Allogeneic NK Cell ("SMT-NK") in Combination With Pembrolizumab in Advanced Biliary Tract Cancer

[Inclusion Criteria]

Patients who received a histopathological or cytologic diagnosis of nonresectable, advanced biliary tract carcinoma (intrahepatic or extrahepatic cholangiocarcinoma, gallbladder cancer) and patients with refractory disease after chemotherapy and/or patients who have difficulty with chemotherapy due to side effects of chemotherapy.

• A person who receives an explanation from the trial manager about the purpose, contents, and characteristics of the Investigational products for the clinical trial and is signed by the person, guardian or legal representative in the written informed consent.
• Be ≥19 years of age on day of signing informed consent.
• Histopathological or cytologic diagnosis of advanced adenocarcinoma of the biliary tract.
• Have a performance status of ≤2 on the ECOG Performance Scale.
• Patients who survival period is expected to be at least 3 months.
• Patients who meet the following conditions:

• ANC(Absolute Neutrophil Count) ≥ 1,500/μL
• Hemoglobin≥ 10 g/dL
• Platelet> 100,000/μL
• Serum BUN & Creatinine ≤ 1.5 x upper limit of normal (ULN)
• AST & ALT ≤ 2.5 x upper limit of normal (ULN)
• Bilirubin ≤ 3mg/L
• Patients who agreed to the allogeneic natural killer cells therapy separated from the family of the patient or healthy donor's blood.
• Patients have a negative serum or urine pregnancy test (HCG, human chorionic gonadotropin) within 72 hours prior to receiving the first dose of study medication and agreed to use 2 methods of contraception. The period of contraception is up to 6 months after the last administration of Pembrolizumab.
• Patients who meet one or more of the following conditions.

• Patients have at least 1% Combined Positive Score (*CPS) PD-L1 expression detected on the tumor, as determined by **immunohistochemistry performed by a central laboratory.

*CPS = (number of PD-L1 positive tumor cells, lymphocytes, macrophage)/ (total number of viable tumor cells) X 100

**immunohistochemistry: IHC 22C3 pharmDx test

• Patients who have a positive *MSI-H or **dMMR test.

• MSI-high positive tumors analyzed by PCR.
• dMMR positive tumors analyzed by immunohistochemical staining .

• *MSI-H was measured by PCR, and positive finding when two or more unstable markers were detected in PCR for 5 microsatellite markers.
• **dMMR is analyzed by immunohistochemical staining and positive when the discovery of one or more genes in MLH1, MSH2, MSH6 and PMS2 staining is lost.

[Exclusion Criteria]

• Patients who have previous history of Immune deficiency or autoimmune disease that can be aggravated by immunotherapy(for example: Rheumatoid arthritis, systemic lupus erythematosus, vasculitis, multiple sclerosis, Crohn's disease, ulcerative colitis, adolescent-developed insulin-dependent diabetes mellitus).
• Diagnosis of immunodeficiency or is receiving systemic steroid therapy.
• Have with pneumonia, colitis, hepatitis, nephritis, endocrine disorders(for example: Pituitary gland, thyroid dysfunction, Type 1 diabetes, etc.) associated with immunodeficiency.
• Other malignant tumors within 5 years before the study enrollment.
• Previous history of anti-angiogenic agent treatment before the study enrollment.
• Received chemotherapy not less than 4 weeks old before the first administration of investigational products.
• Apparent myocardial infarction or uncontrolled arterial hypertension.
• Serious allergic history.
• Serious mental illness.
• Female who are pregnant, breastfeeding or intending to become pregnant during the study period.
• A person who participated in another clinical trial within 4 weeks prior to the start of the study(based on the date of signing the informed consent.).
• Previously administrated Pembrolizumab and other anti-PD-1/PD-L1 agent.
• Previously administrated natural killer cell.
• Patients who did not resolve the adverse event of the drug administered 4 weeks prior to enrollment.
• Previous history of active central nervous system (CNS) metastasis and/or carcinomatous meningitis.
• Previous history of non-infectious pneumonia.
• Previous history of Has an active infection requiring systemic therapy.
• Previous historyof Human Immunodeficiency Virus (HIV).
• Previous history of active Hepatitis B (e.g., HBsAg reactive), Hepatitis C, Active tuberculosis.
• Have received a live vaccine within 4 weeks before the first administration of investigational products.
• Hypersensitivity to Pembrolizumab additive.