Randomised study of immunotherapy with OK-432 in uterine cervical carcinoma

Kikkawa, Fumitaka; Hawai, Michiyasu; Oguchi, Hidenori; Kojima, M.; Ishikawa, Hisatake; Iwata, Mitsumasa; Maeda, Osamu; Tsutsumi, Yutaka; Arii, Yoshitaro; Kuzuya, Kazuo; Ohta, Makoto; Ishizuka, Takao; Hattori, Shinobu; Aoki, Kunio

doi:10.1016/0959-8049(93)90291-m

Cited by 41 publications

(20 citation statements)

References 16 publications

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“…We now understand that microbe-derived therapeutics work by stimulating TLR signaling and activating both innate and adaptive immune responses to enhance tumor immunotherapy. OK-432, which is a penicillin-killed and lyophilized preparation of a low-virulence strain of Streptococcus pyogenes (group A), is a TLR4 agonist, and it has been successfully used as an immunotherapeutic agent in many types of malignancies, including head, neck, cervical, and gastric cancer and oral squamous cell carcinoma (Okamoto et al, 1967(Okamoto et al, , 2003Kikkawa et al, 1993;Maehara et al, 1994;Sato et al, 1997). Another bacterial strain, Mycobacterium bovis BCG, which acts as a TLR2/4 agonist, is effective against superficial bladder tumors (Morales et al, 1976).…”

Section: Tlr As a Negative Regulator Of Cancermentioning

confidence: 99%

Roles of toll-like receptors in Cancer: A double-edged sword for defense and offense

et al. 2012

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Toll-like receptors (TLRs) belong to a class of pattern-recognition receptors that play an important role in host defense against pathogens by recognizing a wide variety of pathogen-associated molecular patterns (PAMPs). Besides driving inflammatory responses, TLRs also regulate cell proliferation and survival by expanding useful immune cells and integrating inflammatory responses and tissue repair processes. TLR signaling, which is centrally involved in the initiation of both innate and adaptive immune responses, has been thought to be restricted to immune cells. However, recent studies have shown that functional TLRs are expressed not only on immune cells, but also on cancer cells, thus implicating a role of TLRs in tumor biology. Increasing bodies of evidence have suggested that TLRs act as a double-edged sword in cancer cells because uncontrolled TLR signaling provides a microenvironment that is necessary for tumor cells to proliferate and evade the immune response. Alternatively, TLRs can induce an antitumor immune response in order to inhibit tumor progression. In this review, we summarize the dual roles of TLRs in tumor cells and, more importantly, delve into the therapeutic potential of TLRs in the context of tumorigenesis.

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Section: Tlr As a Negative Regulator Of Cancermentioning

confidence: 99%

Roles of toll-like receptors in Cancer: A double-edged sword for defense and offense

et al. 2012

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“…CpG and other TLR9 agonists are in phase I, II or III trial for non-small-cell lung carcinoma, non-Hodgkin's lymphoma, renal cell carcinoma and colorectal cancer (Krieg, 2006). The TLR4 agonist OK-432 from Streptococcus pyogenus or a purified lipoteichoic acid-related derivative, OK-PSA, have been evaluated in uterine cervical cancer and non-small-cell lung cancer (Watanabe and Iwa, 1987;Kikkawa et al, 1993). While many of the trials reported enhancement of antitumour immune responses, there was no definitive mechanism of action and in many patients there was no discernable clinical response (Krieg, 2007).…”

Section: Tlr Ligands As Tumour Immunotherapeuticsmentioning

confidence: 99%

TLR ligand suppression or enhancement of Treg cells? A double-edged sword in immunity to tumours

2008

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“…OK-432, a penicillin-killed and lyophilized preparation of a lowvirulence strain (Su) of Streptococcus pyogenes (group A) that was developed by Okamoto et al (1), is successfully used as an immunotherapeutic agent in malignancies (2,3). We have also reported that OK-432-based immunotherapy exhibits a marked antitumor effect in patients with oral squamous cell carcinomas (4,5).…”

Section: Introductionmentioning

confidence: 99%

Expression of Toll-Like Receptor 4 on Dendritic Cells Is Significant for Anticancer Effect of Dendritic Cell-Based Immunotherapy in Combination with an Active Component of OK-432, a Streptococcal Preparation

et al. 2004

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A lipoteichoic acid-related molecule OK-PSA is an active component of OK-432, a Streptococcus-derived anticancer immunotherapeutic agent. In the present study, we first examined the effect of OK-PSA on the maturation of dendritic cells (DCs) in vitro by using the DCs derived from 5 healthy donors and 10 patients with head and neck cancer with or without expression of toll-like receptor 4 (TLR4) or MD-2 mRNA. OK-PSA treatment effectively increased the surface expression of MHC class II, CD80, CD83, and CD86. OK-PSA-stimulated DCs secreted the cytokines that can induce helper T-cell 1 (Th1)-type T-cell response, and stimulated allogeneic T cells to produce IFN-␥ and to elicit an allogeneic antigen-specific cytotoxicity. These activities almost depended on expression of TLR4 and MD-2 genes. We next investigated the in vivo anticancer effect of intratumoral administration of syngeneic DCs followed by OK-PSA against established tumors in mice. C57BL/6 mice, which express wild-type TLR4, and C57BL/6-derived TLR4-knockout (TLR4 ؊/؊ ) mice were used. Although OK-PSA accelerated the antitumor effect of intratumoral DC administration in wild-type mice bearing syngeneic tumors, the antitumor effect of OK-PSA as well as of the combination therapy with DCs and OK-PSA was not significant in TLR4 ؊/؊ mice. Interestingly, an administration of wild-type-mouse-derived DCs followed by OK-PSA exhibited a marked antitumor effect even in the TLR4 ؊/؊ mice. These findings suggest that OK-PSA may be a potent adjuvant for local DC therapy, and that DC therapy followed by OK-PSA is able to elicit anticancer activity even in a TLR4-deficient host when TLR4 is expressed only in DCs injected intratumorally.

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Randomised study of immunotherapy with OK-432 in uterine cervical carcinoma

Cited by 41 publications

References 16 publications

Roles of toll-like receptors in Cancer: A double-edged sword for defense and offense

Roles of toll-like receptors in Cancer: A double-edged sword for defense and offense

TLR ligand suppression or enhancement of Treg cells? A double-edged sword in immunity to tumours

Expression of Toll-Like Receptor 4 on Dendritic Cells Is Significant for Anticancer Effect of Dendritic Cell-Based Immunotherapy in Combination with an Active Component of OK-432, a Streptococcal Preparation

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