picibanil and Glioma

Topics: Animals; Antibodies, Monoclonal; BCG Vaccine; Brain Neoplasms; Cell Fusion; Glioma; Humans; Hybridomas; Immunotherapy; Interferon Inducers; Interferons; Leukemia; Levamisole; Lymphoma; Mice; Mice, Inbred BALB C; Picibanil

During the period from January 1981 to December 1983, two groups of a total of 51 patients (31 malignant astrocytomas, 17 glioblastomas, and 3 others) were treated with radioimmunochemotherapy using nimustine hydrochloride (ACNU) plus Picibanil (OK-432) (group A) and radiochemotherapy with ACNU only (group B) in a randomized controlled study. Group A consisted of 24 patients and group B of 27 patients. The differences in the background of the two groups were not statistically significant. Survival curves of both groups were shown by the Kaplan-Meier method. The postoperative survival rate at 1 year and 3 years was 70% and 30%, respectively, equal in both groups, and the differences between groups A and B were not statistically significant by the Cox-Mantel test. The side effects seen in group B were most prominent in the bone marrow, and severe leukopenia occurred. However, in group A leukopenia was suppressed after 2 months. Immunologic parameters, such as the purified protein derivative skin reaction test, did not change, but the streptococcus pyogenes Su-strain polysaccharide skin-reaction test became more positive after therapy in group A.

Topics: Adult; Aged; Biological Products; Brain Neoplasms; Clinical Trials as Topic; Combined Modality Therapy; Female; Glioma; Humans; Leukopenia; Male; Middle Aged; Nimustine; Nitrosourea Compounds; Picibanil; Random Allocation; Skin Tests

Topics: Adult; Aged; Antineoplastic Agents; Biological Products; Brain Neoplasms; Combined Modality Therapy; Female; Glioma; Humans; Male; Middle Aged; Nimustine; Nitrosourea Compounds; Picibanil; Random Allocation

Adoptive immunotherapy using OK-432-activated mononuclear cells (OK-MCs) offers cell-mediated and cytokine-mediated pathways for antitumor activity. The effectiveness of direct intratumoral administration of OK-MCs via a catheter/reservoir system was studied in patients with malignant brain tumors. Seventeen patients, 12 with malignant glioma, four with metastatic adenocarcinoma, and one with primary sarcoma of the brain, were treated by OK-MC therapy (1.0 to 11.2 x 10(7) cells/person) between June 1989 and April 1999. The OK-MC therapy was given to patients with tumors progressing despite previous cytoreductive surgery, radiation, or chemotherapy. Adverse effects seen after the therapy were fever in 10 patients, seizure in two patients, and hypotension in one patient. Evaluation by computed tomography or magnetic resonance imaging revealed that seven patients showed no change including three with minor response, and 10 showed progressive disease. Adoptive immunotherapy using OK-MC was safe and well tolerated, but the therapeutic potential is limited.

Topics: Adenocarcinoma; Adult; Aged; Brain Neoplasms; Combined Modality Therapy; Female; Glioma; Humans; Immunotherapy, Adoptive; Male; Middle Aged; Monocytes; Picibanil; Sarcoma; Treatment Outcome

We have been applying an adoptive immunotherapy protocol to patients with malignant brain tumors using OK-432-activated peripheral blood mononuclear cells (OK-MCs). In order to elucidate the mechanism of OK-MCs' cytotoxicity, we examined the expression of Fas ligand mRNA in OK-MCs and the cytocidal activity of these cells against a human glioma cell line, T98G which expresses a high level of Fas. The expression of Fas ligand mRNA was low in non-treated peripheral blood mononuclear cells and was elevated by treatment with OK-432, irrespective of the dose employed. Apoptosis of T98G cells induced by OK-MCs was unequivocally inhibited by the pretreatment of T98 G cells with ZB4 monoclonal antibody, which binds to Fas and blocks the binding of Fas ligand to Fas. These data indicate that the cytotoxic activity of OK-MCs via apoptosis seems to be at least partly mediated by the Fas ligand/Fas system. Adoptive immunotherapy using the Fas ligand/Fas system could be a new treatment modality for human malignant brain tumors.

Topics: Adjuvants, Immunologic; Adult; Antibodies, Monoclonal; Apoptosis; Brain Neoplasms; DNA Damage; Fas Ligand Protein; fas Receptor; Glioma; Humans; Immunotherapy, Adoptive; Leukocytes, Mononuclear; Membrane Glycoproteins; Picibanil; RNA, Messenger; Tumor Cells, Cultured

We have employed IAR therapy [combination of postirradiation, chemotherapy and interferon (IFN)] for malignant glioma patients. Changes of lymphocyte fractions in patients were evaluated before and after IAR therapy, using a recently developed two-color analysis. Eight malignant glioma patients received irradiation, chemotherapy (ACNU) and immunotherapy (OK-432 and IFN-beta). Peripheral blood lymphocytes taken during hospitalization with IAR therapy (first half and latter half), and every 3 to 6 months for 2 years at the longest after IAR therapy were double-stained with FITC- and PI-labelled antibodies and two-color analysis was conducted by a FACS Analyzer. Six patients out of 8 survived for 6 months to 2 years, 2 died after 3 and 6 months, respectively. Leu-2a (suppressor/cytotoxic T), especially Leu-2a+ 15- (cytotoxic T) showed a high value. Leu-2a level decreased during treatment, and both Leu-2a+ 15- and Leu-2a+ 15+ (suppressor T) values decreased. Two thirds of the patients showing an increased Leu-2a+ 15+ level died. Leu 3a (helper/inducer T), especially Leu-3a+ 8+ (inducer T) level decreased, but Leu-3a+ 8- (helper T) level increased during treatment. The level decreased in the worse patients. Leu-3a/Leu-2a ratio was low, but it increased during treatment as compared with the results of conventional therapy. Leu-7, Leu-11a, NK activity, and gamma-IFN productivity were further studied. Treatment combined with IFN revealed an influence on the T cells resulting in an increase of helper T level and suppression of suppressor T level.

Topics: Adult; Aged; Brain Neoplasms; Combined Modality Therapy; Female; Glioma; Humans; Interferons; Male; Middle Aged; Nimustine; Picibanil; Radiotherapy Dosage; T-Lymphocyte Subsets; T-Lymphocytes, Cytotoxic; T-Lymphocytes, Helper-Inducer; T-Lymphocytes, Regulatory

In this study, we tried to examine the efficacy of a cytotoxic factor which is induced by periodic, repeated local administration of OK-432 into the tumor cavity of malignant glioma patients. OK-432 was administered intratumorally via a tube to 4 malignant glioma patients on Days 1, 3, 5, 7 and 12 in doses of 0.5 KE, 1 KE, 2 KE, and 3 KE, respectively. Cerebrospinal fluid (CSF) was collected several times during the 24-hour period beginning immediately after the administration on Day 12. The CSF was added to the culture medium of rat glioma cells (GA-1 and C-6) in order to observe the cytotoxic effect morphologically. The clinical efficacy in the patients was evaluated from the changes in tumor size observed by CT. CSF collected from the tumor cavity of 3 patients was bloody. By adding this bloody CSF, a significant morphological cytotoxic effect was observed on both the GA-1 and C-6 glioma cells in culture. The level of cytotoxicity was higher with the bloody fluid collected at 4 to 24 hours after the final administration than with the bloody fluid collected immediately after the final administration. The cytotoxic effect of this fluid was stronger than that of rabbit TNF (tumor necrosis factor) serum induced with P. acnes and LPS.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Brain Neoplasms; Glioma; Humans; Injections, Intralesional; Picibanil; Rabbits; Rats

To ascertain whether tumor-specific immune response occurs in patients with malignant brain tumors, lymphocyte blastogenetic responses to tumor cells were examined in 18 patients prior to operation and other treatment. Among 12 patients with malignant glioma, the peripheral blood lymphocytes (PBL's) showed a positive blastogenetic response to their own glioma cells in seven (58.3%), whereas the tumor-infiltrating lymphocytes (TIL's) showed a positive response in only three (25%). In four (66.7%) of six patients with metastatic brain tumors, however, both the PBL's and TIL's showed a positive blastogenetic response to their own tumor cells. In these four patients, this lymphocyte blastogenetic response to tumor cells were at a much lower level compared with phytohemagglutinin P or allogeneic lymphocyte stimulation. Furthermore, these responses were increased when the cells were cultured with interferon-gamma (500 U). Other lymphokines had no effect on the response. This method appears to be useful in identifying the tumor-specific immune response in patients with malignant brain tumor.

Topics: Adolescent; Adult; Aged; Antibody Formation; Brain Neoplasms; Glioma; Humans; Interferon-gamma; Interleukin-2; Lymphocyte Culture Test, Mixed; Lymphocytes; Middle Aged; Picibanil

In considering immunological approaches to treatment of the patients with malignant brain tumors, it seems very important to enhance the tumor specific immunity. Then, to ascertain whether tumor specific immune response occurs in these patients with malignant brain tumors, lymphocyte blastogenetic responses to tumor cells were examined in 18 patients with malignant brain tumors. Furthermore, to compare the systemic immunological responses with the local responses in the brain tumor tissues, both peripheral blood lymphocyte (PBL) and tumor infiltrating lymphocyte (TIL) were used as blastogenetic stimulators to the tumor cells. The PBL from the patients with malignant gliomas showed any positive blastogenetic response to their own glioma cells in 7 or 12 cases (about 58%). But, TIL from these patients showed a positive response in the only 3 cases (25%). In 6 cases of metastatic brain tumors, otherwise, their PBL showed any positive blastogenetic response to their own tumor cells in 4 of 6 cases (about 67%), and their TIL showed any positive blastogenetic responses in these same 4 cases. So, the tumor specific immunological responses may be stronger in the patient with metastatic brain tumors than in the patient with malignant gliomas. These immunological responses were, furthermore, more weak in the brain tumor tissues than in the systemic immunity. Then, this lymphocyte blastogenetic response to tumor cells were compared with other lymphocyte stimulating examination such as rectine or allogenetic lymphocyte stimulation. Our studies revealed that this lymphocyte blastogenetic response to tumor cells were at lower level compared with rectine such as PHA, PWM, and Con A, or allogenetic lymphocyte stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Brain Neoplasms; Female; Glioma; Humans; Interferon-gamma; Interleukin-2; Lymphocyte Activation; Lymphocyte Culture Test, Mixed; Male; Middle Aged; Picibanil; Tumor Cells, Cultured

Chronological changes of glioma tissues treated with local immunotherapy with OK-432 were examined by immunohistochemical method. OK-432 was injected into glioma tissues through Ommaya's reservoir 3 days (3 patients), 7 days (2 patients) and 14 days (2 patients) prior to the operation. Frozen sections surgically obtained from these patients were stained with avidin-biotin-peroxidase complex method using Leu-series monoclonal antibodies for pan T lymphocytes (Leu-1), cytotoxic/suppressor T lymphocytes (Leu-2 a), helper/inducer T lymphocytes (Leu-3 a), B lymphocytes (Leu-12), MHC class I antigen (beta 2m) and MHC class II antigen (HLA-DR). In 2 out of 7 glioma tissues obtained before local injection of OK-432, only few T lymphocytes were found infiltrating around the small blood vessels. In all glioma tissues obtained 3 and 7 days after injection, coagulation necrosis of glioma tissues was observed within 1-2 cm from Ommaya's tube and many T lymphocytes granulocytes and macrophages were infiltrating diffusely in the glioma tissues. Whereas in all glioma tissues obtained 14 days after injection, coagulation necrosis was also observed, however granulocytes and macrophages were scarce. The most of the infiltrating cells were T lymphocytes. Examination of T lymphocytes phenotypes revealed that both cytotoxic/suppressor and helper/inducer phenotypes of T lymphocytes were intermingled with each other in all cases. beta 2m was expressed on the most of glioma cells in all cases before and after injection. Whereas HLA-DR antigen was expressed on the tumor cells in 4 out of 7 cases before injection, however this antigen was expressed in all cases after injection.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Antibodies, Monoclonal; Biological Products; Female; Glioma; Histocompatibility Antigens Class I; Histocompatibility Antigens Class II; Humans; Immunohistochemistry; Immunotherapy; Lymphocytes; Male; Middle Aged; Picibanil

Topics: Animals; Astrocytoma; Biological Products; Brain Neoplasms; Cobalt Radioisotopes; Combined Modality Therapy; Glioma; Humans; Nimustine; Nitrosourea Compounds; Picibanil; Rats

Topics: Brain Neoplasms; Glioma; Humans; Interferon-gamma; Interleukin-2; Picibanil

A crucial manifestation of malignant gliomas is the regrowth of already-invaded neoplastic cells after surgical intervention. One possible approach for inhibiting such tumor growth is to utilize the tumoricidal potential of macrophages. In order to investigate the clinical application of this concept, peritoneal exudate cells (PEC) activated in vitro and in vivo by immunomodulating agents were tested for cytotoxic activity against murine glioma (203-glioma) cells. As immunomodulating agents, heat-killed Propionibacterium acnes (P. acnes), OK-432 and Concanavilin A supernatant (Con A sup) were used in these experiments. P. acnes was provided by Kowa Pharmaceutical Co., Tokyo, and OK-432 by Chugai Pharmaceutical Co., Ltd., Tokyo. Klinische Einheit (KE) units were used to express the strength of the preparation, with 1 KE equal to 0.1 mg of dried streptococci. Con A sup was produced by Con A pulsing of BALB/c splenocytes resuspended in complete medium. PEC harvested from mice to which 5% glycogen in saline had been inoculated intraperitoneally 6 d previously were activated in vitro by P. acnes (P. acnes-PEC), OK-432 (OK-432-PEC) and Con A sup (Con A-PEC). The cytotoxic activities of P. acnes-PEC, OK-432-PEC and Con A-PEC were approximately 25%, 65% and 60%, respectively. PEC were then collected from mice into which either 100 micrograms of P. acnes or 1 KE of OK-432 had been injected intraperitoneally several times. The antitumor effects of P. acnes-PEC and OK-432-PEC were about 35% and 50%, respectively. These activated PEC demonstrated cytotoxic activity against murine glioma in the tumor neutralization assay (Winn assay). Also, the antitumor efficacy of OK-432-PEC belonged mainly to adherent cells. Meningeal gliomatosis (MG) models were prepared for clinical studies. Viable 203-glioma cells (5 X 10(6) were injected percutaneously into the cisterna magna of C57BL/6 mice. The median survival time (MST) of the untreated group was 8.5 days. The MST of the groups treated by intraperitoneal and intracisternal administration of P. acnes were 26 and 33 days. This therapy significantly prolonged the survival time of these models, particularly by the intracisternal treatment. The differential cell count by Giemsa staining and latexphagocytic cell findings revealed that macrophages accounted for more than 90% of the P. acnes-PEC. These results may indicate that activated (PEC) macrophages were induced intracisternally by P. acnes and that activated macrophages induc

Topics: Animals; Concanavalin A; Cytotoxicity, Immunologic; Female; Glioma; Macrophage Activation; Macrophages; Mice; Mice, Inbred C57BL; Picibanil; Propionibacterium acnes

Topics: Adolescent; Adult; Biological Products; Cerebellar Neoplasms; Child; Combined Modality Therapy; Female; Glioma; Humans; Male; Medulloblastoma; Picibanil; Pinealoma; Radiotherapy Dosage; Spinal Cord

Topics: Adult; Aged; Animals; BCG Vaccine; Biological Products; Brain Neoplasms; Female; Glioma; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Middle Aged; Picibanil

In the first part of this paper, various chemotherapies were performed against oligodendrogliomas subcutaneously transplanted in to nude mice. Vincristine (VCR), adriamycin, and 1000 rads irradiation were effective against this tumors. Concerning these two drugs, dose response effect was observed. And the effect of 1 mg/kg injection of VCR roughly corresponded to that of five weekly injections of 0.2 mg/kg. In the second part of this experiment, single or combined effects of VCR and immunotherapeutic agents including OK-432 (OK), PSK, and recombinant leucocytic interferon (IFN) were examined. Two glioma lines including oligodendroglioma and glioblastoma were used. Following results were obtained from this experiment: 1) Effect of OK and VCR against oligodendrogliomas were as follows: control less than OK local injection (Local) less than OK intraperitoneal injection (IP); VCR; OK (IP X 2) less than VCR + OK(IP) less than VCR + OK (IP X 2). Effects of OK and VCR were expressed in order of their effects against glioblastomas: control less than VCR less than OK (IP); OK(IP X 2); OK(Local) less than VCR + OK (IP); VCR + OK (IP X 2). Effects of PSK and VCR against glioblastomas were as follows: control; PSK (Local) less than VCR less than VCR + PSK (Local) less than VCR + PSK (IP). Effects of IFN and VCR against oligodendrogliomas were as follows: control; IFN (IP) less than VCR less than IFN (Local) less than VCR + IFN (IP); VCR + IFN (Local). Effects of IFN and VCR against glioblastomas were as follows: control less than IFN (IP) less than VCR; IFN (Local); VCR + IFN (IP).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Biological Products; Doxorubicin; Glioma; Humans; Interferon Type I; Mice; Mice, Nude; Neoplasm Transplantation; Oligodendroglioma; Picibanil; Proteoglycans; Specific Pathogen-Free Organisms; Vincristine

Chemotherapy was applied for experimental subarachnoid dissemination model of brain tumor which was established in male Wister-SPF (SLC) rats inoculated intracisternally with 2 X 10(5) C6 rat glioma cells. Nontreated animals died about 24 days after inoculation. Autopsy findings of the animals showed localized or multifocal invasion of the tumor on leptomeninges in cisterna magna, and partially infiltration into the parenchyma of the cerebellum and medulla oblongata. Three days after inoculation, the tumor deposition and proliferation already occurred. Several tumor cell layers were found in the subarachnoid space over the cerebellomedullary surface. Tumor bearing animals were at first treated by single agent. These are ACNU administered intraperitoneally, methotrexate administered intracisternally, and OK-432 administered intraperitoneally. In the next stage, combination of these drugs was applied. ACNU, 3 mg/kg i. p., on Day 3, was effective in elongation of median survival time by 23.6%, statistically significant (P less than 0.02). Methotrexate, 0.25 mg/kg i.th., on Day 3, was also effective in elongation of median survival time by 8.4%, statistically significant (P less than 0.05). OK-432, 0.1 KE/kg i. p., daily, 14 times, from Day 3 to Day 16, was ineffective in elongation of median survival time. Combination of ACNU, methotrexate and OK-432, in the same schedule as described above, produced the longest median survival time of 42.4%, statistically significant (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Glioma; Injections, Intraperitoneal; Meningeal Neoplasms; Methotrexate; Neoplasm Transplantation; Nimustine; Nitrosourea Compounds; Picibanil; Rats; Rats, Inbred Strains

Topics: Astrocytoma; Biological Products; Brain Neoplasms; Combined Modality Therapy; Drug Therapy, Combination; Ependymoma; Fluorouracil; Glioma; Humans; Lymphoma; Meningeal Neoplasms; Meningioma; Nimustine; Nitrosourea Compounds; Oligodendroglioma; Picibanil

Topics: Adult; Aged; Brain Neoplasms; Child; Female; Glioma; Humans; Immunity, Cellular; Immunotherapy; Male; Middle Aged; Phytohemagglutinins; Picibanil; Tuberculin Test

Topics: Antineoplastic Agents; Brain Neoplasms; Doxorubicin; Drug Therapy, Combination; Glioma; Humans; Picibanil; Semustine

Thirteen patients with malignant brain tumors, 12 anaplastic gliomas and one metastatic tumor, received repeated intratumoral injections of an immunopotentiator, Picibanil, prepared from streptococcus pyogenes. All patients tolerated this therapy; morbidity rates were acceptable. Significant tumor regression was noted on computerized tomography scanning for 6 of 12 patients for whom scanning was performed. Histologic examination of the post-therapy specimens obtained from 8 patients revealed that inflammatory reactions were evoked in all of the tumors, although the extent of inflammatory changes varied from patient to patient and mostly was localized to an area surrounding the intratumoral tubes.

Topics: Adjuvants, Immunologic; Adult; Aged; Biological Products; Brain Neoplasms; Female; Glioma; Humans; Injections; Male; Middle Aged; Neoplasm Metastasis; Picibanil; Streptococcus pyogenes; Tomography, X-Ray Computed