Use of fibrinogen to enhance the antitumor effect of OK-432. A new approach to immunotherapy for colorectal carcinoma

Monden, Takushi; Morimoto, Hideki; Shimano, Takashi; Yagyu, Tomohiko; Murotani, M; Nagaoka, Hirohito; Kawasaki, Yoshikane; Kobayashi, Tetsuro; Mori, Takesada

doi:10.1002/1097-0142(19920201)69:3<636::aid-cncr2820690306>3.0.co;2-w

Cited by 33 publications

(10 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…OK-432 is a non-specific immunopotentiator of bacterial origin that has been reported to induce cytotoxic CD4+ T cells in both mice and humans (Ozaki and Suginoshita, 1989;Ozaki et al, 1990;Nagaoka et al, 1992). In the present study, we generated cytotoxic CD4+ T lymphocytes from the TILs of thyroid cancer patients treated with our augmented immunisation protocol using OK-432/ fbg .…”

Section: Resultsmentioning

confidence: 92%

“…This local immunotherapy effectively induces the marked infiltration of inflammatory cells into the tumour stroma on the day after injection and can contribute to tumour regression. We have also demonstrated that the regional lymph nodes of cancer patients receiving this local immunotherapy were a useful source of competent B lymphocytes for the establishment of human-human hybridomas (Baba et al, 1992;Yagyu et al, 1993), and we have established cytotoxic CD4+ T-cell clones from such lymph nodes (Nagaoka et al, 1992). In the present study, we generated cytotoxic CD4+ T cells from the tumour-infiltrating lymphocytes (TILs) of thyroid cancer patients who had received the intratumoral injection of OK-432 with fibrinogen.…”

mentioning

confidence: 87%

“…Several reports have documented that both CD4+ and CD8+ cells show cytolytic activity when activated by target cells bearing the appropriate antigen or by non-specific stimulants (Fleischer, 1984;Tite et al, 1985;Noguchi et al, 1989;Erb et al, 1990;Ju et al, 1990). Cytolysis mediated by CD8+ T lymphocytes is now well documented, but as is the case for CD4+ cells, the mechanisms involved are still controversial (Nagaoka et al, 1992;Nishimura et al, 1992;Ozdemirli et al, 1992;Apasov et al, 1993).…”

mentioning

confidence: 99%

See 2 more Smart Citations

Analysis of cytotoxic activity of the CD4+ T lymphocytes generated by local immunotherapy

Katsumoto

Monden²,

Takeda³

et al. 1996

Br J Cancer

View full text Add to dashboard Cite

Summary We previously reported that the anti-tumour effect of OK-432 is considerably enhanced by its intratumoral injection together with fibrinogen. In the present study, we generated killer T cells by culturing tumour-infiltrating lymphocytes from thyroid cancer patients who had received this local immunotherapy. Phenotypic analysis revealed that the T cells were positive for CD3+, CD4+, Leu8-, CD45RO+ and T-cell

show abstract

Section: Resultsmentioning

confidence: 92%

mentioning

confidence: 87%

mentioning

confidence: 99%

See 1 more Smart Citation

Analysis of cytotoxic activity of the CD4+ T lymphocytes generated by local immunotherapy

Katsumoto

Monden²,

Takeda³

et al. 1996

Br J Cancer

View full text Add to dashboard Cite

show abstract

“…The OK/IL-2AK cells produced T helper type-1 (Th1) cytokines TNF-a and IFN-g, and that Th2 cytokines, that is, IL-4 and IL-6, were not produced under these conditions. Monden et al (1992) demonstrated that the intratumoral injection of the mixture of OK-432 and fibrinogen enhanced the regression of colorectal cancer, in which a granulomatous hypersensitive response containing many giant cells was generated in the tumour stroma. That feature highly resembled the delayed-type hypersensitivity reaction, which is associated with Th1 responses.…”

Section: Discussionmentioning

confidence: 99%

Locoregional immunotherapy of malignant effusion from colorectal cancer using the streptococcal preparation OK-432 plus Interleukin-2

et al. 2003

View full text Add to dashboard Cite

In total, 16 patients with cytologically proven malignant effusion from colorectal cancer were treated by locoregional administration of the streptococcal preparation OK-432 alone or OK-432 plus the T-cell growth factor interleukin (IL)-2, and the action mechanism of the treatment was studied. A positive clinical response, showing a cytologic disappearance of cancer cells and decrease of effusion, was observed in nine of 11 (82%) patients treated with OK-432 alone and in all five patients treated with OK-432 plus IL-2. Flow cytometric analysis revealed that OK-432 plus IL-2 locally induced acute inflammation-like responses, including serial cellular infiltrations of granulocyte migration within a matter of hours, and activation of macrophages and T lymphocyte involvement within the following days, and that a predominant expansion of CD3 þ CD4 þ lymphocytes (CD: cluster of differentiation) was induced by in vitro stimulation with IL-2 of locoregional cells after the OK-432 administration (OK/IL-2AK cells). The OK/IL-2AK cells produced tumour necrosis factor-a and interferon-g, but these cells did not produce IL-4 and IL-6. The OK/IL-2AK cells expressed potent killing activity against autologous tumour cells. This activity was abrogated by treatment of the lymphocytes with anti-CD3, -CD4, -TCRab antibody, and by the treatment of target cells with anti-human leukocyte antigen (HLA)-DR antibody. The OK/IL-2AK cells expressed Fas-L gene, and flow cytometric analysis demonstrated HLA-DR expression in approximately 75% of CEA þ or cytokeratin þ effusion cells. TCRVb gene analysis of the OK/IL-2AK cells showed an oligoclonal usage of TCRb20, which was also involved in the cytotoxic mechanism of the OK/IL-2AK cells. Single-strand conformational polymorphism analysis demonstrated the clonotypes for the TCRVb20 gene, and the CDR3s of the gene were sequenced. The clonotypic PCR using the TCRVb20-CDR3 sequences could detect the CDR3-identical TCRs in effusion lymphocytes from the other patients. Taken together, it is suggested that locoregional administration of OK-432 plus IL-2 is highly effective for the management of malignant effusion from colorectal cancer. OK-432 plus IL-2 induces autologous tumour-reactive CD4 þ Th1 killer lymphocytes, which recognise tumour antigen(s) presented with HLA class II molecules on effusion tumour cells by means of preferential usage of TCRVb20. The clonotypic PCR using the TCRVb20-CDR3 sequences may be informative for treating malignant effusion from colorectal cancer using OK-432 plus IL-2.

show abstract

“…OK-432 induced a markedly augmented antitumor effect on colorectal cancers when injected intratumorally together with fibrinogen [10]. This type of local immunotherapy is effective not only in inducing local tumor regression but also in activating various cell components of regional lymph nodes [11].…”

Section: Introductionmentioning

confidence: 97%

The effect of local immunotherapy for breast cancer using a mixture of OK-432 and fibrinogen supplemented with activated macrophages

et al. 1993

Self Cite

View full text Add to dashboard Cite

OK-432 is an immunomodulatory agent prepared from a strain of Streptococcus pyogenes. We have previously reported that intratumoral injection of a mixture of OK-432 and fibrinogen (hereinafter referred to as OK/fbg) is very effective in the local immunotherapy for colorectal cancer. However, we found that the intratumoral injection of OK/fbg into tumor tissues of breast cancers did not always induce a strong antitumor effect. With conventional OK/fbg treatment, tumor necrosis observed in breast cancer tumors was significantly less than that in colorectal cancer tumors; the formation of fibrin meshwork and macrophage infiltration, in particular, were poor. In this study, the OK/fbg mixture was supplemented with activated macrophages for local immunotherapy of breast cancers. Macrophages were prepared from peripheral blood of breast cancer patients and activated with 0.05 mg/ml of OK-432. Between 2-7 days before operation, a single intratumoral injection of the above mixtures was done. The addition of activated macrophages to the OK/fbg mixture resulted in marked degrees of fibrin meshwork formation, macrophage infiltration and cancer cell necrosis. These findings suggest that the recruitment of macrophages in tumor stroma and their activation are necessary for sufficient induction of antitumor immunity, and supplementation of activated macrophages at the site of immune reaction may be an alternative method for reinforcement of the antitumor effect of local immunotherapy.

show abstract

Use of fibrinogen to enhance the antitumor effect of OK-432. A new approach to immunotherapy for colorectal carcinoma

Cited by 33 publications

References 36 publications

Analysis of cytotoxic activity of the CD4+ T lymphocytes generated by local immunotherapy

Analysis of cytotoxic activity of the CD4+ T lymphocytes generated by local immunotherapy

Locoregional immunotherapy of malignant effusion from colorectal cancer using the streptococcal preparation OK-432 plus Interleukin-2

The effect of local immunotherapy for breast cancer using a mixture of OK-432 and fibrinogen supplemented with activated macrophages

Contact Info

Product

Resources

About