OK-432 stimulation of WB giving a minimal MIP-1alpha/beta response. Upon culture on low-attachment wells, a spontaneous chemokine secretion was observed, with an unchanged secretion following OK-432 stimulation. Inhibition of Syk kinase and/or PI-3 kinase did not significantly change the chemokine response to OK-432, except for MIP-1alpha production being increased upon Syk inhibitor addition and an increased MCP-1 response upon addition of both inhibitors. Adhesion may possibly involve beta1 and/or beta3 integrins, not beta2, whereas beta(1-3) integrins may act as co-stimulatory receptors for OK-432. Based on direct blockage of CD36 or CD18 by antibodies, MCP-1 production may be mediated by CD18 while MIP-1beta and MCP-1 production may occur upon binding to CD36.
CONCLUSION
Adherent human MOs produce MCP-1 and MIP-1alpha/beta upon stimulation with OK-432. CD36 modulates MIP-1beta and MCP-1 response. Thus, to some extent OK-432 acts as a substance whereby only MOs adhered to surfaces secrete MCP-1 and MIP-1alpha/beta, in part explaining why OK-432 is suited as a biological response modifying drug.
Topics: Antineoplastic Agents; CD18 Antigens; CD36 Antigens; Carcinoma, Squamous Cell; Cell Adhesion; Chemokine CCL2; Chemokine CCL3; Chemokine CCL4; Chemokines; Head and Neck Neoplasms; Humans; Immunotherapy; Intracellular Signaling Peptides and Proteins; Lymphocyte Activation; Male; Middle Aged; Monocytes; Phosphatidylinositol 3-Kinases; Phosphorylation; Picibanil; Protein Binding; Protein-Tyrosine Kinases; Signal Transduction; Streptococcus pyogenes; Syk Kinase
PubMed: 19175917
DOI: 10.1186/1471-2172-10-6 -
PloS One 2013Induction of antitumor immunity by dendritic cell (DC)-tumor fusion cells (DC/tumor) can be modulated by their activation status. In this study, to address optimal...
Induction of antitumor immunity by dendritic cell (DC)-tumor fusion cells (DC/tumor) can be modulated by their activation status. In this study, to address optimal status of DC/tumor to induce efficient antigen-specific cytotoxic T lymphocytes (CTLs), we have created various types of DC/tumor: 1) un-activated DC/tumor; 2) penicillin-killed Streptococcus pyogenes (OK-432; TLR4 agonist)-activated DC/tumor; 3) protein-bound polysaccharides isolated from Coriolus versicolor (PSK; TLR2 agonist)-activated DC/tumor; and 4) Combined OK-432- and PSK-activated DC/tumor. Moreover, we assessed the effects of TGF-β1 derived from DC/tumor on the induction of MUC1-specific CTLs. Combined TLR2- and TLR4-activated DC/tumor overcame immune-suppressive effect of TGF-β1 in comparison to those single activated or un-activated DC/tumor as demonstrated by: 1) up-regulation of MHC class II and CD86 expression on DC/tumor; 2) increased fusion efficiency; 3) increased production of fusions derived IL-12p70; 4) activation of CD4(+) and CD8(+) T cells that produce high levels of IFN-γ; 5) augmented induction of CTL activity specific for MUC1; and 6) superior efficacy in inhibiting CD4(+)CD25(+)Foxp3(+) T cell generation. However, DC/tumor-derived TGF-β1 reduced the efficacy of DC/tumor vaccine in vitro. Incorporating combined TLRs-activation and TGF-β1-blockade of DC/tumor may enhance the effectiveness of DC/tumor-based cancer vaccines and have the potential applicability to the field of adoptive immunotherapy.
Topics: B7-2 Antigen; Cancer Vaccines; Cell Fusion; Cell Line, Tumor; Dendritic Cells; Forkhead Transcription Factors; Gene Expression Regulation; Humans; Interferon-gamma; Interleukin-12; Lymphocyte Activation; Mucin-1; Picibanil; Proteoglycans; Signal Transduction; T-Lymphocytes, Cytotoxic; Toll-Like Receptor 2; Toll-Like Receptor 4; Transforming Growth Factor beta1
PubMed: 23555011
DOI: 10.1371/journal.pone.0059280 -
Internal Medicine (Tokyo, Japan) 2012The intrathoracic administration of OK-432, a lyophilized preparation of the heat- and penicillin-treated Su-strain of type 3, group A Streptococcus pyogenes, is...
OBJECTIVE
The intrathoracic administration of OK-432, a lyophilized preparation of the heat- and penicillin-treated Su-strain of type 3, group A Streptococcus pyogenes, is performed in Japan for pleurodesis of malignant pleural effusion or pneumothorax. Persistent fever is often observed after pleurodesis. To elucidate whether procalcitonin (PCT) is useful for distinguishing between the side effects of OK-432 and infection, we measured the serum PCT levels before and after pleurodesis.
METHODS
We performed a prospective study of 12 patients with refractory pleural effusion or pneumothorax who required pleurodesis using OK-432 between August 2011 and February 2012. The serum PCT and C-reactive protein (CRP) levels were measured on days 1 and 3.
RESULTS
Of the 12 patients, five had pneumothorax and seven had uncontrolled pleural effusion with carcinomatous pleurisy. The median serum levels of PCT and CRP increased from 0.055 to 1.59 ng/mL (p=0.0022) and from 1.52 to 16.82 mg/dL (p=0.0022), respectively. The fevers subsided without antibiotic administration.
CONCLUSION
The serum PCT level may not be useful for distinguishing fever caused by side effects of OK-432 from that caused by bacterial infection. The intrathoracic administration of OK-432 increased the serum levels of both PCT and CRP in the absence of any bacterial infection.
Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Bacterial Infections; C-Reactive Protein; Calcitonin; Calcitonin Gene-Related Peptide; Female; Fever; Humans; Male; Picibanil; Pleural Effusion, Malignant; Pleurodesis; Pneumothorax; Prospective Studies; Protein Precursors
PubMed: 23037463
DOI: 10.2169/internalmedicine.51.8315 -
Clinical and Experimental Immunology Feb 2011Despite curative locoregional treatments for hepatocellular carcinoma (HCC), tumour recurrence rates remain high. The current study was designed to assess the safety and...
Despite curative locoregional treatments for hepatocellular carcinoma (HCC), tumour recurrence rates remain high. The current study was designed to assess the safety and bioactivity of infusion of dendritic cells (DCs) stimulated with OK432, a streptococcus-derived anti-cancer immunotherapeutic agent, into tumour tissues following transcatheter hepatic arterial embolization (TAE) treatment in patients with HCC. DCs were derived from peripheral blood monocytes of patients with hepatitis C virus-related cirrhosis and HCC in the presence of interleukin (IL)-4 and granulocyte-macrophage colony-stimulating factor and stimulated with 0·1 KE/ml OK432 for 2 days. Thirteen patients were administered with 5 × 10⁶ of DCs through arterial catheter during the procedures of TAE treatment on day 7. The immunomodulatory effects and clinical responses were evaluated in comparison with a group of 22 historical controls treated with TAE but without DC transfer. OK432 stimulation of immature DCs promoted their maturation towards cells with activated phenotypes, high expression of a homing receptor, fairly well-preserved phagocytic capacity, greatly enhanced cytokine production and effective tumoricidal activity. Administration of OK432-stimulated DCs to patients was found to be feasible and safe. Kaplan-Meier analysis revealed prolonged recurrence-free survival of patients treated in this manner compared with the historical controls (P = 0·046, log-rank test). The bioactivity of the transferred DCs was reflected in higher serum concentrations of the cytokines IL-9, IL-15 and tumour necrosis factor-α and the chemokines CCL4 and CCL11. Collectively, this study suggests that a DC-based, active immunotherapeutic strategy in combination with locoregional treatments exerts beneficial anti-tumour effects against liver cancer.
Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Hepatocellular; Combined Modality Therapy; Cytokines; Dendritic Cells; Disease-Free Survival; Embolization, Therapeutic; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Hepatitis C; Humans; Immunotherapy, Active; Interleukin-4; Liver Neoplasms; Male; Middle Aged; Monocytes; Neoplasm Recurrence, Local; Picibanil; Radiography
PubMed: 21087443
DOI: 10.1111/j.1365-2249.2010.04246.x -
International Journal of Molecular... Dec 2022Integrin beta 7 (β7), a subunit of the integrin receptor, is expressed on the surface of immune cells and mediates cell-cell adhesions and interactions, e.g., antitumor...
Integrin beta 7 (β7), a subunit of the integrin receptor, is expressed on the surface of immune cells and mediates cell-cell adhesions and interactions, e.g., antitumor or autoimmune reactions. Here, we analyzed, whether the stimulation of immune cells by dendritic cells (of leukemic derivation in AML patients or of monocyte derivation in healthy donors) leads to increased/leukemia-specific β7 expression in immune cells after T-cell-enriched mixed lymphocyte culture-finally leading to improved antileukemic cytotoxicity. Healthy, as well as AML and MDS patients' whole blood (WB) was treated with Kit-M (granulocyte-macrophage colony-stimulating factor (GM-CSF) + prostaglandin E1 (PGE1)) or Kit-I (GM-CSF + Picibanil) in order to generate DCs (DC or monocyte-derived DC), which were then used as stimulator cells in MLC. To quantify antigen/leukemia-specific/antileukemic functionality, a degranulation assay (DEG), an intracellular cytokine assay (INTCYT) and a cytotoxicity fluorolysis assay (CTX) were used. (Leukemia-specific) cell subtypes were quantified via flow cytometry. The Kit treatment of WB (compared to the control) resulted in the generation of DC/DC, which induced increased activation of innate and adaptive cells after MLC. Kit-pretreated WB (vs. the control) led to significantly increased frequencies of β7-expressing T-cells, degranulating and intracellular cytokine-producing β7-expressing immune cells and, in patients' samples, increased blast lysis. Positive correlations were found between the Kit-M-mediated improvement of blast lysis (vs. the control) and frequencies of β7-expressing T-cells. Our findings indicate that DC-based immune therapies might be able to specifically activate the immune system against blasts going along with increased frequencies of (leukemia-specific) β7-expressing immune cells. Furthermore, β7 might qualify as a predictor for the efficiency and the success of AML and/or MDS therapies.
Topics: Humans; Granulocyte-Macrophage Colony-Stimulating Factor; Dendritic Cells; Leukemia, Myeloid, Acute; Lymphocyte Activation; Cytokines; Integrins
PubMed: 36613907
DOI: 10.3390/ijms24010463 -
Otolaryngology--head and Neck Surgery :... Jun 2010Intralesional injection therapy with OK-432 was developed as a therapy for operatively difficult lymphangioma (cystic hygroma) and is currently becoming a first-choice...
OBJECTIVES
Intralesional injection therapy with OK-432 was developed as a therapy for operatively difficult lymphangioma (cystic hygroma) and is currently becoming a first-choice treatment for this disease. The aim of this article was to evaluate the outcome and complications of the treatment of patients with auricular hematoma by OK-432 therapy.
STUDY DESIGN
Case series with planned data collection.
SETTING
Yamagata University School of Medicine.
SUBJECTS AND METHODS
We tried this therapy in 21 patients with auricular hematoma between January 2001 and February 2009. We injected OK-432 solution into the lesion with a 27-gauge needle to prevent the leak of the agent out of the hematoma. We performed this treatment on an outpatient basis without hospitalization.
RESULTS
Disappearance or marked reduction of the lesion were observed in all patients who had this therapy, and local scarring and deformity of the auricle did not occur in any patients. As for side effects, local pain at the injection site and fever (37 degrees C-38 degrees C) were observed in a few of the patients who had this therapy, but such problems resolved within a few days.
CONCLUSION
These results may allow us to speculate that intralesional injection therapy with OK-432 is simple, easy, safe, and effective and can be used as a substitute for surgery in the treatment of auricular hematoma.
Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Ear Auricle; Ear Diseases; Female; Hematoma; Humans; Injections, Intralesional; Male; Middle Aged; Picibanil; Prospective Studies; Treatment Outcome; Young Adult
PubMed: 20493359
DOI: 10.1016/j.otohns.2010.03.006