Immunotherapy using the streptococcal preparation OK-432 for the treatment of uterine cervical cancer

The clinical efficacy of LC9018, a biological response modifier prepared from heat-killed Lactobacillus casei YTT9018, used in combination with radiation was studied in a randomized controlled trial on 61 patients with carcinoma of the uterine cervix of Stage IIB or III. The combination therapy with LC9018 demonstrated a significant effect on tumor reduction, compared with radiation therapy alone, at the cumulative doses of 15-Gy and 30-Gy external irradiation (P less than 0.05). Histologic study confirmed that LC9018 also enhanced the therapeutic effect of the irradiation. Moreover, LC9018 seemed to be useful in protecting the patients from leukopenia during radiotherapy. This study suggests that LC9018, when used in combination with radiotherapy, will be an effective adjuvant immunotherapeutic agent. More studies in a large series of patients will, however, be needed to establish its long-term efficacy, safety, and effects on both prognosis and enhancing radiotherapy.

Phase II randomized clinical trial of LC9018 concurrently used with radiation in the treatment of carcinoma of the uterine cervix. Its effect on tumor reduction and histology

Okawa

Kita

Arai³

et al. 1989

Effect of lc9018 combined with radiation therapy on carcinoma of the uterine cervix. A phase iii, multicenter, randomized, controlled study

Okawa

Niibe

Arai³

et al. 1993

Background. The failure rate with radiation therapy alone for Stage III cervical cancer is quite high, and therefore other modalities are being pursued as adjuvants to radiation therapy in hopes of improving the results. Methods. A randomized, controlled, comparative study on the efficacy and safety of radiation therapy combined with LC9018 (a biologic response modifier prepared from heat‐killed Lactobacillus casei YIT9018) was conducted using 228 patients with Stage IIIB cervical cancer. Results. LC9018 enhanced tumor regression (P < 0.1) by radiation after both 30 Gy of external radiation and at the completion of radiation therapy. The combination therapy also prolonged survival and the relapse‐free interval (P < 0.05) compared to radiation alone. Analysis of survival using the Cox proportional hazard model indicated that use of LC9018 was a significant factor related to survival duration. Major side effects of combined LC9018 included fever and skin lesions at the injection site, but no severe symptoms were noted. Radiation‐induced leukopenia was significantly less severe (P < 0.05) in the LC9018‐combined group than in the radiation‐alone group, suggesting that this agent might help to prevent leukopenia during radiation therapy. Conclusions. LC9018 was shown to be an effective agent for adjuvant immunotherapy when combined with radiation therapy.

Intratumoral injection of a streptococcal preparation, OK-432, before surgery for gastric cancer. A randomized trial

Tanaka

Gouchi

Ohara

et al. 1994

Background. The preoperative intratumoral injection with OK‐432 (Picibanil, Chugai Pharmaceutical Co., Tokyo, Japan), an immunomodulatory agent prepared from an attenuated strain of streptococcus pyogenes, activates the regional immune system and causes degeneration of cancer tissue in carcinoma of the stomach. Methods. A multi‐institutional randomized trial of OK‐432 to determine its clinical usefulness was conducted. Three hundred and ninety‐five patients with gastric cancer were assigned randomly either to receive or not to receive a preoperative intratumoral injection of OK‐432. Among them, 277 patients with advanced cancer were treated by common postoperative chemoimmunotherapy consisting of mitomycin C, tegafur, and OK‐432. All patients were followed for at least 5 years. Results. The adverse effects of OK‐432 injected intratumorally predominantly were mild fever, anorexia, and abdominal pain, however, no treatment was required for these symptoms. Overall, there were no differences in outcome between the OK‐432 and control groups. However, analysis based on stage showed that a preoperative intratumoral injection of OK‐432 significantly improved the 5‐year survival rate of patients with Stage III cancer (P = 0.0229), at 47.7% for the OK‐432 group and 27.5% for the control group. In subset analysis, when the 5‐year survival of patients with and without tumor infiltrating lymphocytes (TIL) was compared, OK‐432 injected intratumorally had a significant positive effect on the group showing a moderate to marked number of TIL (P = 0.0438). Conclusion. These results showed that the intratumoral injection of OK‐432 may improve survival of patients with Stage III gastric cancer.