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

Abstract

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.

Intratumoral Vaccination and Diversified Subcutaneous/ Intratumoral Vaccination with Recombinant Poxviruses Encoding a Tumor Antigen and Multiple Costimulatory Molecules

“…approaches can be divided into two types based on the proposed antitumor mechanism: (a) direct eradication of tumor cells after the introduction of genetic materials, e.g., a replacement or inactivation of defective genes such as p53 in tumor cells, leading to tumor cell apoptosis (11)(12)(13); or (b) indirect approaches mediated by immune cells, e.g., the introduction of immunostimulatory molecules or vectors encoding immunostimulatory transgenes to influence the immune milieu of the tumor, culminating in the introduction of antitumor immune responses. For this purpose, biological response modifiers such as Bacillus Calmette-Guérin were originally used intratumorally not only in animal models (14 -17) but also in clinical trials (18,19). Recently, particular cytokines [e.g., interleukin 2, tumor necrosis factor ␣, granulocyte macrophage colony-stimulating factor (GM-CSF), and interleukin 12] have been noted to elicit antitumor immunity effectively, and viral vectors (e.g., vaccinia virus and herpes simplex virus) encoding a cytokine have been injected intratumorally in animal models (4, 20 -26) and used in clinical trials (27,28).…”

A role of cytokines in OK-432 injection therapy for cystic lymphangioma: an approach to the mechanism

“…This preparation induces various cytokines and activation of immunologic effecter cells, producing an antitumor effect. [4][5][6] A similar cytotoxic mechanism is thought to work in the OK-432 injection therapy for cystic lymphangioma. 1,7 We examined the changes in cytokine levels in lymphangioma cysts for several weeks after the injection of OK-432.…”

Surgical immune interventions for solid malignancies

“…(58, 59) Bacterial-based vaccines have also been evaluated for intratumoral injection into breast, head and neck, and gastric cancers. (60–64) The streptococcal-derived agent, OK-432, was injected successfully into the tumor preoperatively and reduced the rate of lymph node metastasis. (63) However, bacterial-based vaccines injected intratumorally have not yielded significant differences in overall outcome of solid tumors.…”