PICIBANIL® 必醫你舒®

5 KE 針劑

(OK-432) MULTI-CYTOKINE INDUCER

Excellent Anticancerous BRM Agent

台灣中外製藥(股)

癌性胸水/腹水首選用藥

Introduction

Mechanism of OK-432 antitumor activity

Clinical efficacy of OK-432

Effect on malignant pleural

effusion/ascites

The product of OK-432

Outline

History of the Development

1868 Busch

Report of contraction of giant tumor due to complication of erysipelas

1882 Fehleisen

Affirmation of tumor contraction by erysipelas

Explication of Streptococcus being a etiologic agent of erysipelas

1939 Okamoto, Koshimura

Start of research for the relation between Streptococcus and cancer

1954 Discovery of the phenomenon : the destruction of cancer cells caused by

the mixing of Streptococcus and cancer

1966 Development of OK- 431 : heat-treated Su strain in Bernheimer’s basal medium

1968 Development of OK- 432 : Lyophilized OK-431

1975 Launch of Picibanil ® (OK-432)

Gram positive bacterium

Serologic grouping : A to V

Pyogenic exotoxin (erythrogenic toxin) :

exotoxin A, B, C stimulate T cells

Streptodornase A-D : deoxyribonuclease,

ribonuclease activities

Streptococcus pyogenes

Process of OK-432 Production

Streptococcus Pyogenes Su strain (Group A3)

Elevation of antitumor activity

Elevation of antitumor activity

Loss of streptolysin S production

OK-432 (Picibanil® )

Exposure to H2O2 at 0℃

Bernheimer’s basal medium

Containing 27000 Units / ml penicillin G potassium

Incubation at 37℃ for 20 min

Incubation at 45℃ for 30 min

Lyophilization

OK-432 (Picibanil ® ) Composition

Picibanil 1 KE 5 KE

Ingredient Content in each vial

Active ingredient

Lyophilized powder 2.8mg 14mg Amount of the dried cells 0.1mg 0.5mg

Inactive ingredients

Magnesium sulfate 0.10 mg 0.48 mg DL-methionine 0.20 mg 1.00 mg Maltose 8.37 mg 1.34 mg Benzylpenicillin potassium (JP) 2,690 U 13,470 U

Streptococcus pyogenes Su strain (group A)

Elevation of antitumor activity Loss of streptolysin S production (SLS)

OK-432 (Picibanil® )

Exposure to H2O2 at 0℃ / Bernheimer’s basal medium Containing 27,000 units/ml of penicillin G potassium Followed by incubation at 37 ℃ for 30min. Incubation at 45 ℃ for 30 min.

Lyophilization

The Meaning of “KE”

KE (Klinische Einheit) : Clinical Unit

The strength of the preparation / amount of the cells.

1 KE ≒ 0.1 mg of the lyophilized cells ( 1×108 cells )

Cancer Treatment Report 70 (1) ;171-176, 1986 National Cancer Institute (NCI)

Biological Response Modifier

生物反應調節劑

BRMs are those agents of approaches that

modify the relationship between the tumor

and host by modifying the host’s

biological response to the tumor cells,

which resultant therapeutic effects.

凡任何製劑或方法，可經由宿主調節對腫瘤細

胞之生物反應，而改變宿主與腫瘤關係進而達

到治療效果者，稱為生物反應調節劑。

Direct Cytocidal effect on tumor cells

Growth inhibition Inhibits DNA and RNA synthesis

Effector cell Activity Neutrophil Macrophage Lymphocyte Natural Killer Other cells

Multi-cytokine inducer IL-1β IFN- α, γ IL-2 TNF-α,β IL-6 TGIF IL-8 Others IL-12

Indirect Host –Mediated Actions (BRM)

Prolongation of survival

Mechanisms of OK-432

Antitumor Activity

OK-432

The Possible Mechanisms of Tumor Cell Disappearance in Ascitic Fluid

M. Torisu et. al., Management of malignant effusion

Attachment Infiltration Disconnection

Cluster of tumor cells

Activation

Peritoneal metastasis

Destruction

M. Torisu et al., Management of malignant effusion

The Possible Mechanisms of Fluid Disappearance in Peritoneal Cavity

M. Torisu et al., Management of malignant effusion

Release from Symptoms (Anorexia) Elevation of serum Protein level

Peritoneal cavity

Activation of Complement system OK-432

Disappearance of ascites fluid

Fibrosis Block of fluid production

M. Katano et al., Anti-Cancer Research (18);3917-26 (1998)

IFN-γ- induced ICAM -1 expression on tumor cells

IFN-γ↑ TNF-α↑

TNF-α - induced CD11b/CD18 expression on neutrophil

Enhanced Adherence Activity of Peritoneal Neutrophils to Tumor Cells by OK-432

Clinical Efficacy

Reduction of Malignant Pleural Effusion /Ascites

Inhibition of recurrence and metastasis

Activation of bone marrow function

Reduction of Tumor size

Prolongation of Survival of Cancer Patients

Fig. 1. Effect of intraperitoneal or intrapleural injection of OK-432 on disappearance of ascitis fluid and pleural effusion.

Effect of OK-432 Therapy on Disappearance of Effusion

M. Torisu et al., Management of malignant effusion

0 10 20 30 40 50 60 70 80

61.5%

38.5%

76%

24%

112 Responders

38 Responders

Non-Responders

Non-Responders

Patient groups with cancer: gastric, colorectal, breast, biliary tract, pancreas etc.

Relationship between Disappearance of Ascites and Cytologic Findings of Ascitic Fluid before the Treatment with OK-432

These results strongly suggest that this therapy is more effective for patients with tumor cell bearing ascites than for those who only have ascitic fluid.

M. Torisu et al., Management of malignant effusion

Positive for tumor cells n = 85

80%

68/responders

Negative for tumor cells n = 65

24.6%

16/responders

Duration of OK-432 Injection to Disappearance of Ascites and

Pleural Effusion

M. Torisu et al., (1983)

With ascites 100 6-56

(22.5 ±7.8)

With pleural 38 1.5-42

Effusion (15.4 ±15.1)

No. of Duration: days patients (mean ± SD)

Typical Change in Numbers of Intraperitoneal Neutrophils and Lymphocytes after an OK-432 Injection

These results strongly indicate that OK-432 induced neutrophils might have a major cytostatic effect against the tumor cells

Time in Days

Neu

tro

ph

ils (

/mm

3)

Lym

ph

oc

yte

s (

/mm

3) OK-432(I.P) OK-432(I.P) OK-432 (I.P)

Neutrophils

Lymphocytes

M. Torisu et. al., Management of malignant effusion

This observations indicate that neutrophils induced by OK-432 play an important role in tumor cell destruction.

M. Torisu et. al., Management of malignant effusion

Neu

tro

ph

ils (

/mm

3)

Tu

mo

r c

ell

s

(/m

m3)

Neutrophils Tumor cells

OK-432 I.P

Time in Days

Typical Change Numbers of Intraperitoneal Neutrophils and Tumor Cells after OK-432 Injection

Changes of OK-432 Induced

PEC Population

Nu

mb

er

of

cell

s (/

mm

3)

Hours after OK-432 injection

K. Ogawa, et al., Biotherapy 4(2) ; 155-65, (1990) PEC : Peritoneal exudate cells

H. Kitsuki, et al. Clin Immunol Immunopathol 78; 283-90, (1996)

IFN- γ

IL-1β TNF- α

OK-432 (5-10KE) Time after OK-432 injection (hr)

Representative Kinetics of

Induction of Cytokines in the Ascitic

Fluid after OK-432 Injection

Host Inflammatory Cells Induced by OK-432 Before administration

Cancer cells form clusters and few inflammatory cells exit

After 12 hrs

The cluster is getting out of shape by infiltrating neutrophils

After 3 days

Infiltrating macrophages are attacking cancer cells

After 4 days

Infiltrating lymphocytes are attacking cancer cells

Responders (112 cases)

Non-responders (70 cases)

Palliative therapy (50 cases))

These results indicate that OK-432 therapy induces significant prolongation of survival time for patients with malignant effusion.

M. Torisu et. al., Management of malignant effusion

Su

rviv

al ra

te (

%)

Time in months

*15.6 *2.9

*P<0.001

Comparison of Survival Rate between Responders and Non- responders or Palliative Therapy Group

Responders (112 cases)

Non-responders (70 cases)

Palliative therapy (50 cases))

Treatments for Malignant

Pleuritis and Peritonitis

Agent Method Mechanism Side effects

BRMs (OK-432, IL-2) Anticancer drugs (BLM, MMC, ADM) Tetracycline Minocycline Talc Insufflation

Non-specific inflamation Tumoricidal effect Non-Specific inflamation Fibrogenic effects Pleural adhesion Non-specific inflamation

Pleural adhesion

Intraperitoneal

Intraperitoneal Paracentesis Tube drinage

Non-specific inflamation Tumoricidal effect

Non-Specific inflamation No tumoricidal effect Removal of ascites

Fever

(>39℃ : ~48%)

Systemic reaction

BM suppression

Pain

Induced pneumothroax/ pneumonia

BRMs (OK-432)

Anticancer drugs (CDDP, MMC, 5-FU)

Diuretic, Systemic Chemotherapy

Fever (>39℃ : ~48%)

Frequent Peritonitis Fibrosis lead ileus

Lead to worsen of nutritional condition

Poor effect

Treatment for Malignant Peritonitis

Treatment for Malignant Pleuritis

Pleurodesis Intrapleural Pleurodesis Intrapleural

Pleurodesis Pleurodesis/ Thoracoscopy

Complication after Pleurodesis with OK-432 and Mitomycin C in Patients with Malignant Pleural Effusions

Luh et al., Cancer 89;874-9 (1992)

Complication OK-432 Mitomycin C n=26 n=27

Fever (>38℃ ) 20 3

Chills 4 0

Pain 2 2

Dyspnea 3 2

Leukopenia 0 1

(< 3000/ul)

No toxicity 5 18

Summary

Efficacy Both OK-432 and MMC are effective for control MPE patients

Complete Response

Pleurodesis with OK-432 has higher complete response rate than with MMC

Survival Time Medium survival time were similar

Luh et al., Cancer 89;874-9 (1992)

Effusion- Free period

OK-432 group was significantly longer and recurrences of pleural effusion were less frequent

Adverse Reactions

Reported in 8,312 out of 26027 patients (31.9%)

at the end of the adverse reaction incidence report : March 1982

Adverse Reactions Incidence (%)

Fever 6019 23.1

Injection site pain 2893 11.1

Injection site redness 1198 4.6

General malaise 848 3.3

Anorexia 789 3.0

Administration Method of Picibanil® for Malignant Ascites

Treatment & control of patients

Diagnosis & adjuvant therapy

Penicillin intradermal reaction

Cytological diagnosis of ascites

Abdomen touch

Poor nutrition condition, give albumin etc.

Confirm the aspiration site CT/ echo

Picibanil® 10KE Injected with 100-200ml N/S

Sufficient change of positions ~2hrs

Fever Analgesic antipyretic

Picibanil®

5-20 KE 3– 4 times

Positive patients for cancer cells

by cytological diagnosis of ascites (if negative, included with consideration of the performance status)

Patients

Treatment schedule

Days

( ) ( )

Picibanil® Intraperitoneal Injection

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

Complete drainage of Pleural Effusion as possible (<100- 200ml), then close 3-way

Infusion of OK-432 10KE dissolved in 20-100ml of N/S

Postural change (~2 hrs)

Drainage of OK-432 and the remaining effusion Chang Gung HP

Intrapleural Administration Pleurodesis --- Pig-tail Drainage

Pig-tail 裝置一覽表 固定 3 – way 完成

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Days

Picibanil®

10-20 KE

Picibanil Thoracentesis Method

Patients Treatment resistant malignant

pleuritis (8 patients: lung cancer

/adenocarcinoma)

Injection time

Median frequency of injection = 2.5 times

Treatment schedule

Indications & Dosage

In patient with gastric cancer or primary lung cancer under concomitant use with chemotherapy. Initiate : 0.2-0.5 KE, Maintain : 2-5 KE, 1-2 times a week.

In patients with digestive tract cancer or lung cancer. 10-20 KE, inject into serous cavity 1-2 times a week

(maxillary cancer, laryngeal cancer, pharyngeal, cancer, tongue cancer) and thyroid cancer where the other medicine have been ineffective. 5-10 KE, inject into tumor daily/every of few days.

initiate : 0.05-0.1 KE, Max dosage : 2 KE, the dosage may be adjusted depending on the patient’s age and symptoms.

1.Extensive of survival period

2.Reduction of cancerous pleural effusion/ascites

3. Head and neck cancer

4. Lymphangioma

OK-432 (Picibanil® ) Package

OK-432 (Picibanil® ) Storage and Handling

Use only freshly prepared suspension Powerful and designated drugs. Use only pursuant to the prescription or directions of a physician, etc. Store at a temperature below 10℃, avoid freezing. 2 years (specified on the outer package)

Notice

Regulatory classification

Storage

Expiration date

A potent biological response modifier (BRM)

Clinical efficacy Prolongation of survival Reduction of cancerous pleural effusion/ascites

Dual function activities Direct tumoricidal Immunopotentiating

A penicillin-treated Streptococcus pyrogenes lyophilized preparation

Summary

Picibanil (OK-432) 健保使用規範

限惡性腫瘤患者患有惡性腹水、

肋膜積水或心包膜積水時使用，須

檢附病歷摘要。

Thanks for your attention

~ The End ~