Clinical significance of immunotherapy for lung cancer--present and future

To evaluate the clinical efficacy of OK-432 immunotherapy as an surgical adjuvant for lung cancer patients, three kinds of randomized controlled trials were done. In the first trial, patients were randomized into two groups: an immunochemotherapy (IM-C) group and a chemotherapy (control) group. For IM-C group, OK-432 (2KE/w) was injected intramuscularly for three years. Significant improvement of the survival rates in the IM-C group was noted in the following items: all resected cases, stages I+II cases, stage III cases, completely resected cases, incompletely resected cases and cases with epidermoid carcinoma. However, in comparison to adenocarcinoma there was no significant difference between the two groups. In the second trial, patients were randomized into an intramuscular injection group and an intradermal injection group. In comparisons to the survival rates, there were no significant differences between the two groups. In the third trial, stage I patients were randomized into a group treated with intradermal injection (5KE/w) and no adjuvant group. To date, there was no significant difference between the two groups. It is concluded that OK-432 immunotherapy, with concomitant use of chemotherapy, have favourable effect on the patient with squamous cell carcinoma. No definitive difference of clinical effects between intramuscular injection and intradermal injection.     

A comprehensive multi-institutional study on postoperative adjuvant immunotherapy with oral streptococcal preparation OK-432 for patients after gastric cancer surgery. Kyoto Research Group for Digestive Organ Surgery.

The current study was designed to compare the effects of oral administration of the streptococcal preparation, OK-432, as an adjuvant immunotherapy versus those of intradermal administration of OK-432 on the survival of patients after surgery for gastric cancer. The patients were stratified into two groups after surgery: a curative surgery stratum and a palliative surgery stratum. Then the patients in each stratum were randomly assigned into three groups: an oral placebo group, an oral OK-432 group, and an intradermal OK-432 group. All of the patients were given fluoropyrimidines orally in combination with OK-432 or placebo for 2 years after surgery. A total of 1011 patients were registered between 1982 and 1985, and 970 patients were eligible for statistical analysis. The survival rate of the oral OK-432 group was significantly higher than those of the other two groups after curative surgery. There were no significant difference in the survival rates between the three groups after palliative surgery, however. The effect of oral OK-432 was quite pronounced in patients after curative surgery for stage II to IV gastric cancer, especially in those patients with regional node involvement. Furthermore, it was found that the spleen is necessary for effective immunotherapy with oral OK-432, because the survival rate of the oral OK-432 group was significantly improved in patients whose spleens were preserved, when compared with splenectomized patients. These results demonstrate that oral adjuvant immunotherapy with OK-432 is beneficial after curative surgery for gastric cancer.     

Immunity of gut-associated lymphoid tissue and the role of the oral immunotherapy in multi-disciplinary treatment of the digestive organ cancer

In order to augment antitumor immunity of gut-associated lymphoid tissue in digestive organ cancer, oral administration of various biological response modifiers were studied using mice transplanted with cecal tumor. Among them OK-432 was the most effective and clinical application of oral OK-432 was studied. Autoradiogram and immunofluorescence studies showed the absorption of orally administered OK-432 from the gut. In phase I study oral OK-432 was much less toxic than other administration routes. Phase II study showed that oral OK-432 at various doses augmented antitumor immunity of the lymphocytes of peripheral blood and regional lymph node. In a multi-institutional study on postoperative adjuvant immunotherapy, 1011 gastric cancer patients were accumulated and randomized to compare the effects of oral and intradermal OK-432. In patients who underwent curative operation, 1-, 2- and 3-year survival rates (%) were 95, 88 and 82 for oral OK-432 group (n = 255), 88, 83 and 80 for the placebo group (n = 260), and 89, 79 and 73 for intradermal OK-432 group (n = 261). There was significant differences among cumulative survivals of three groups, and this life-prolonging effect of oral OK-432 was remarkable for stage II or III patients. These results demonstrate that oral immunotherapy with OK-432 is useful as an immunotherapy of digestive organ cancers.     

A randomized controlled study to compare bladder instillation therapy of anticancer agents and combination therapy with OK-432 injection in prevention of post-TUR recurrence of bladder cancer

To evaluate the effects of bladder instillation chemotherapy of anticancer agents with OK-432 intradermal injection (group A) in preventing postoperative recurrence of bladder carcinoma, a randomized controlled study with intravesical instillation chemotherapy of anticancer agents (group B) as the reference standard was performed. As the anticancer agents, pepleomycin (PEP) was usually used at a concentration of 30 mg/30 ml physiological saline. OK-432 injection dose was gradually increased from 0.5 KE to 5.0 KE and maintenance dose was decided by local skin reactions. There were no differences in the patient's background factors between group A (22 cases) and group B (17 cases). The no-recurrence rate of bladder carcinoma was similar in the two groups, but the no-recurrence rate for the virgin tumor or the stage T0 cases was higher in group B. On the other hand, the values for the recurrent cases or the stage T1,2 cases was higher in group A. The SU-PS skin reaction as an immunological response was significantly higher in group A. There were no severe side effects derived from anticancer bladder instillation or OK-432 injection.     

Treatment of tumors of the urinary bladder with so-called immunopotentiators

Eighty-eight cases of urinary bladder tumor were treated in our Department from 1976 to 1978. The effect of so-called immunopotentiators (OK-432, Levamisole and PSK) was studied in 23 patients. The following results were obtained. Pretreatment intracutaneous response to PHA was significantly lower in the high stage and high grade group than in the low stage and low grade group (P less than 0.025). However, there was no correlation between the effect of immunotherapy and PHA skin reaction. Of the immunoglobulins, only IgM was significantly lower in the high grade group than in the low grade group (P less than 0.025). The one-year survival rate for the patients in the high stage group was higher receiving immunotherapy than those not treated. This suggests that immunotherapy may be useful for prolonging the survival time of patients with advanced bladder carcinoma.     

Postoperative adjuvant immunochemotherapy with mitomycin C,tegafur, PSK and/or OK-432 for gastric cancer,with special reference to the change in stimulation index after gastrectomy

In order to evaluate the efficacy of combined immunochemotherapy with mitomycin-C, tegafur, PSK and/or OK-432 as an adjunct for curatively resected gastric cancer, a prospective randomized controlled study using the envelope method was performed, in which 266 institutions from around Japan participated. The 3 year survival rates for all cases, and for ps(+)·n(+) cases, were insignificantly higher in the immunochemotherapy groups receiving PSK and/or OK-432 than in the control group. However, because 28.2 per cent of the cases were excluded from the final statistical analyses, the results of this study may have questionable statistical credibility. Changes in the stimulation index (SI) suggest that the administration of PSK may result in an inhibition of the immunosuppressive activity of cancer patients. The high SI group showed a significantly higher 4 year survival rate than the low SI group. The Cooperative Project No. 1 of the Japanese Foundation for Multidisciplinary Treatment of Cancer     

Postoperative adjuvant immunochemotherapy with mitomycin C, tegafur, PSK and/or OK-432 for gastric cancer, with special reference to the change in stimulation index after gastrectomy

In order to evaluate the efficacy of combined immunochemotherapy with mitomycin-C, tegafur, PSK and/or OK-432 as an adjunct for curatively resected gastric cancer, a prospective randomized controlled study using the envelope method was performed, in which 266 institutions from around Japan participated. The 3 year survival rates for all cases, and for ps(+).n(+) cases, were insignificantly higher in the immunochemotherapy groups receiving PSK and/or OK-432 than in the control group. However, because 28.2 per cent of the cases were excluded from the final statistical analyses, the results of this study may have questionable statistical credibility. Changes in the stimulation index (SI) suggest that the administration of PSK may result in an inhibition of the immunosuppressive activity of cancer patients. The high SI group showed a significantly higher 4 year survival rate than the low SI group.     

Results of surgery on 6589 gastric cancer patients and immunochemosurgery as the best treatment of advanced gastric cancer.

Results of 6589 gastric cancer operations at the Department of Surgery, Seoul National University Hospital, from 1970 to 1990 were reported. About two thirds (76.6%) were advanced gastric cancer (stages III and IV). The 5-year survival rate of operated stage III gastric cancer was only 30.6%, with frequent recurrence. Conversely, cell-mediated immunities of advanced gastric cancer patients were significantly decreased. Therefore, to improve the cure rate and to prevent or delay recurrence, curative surgery with confirmation of free resection margins and systematic lymph node dissection of perigastric vessels were performed and followed by early postoperative immunotherapy and chemotherapy (immunochemosurgery) in stage III patients. To evaluate the effect of immunochemosurgery, two randomized trials were studied in 1976 and 1981. In first trial, 5-fluorouracil, mitomycin C, and cytosine arabinoside for chemotherapy and OK 432 for immunotherapy were used. The 5-year survival rates for surgery alone (n = 64) and immunochemosurgery (n = 73) were 23.4% and 44.6%, respectively, a significant difference. In the second trial, there were three groups: group I, immunochemosurgery (n = 159); group II, surgery and chemotherapy (n = 77); and group III, surgery alone (n = 94). 5-Fluorouracil and mitomycin C for chemotherapy and OK-432 for immunotherapy were administered for 2 years. The 5-year survival rate of group I was 45.3%, significantly higher than the 29.8% of group II and than the 24.4% of group III. The postoperative 1-chloro-2.4-dinitrobenzene test, T-lymphocyte percentage, phytohemagglutinin- and con-A-stimulated lymphoblastogenesis and the antibody-dependent cell-mediated cytotoxicity test showed more favorable values in the immunochemosurgery group. Therefore, immunochemosurgery is the best multimodality treatment for advanced gastric cancer.     

The clinical efficacy of intratumoral OK-432 administration in advanced cancer patients

The clinical efficacy of intratumoral (IT) OK-432 immunotherapy in advanced cancer patients was investigated. Furthermore, the infiltration of lymphocyte subsets into the tumor tissues after the IT administration of OK-432 was also immunohistologically examined in order to analyze the mechanism of action of OK-432 immunotherapy. Forty-four patients with advanced cancer were treated with IT OK-432 immunotherapy. Ten KE (1 mg) of OK-432 was given either daily or on every second day and repeated as often as possible, the mean frequency of OK-432 injections being 18.1 +/- 14.5 times, ranging between 5 and 25 administrations. Thirty-one of the 44 patients were evaluable, 3 of whom (9.7 per cent) developed a partial response and 5 (16.1 per cent) a minor response. Intratumoral OK-432 immunotherapy, however, did not necessarily prolong the survival time. Leu 1, 3 and 7 reactive cells infiltrated into the tumor tissues treated by OK-432 injection, more frequently, when compared with cells which had been treated by recombinant TNF injection. Thus, it was suggested that IT OK-432 immunotherapy might be effective for the local control of tumor growth through the host mediated action, and that, in combination with systemic therapy, may enhance the clinical effects and prolong the survival time in advanced cancer patients.     

OK-432-combined adoptive immunotherapy as a prognostic factor in peritoneal metastasis from gastric cancer

Prognostic factors, such as preoperative status, intraoperative findings, and postoperative treatments, were evaluated in 61 patients with peritoneal metastasis from gastric cancer treated in our facility between 1979 and 1991. Since 1986, 23 patients have been treated with OK-432-combined adoptive immunotherapy (AIT). OK-432-combined AIT is a sequential treatment via a catheter inserted into the abdominal cavity, using a streptococcal preparation, OK-432, followed by the transfer of lymphocytes cultured with T cell growth factor and sonicated tumor extract. A univariate analysis showed that six factors consisting of: (1) age, (2) resection of primary lesion, (3) grade of peritoneal metastasis or serosal invasion, (4) chemotherapy, (5) OK-432, and (6) OK-432-combined AIT influenced survival. The survival of the patients given OK-432-combined AIT (median survival time; MST = 7.5 months) was significantly (P = 0.0267) longer than that of those not receiving OK-432-combined AIT (MST = 4.3 months). A multivariate analysis showed that the most significant factors associated with survival were chemotherapy, resection of the primary lesion, and OK-432-combined AIT. Since these three factors are all therapeutic procedures, the use of combination therapy including OK-432-combined AIT is thus expected to prolong the survival of gastric cancer patients with peritoneal metastasis.     

The clinical efficacy of intratumoral OK-432 administration in advanced cancer patients

The clinical efficacy of intratumoral (IT) OK-432 immunotherapy in advanced cancer patients was investigated. Furthermore, the infiltration of lymphocyte subsets into the tumor tissues after the IT administration of OK-432 was also immunohistologically examined in order to analyze the mechanism of action of OK-432 immunotherapy. Forty-four patients with advanced cancer were treated with IT OK-432 immunotherapy. Ten KE (1 mg) of OK-432 was given either daily or on every second day and repeated as often as possible, the mean frequency of OK-432 injections being 18.1±14.5 times, ranging between 5 and 25 administrations. Thirty-one of the 44 patients were evaluable, 3 of whom (9.7 per cent) developed a partial response and 5 (16.1 per cent) a minor response. Intratumoral OK-432 immunotherapy, however, did not necessarily prolong the survival time. Leu 1, 3 and 7 reactive cells infiltrated into the tumor tissues treated by OK-432 injection, more frequently, when compared with cells which had been treated by recombinant TNF injection. Thus, it was suggested that IT OK-432 immunotherapy might be effective for the local control of tumor growth through the host mediated action, and that, in combination with systemic therapy, may enhance the clinical effects and prolong the survival time in advanced cancer patients.     

Pathophysiology and treatment of multiple organ failure among hepatectomized cirrhotic patients

Our previous studies have claimed that cirrhotic rats, induced with CCl4, showed depressed reticuloendothelial system (RES) function and increased susceptibility to infection. We have also shown that OK-432, a non-specific immunopotentiator, and ATP-MgCl2, which improves depressed intracellular energy metabolism, improve RES function of cirrhotic rats and that thereby improve survival following peritonitis or hepatectomy. The present study was undertaken to investigate whether OK-432 or ATP-MgCl2 could be beneficial for the prevention of multiple organ failure (MOF) following hepatectomy among the cirrhotics. The cirrhotics with hepatocellular carcinoma, who underwent partial hepatectomy (segmentectomy or subsegmentectomy) were given OK-432 (5 KE/day for 4 days) preoperatively or ATP-MgCl2 (50 mumole/kg) within 24 hours following the operation. The rates of postoperative pulmonary complication and the operative mortality were compared among OK-432 group, ATP-MgCl2 group and controls. The rates of posthepatectomy pulmonary complication and operative mortality were decreased with these treatments compared to the controls. The RES function was also improved with these treatments. These data suggest that the cirrhotic patients are the immunocompromised hosts showing the depressed RES function and that the enhancement of RES function with OK-432 or ATP-MgCl2 is beneficial for the prevention of posthepatectomy MOF among cirrhotics.     

A randomized trial of postoperative CDDP-based chemotherapy/chemoradiotherapy vs short-term immunochemotherapy in lung cancer

BACKGROUND: Although a few reports indicated some benefit to survival, the effect of adjuvant therapy for the patients with resected lung cancer was still controversial. The aim of our study was to evaluate survival advantage of CDDP-based adjuvant therapy compared with short-term immunochemotherapy. METHODS: Experimental design: prospective randomized trial. Patients: from 1990 through 1994, 94 patients were registered. Forty-seven patients were randomly assigned to each group, i.e., CDDP-based therapy group (CB Group, CDDP+VDS+tegafur+OK-432 or CDDP+OK-432+mediastinal irradiation) or immunochemotherapy group (IC Group, tegafur+OK-432). Patients in both groups were followed at 4-month intervals with the routine follow-up program of our department. RESULTS: No significant difference was observed between the patients' characteristics of two groups. Compliance of the regimen in each group was 79% in CB Group and 85% in IC Group. No treatment-related death was observed. Five-year survival rates of CB Group and IC Group were 49% and 51%, and 5-year disease-free survival rates were 46% and 44%, respectively. There were no statistical differences between the two groups. Furthermore, no survival differences could be found between CB Group and IC Group in any subgroup of patients. CONCLUSIONS: Both of these regimens were feasible. However, we have not observed any survival benefit in the CB Group in any subgroup, so far. Induction therapy, new chemotherapeutic agents, or anti-angiogenetic a agents may improve the survival of surgically treated lung cancer patients.     

Intratumoral injection of OK-432 in conjunction with fibrinogen greatly enhances antitumor effect on colorectal carcinomas]

We found that antitumor effect of OK-432, a lyophylized preparation of an attenuated strain of streptococcus pyogenes, on colorectal carcinoma was greatly augmented when it was injected intratumorally in conjunction with fibrinogen. Twenty cases of colorectal cancer received intratumoral injection of 5 KE of OK-432 mixed with 80mg of fibrinogen including factor-XIII and 1ml of aprotinin at the time of endoscopic examination. Changes in the shape of the tumors were observed endoscopically within a few days after injection, and in most cases, decrease in the height of tumor margin was noted. Histopathological findings on surgically resected specimens revealed that the fine meshwork of fibrin was formed at the injected site soon after the injection, and a marked infiltration of inflammatory cells including neutrophils, plasma cells, macrophages, eosinophils and lymphocytes. Such granulomatous changes developed over 7 days after injection, and the degradation of tumors were observed. By 14 days after the injection, tumor tissues were largely replaced with granulomas, and shrinkage of tissues were observed. These findings indicated that fibrinogen including factor-XIII and aprotinin has a potential ability to augment the immunoreaction induced by biological response modifiers, and intratumoral injection of OK-432 in conjunction with fibrinogen solution was superior to intratumoral injection of OK-432 alone as the local immunotherapy of colorectal cancer.     

A randomized comparison of the effects of adjuvant therapy on resected stages II and III non-small cell carcinoma of the lung. The Lung Cancel Study Group.

The Lung Cancer Study Group has evaluated postoperative chemotherapy and immunotherapy in patients with Stages II and III adenocarcinoma and large cell undifferentiated carcinoma. Patients were randomized following surgery and careful intraoperative staging to receive either chemotherapy or immunotherapy. Chemotherapy consisted of CisPlatinum, Adriamycin, and Cytoxan and immunotherapy consisted of Levamisole and Intrapleural BCG. Sixty-eight patients were randomized to the immunotherapy arm and 62 to the chemotherapy arm. There were 49 recurrences in the immunotherapy group and 35 in the chemotherapy group (p = 0.003). These studies indicate that surgical adjuvant chemotherapy is effective in prolonging the disease-free survival in patients with Stages II and III adenocarcinoma and large cell undifferentiated carcinoma. Patients with Stages II and III resected squamous cell carcinoma were randomized to receive postoperative radiation therapy or no further treatment. One hundred and ninety patients were randomized into this study. There was no significant difference in terms of survival between the two treatment groups. However, those who received radiation therapy had a significantly lower incidence of local recurrence (p = 0.001). These studies indicate that postoperative radiation therapy is effective in controlling the local disease but that effective systemic therapy is necessary for improved survival in patients with Stages II and III squamous cell carcinoma of the lung.     

Effect of selective intra-arterial infusion of OK-432 against renal cell cancers

In 8 cases of operable renal cancer, selective intraarterial infusion of the streptococcal preparation, OK-432 was performed and its cytocidal effects on the surgical specimens, which were removed on the 8th day after infusion, were investigated histopathologically with immunological parameters of the peripheral blood. The histopathological study revealed a high grade of sinus histiocytosis of the renal pedicle lymph nodes, but the anti-tumor effect on renal tumors was not so marked in any of the 8 cases. OK-Ia-positive lymphoid cells of peripheral blood were increased significantly and Con-A stimulation index of blastogenesis was lowered without any change in the PHA stimulation index after the OK-432 infusion. No serious complications of the selective intraarterial infusion were experienced except for high fever (less than 38 degrees C). In conclusion, OK-432 selective intraarterial infusion was an effective method for improving regional and systemic immunoactivity, but the cytocidal effect against tumor cells could not be confirmed histopathologically.     

Effect of biological response modifiers on a spontaneous murine renal cell carcinoma regression of metastases caused by the streptococcal preparation OK-432

The effect of the streptococcal preparation OK-432, which is one of the biological response modifiers, was examined in BALB/c mice using a transplantable murine renal cell carcinoma (Renca) of spontaneous origin, and an analysis of effector cells was performed. The tumor grew progressively and metastasized consistently to the abdominal lymph nodes and then to distant organs following the inoculation of Renca cells in the left renal subcapsular site in BALB/c mice, and the survival time of the mice was under 42 days. In this tumor model, i.p. administration of OK-432 after tumor inoculation significantly extended the survival time and significantly inhibited the formation of the inoculated tumor itself. Removal of the left kidney on the 7th day after tumor inoculation neither extended the survival time nor augmented the effect of OK-432. Splenic cells obtained on the 7th day after tumor inoculation from Renca-bearing mice treated with OK-432 were capable of lysing syngeneic Renca cells, NK-sensitive allogenic YAC-1 cells, and LAK-sensitive EL-4 cells in a 4-hour 51Cr-release assay in vitro. Those obtained from healthy mice treated with OK-432 also showed cytotoxic activity against Renca cells. The cytotoxicity of splenic cells from Renca-bearing mice treated with OK-432 was lost almost completely for both Renca and YAC-1 cells after in vitro treatment with anti-asialo GM1 antibody, and was partially lost after in vitro treatment with anti-Thy-1,2 antibody. Additionally, in vivo i.p. administration of anti-asialo GM1 antibody significantly counteracted the effect of OK-432 on survival. These findings demonstrated that Renca cells were NK-sensitive and that the i.p. administration of OK-432 was beneficial for the prevention of the spontaneous metastasis of Renca carcinoma. As the effectors, NK cells played a dominant role and activated T cells were also involved.     

沙培林膀胱灌注对浅表性膀胱癌患者术后疗效观察

目的 研究沙堵林(OK-423)膀胱灌注预防浅表性膀胱癌术后的疗效及安全性.方法 将78例浅表型膀胱癌患者随机分成两组.沙培林组(40例)术后1周开始常规灌注沙培林5KE,膀胱内灌注保留2h,每周1次连续6周,之后每月1次连续8个月.对照组(38例)灌注吡柔比星30mg,灌注方法 同沙墙林组.结果随访6～36个月.原发...     

Local immunotherapy with streptococcal preparation, OK-432 in superficial bladder tumors, and common antigens between OK-432 and the tumor

In 38 patients with superficial bladder, local immunotherapy with streptococcal preparation OK-432 has been performed. We investigated whether OK-432 was an effective biological response modifier (BRM) against bladder tumors or not, and the relationship between the common antigens which OK-432 shared with the tumors, and antitumor effects of OK-432. In six out of 28 patients treated by intravesical instillation, and three out of 10 cases treated by intratumor injection, tumors were eliminated endoscopically. In the other patients, the tumors did not change. The PAP study using an anti-OK-432 antibody, showed a positive reaction in 66.7% of the instillation cases and in 40.0% in the injection cases. In 66.7% of the patients with the common antigens treated by the instillation and in 75.0% of patients with the antigens treated by the injection, tumors were eliminated. However, the PAP study showed a positive reaction in 9.1% of the no-change cases treated by the instillation and in 14.3% out of the no-change cases treated by the injection. We concluded that OK-432 was a favorable BRM for topical immunotherapy against bladder tumor and the presence of the common antigens between OK-432 and tumor may enhance the immune response of patients and promote tumor regression.     

Anti-tumor effects of the oral administration of the streptococcal preparation OK-432 (PICIBANIL)--the inhibition of carcinogenesis and growth in rats with ENNG-induced gastrointestinal tumors

We examined whether the Streptococcal preparation OK-432, an immunopotentiating agent, increases immunocompetence of the gut-associated lymphoid system (GALS), inhibits gastrointestinal carcinogenesis, and has an anti-tumor effect. 14C-labelled OK-432 was orally and intraperitoneally administered to rats, and the distribution of the agent in various organs then serially evaluated. The concentration of OK-432 in Peyer's patches and mesenteric lymph nodes was higher after oral administration than after intraperitoneal administration, and showed a biphasic pattern peaking at 30 minutes and 5 hours following administration, in the Peyer's patches. With regard to immunocompetence, PHA- and PWM-stimulated blastogenesis of lymphocytes derived from the mesenteric lymph nodes and peripheral blood enhanced, and the helper/suppressor T-cell ratio was elevated after the oral administration of OK-432. Moreover, chemotactic activity of peritoneal macrophages was also increased. ENNG-induced gastrointestinal carcinogenesis was observed in 60 per cent of the rats orally administered OK-432 as compared with 88 per cent of the controls. The 13-month survival rate of the rats with gastrointestinal cancer was 50 per cent in those administered OK-432 as compared with 25 per cent in those administered OK-432 as compared with 25 per cent in the controls. When administered orally, the agent prevented reduction in immuno-competence in the course of carcinogenesis, suppressed carcinogenesis, and prolonged the survival of animals with cancer without any of the side effects associated with injection. The oral administration of OK-432 is thus considered to be an effective non-specific immunotherapy against gastro-intestinal malignancies.