Allogeneic NK Cell ("SMT-NK") in Combination With Pembrolizumab in Advanced Biliary Tract Cancer
Allogeneic NK Cell ("SMT-NK") in Combination With Pembrolizumab in Advanced Biliary Tract Cancer
The term of biliary tract cancer (BTC) or cholangiocarcinoma refers to all tumors that arise
 from the biliary tract or the biliary drainage system, including the gallbladder. According
 to the data from National Cancer Information Center in 2016, annual incidence of the cancer
 in Korea is 6,685 (13.1 per 100,000 population) which corresponds to about 2.9% of all
 cancers.

 BTC is one of the most prognostic cancer with less than 30% of 5-year survival rate and the
 case with long-term survival can be possibly done with early detection of the cancer.
 However, most of BTC is found in advanced stages due to the difficulty of early detection,
 resulting in that the 5-year survival rate of the advanced BTC becomes less than 3%. More
 than 50% of the patients depends on Gemcitabine based chemotherapy but response rate of the
 chemotherapy remains around 30%. Thus, improving the survival rate with the standard
 chemotherapy is very limited and furthermore selection of second-line therapy is not easy.
 For this reason, development of an alternative therapeutic agent is urgently required.

 NK (natural killer) cells are important cytotoxic innate immune cells that are involved in
 the elimination of cancer cells. Two main NK cell subsets have been defined on the basis of
 CD56 and CD16 expression: CD56^brightCD16- NK subset produces abundant cytokines including
 interferon-γ (IFN-γ) and tumor necrosis factor-α, whereas CD56^dimCD16+ NK subpopulation has
 high cytolytic activity and releases the granules containing perforin and granzymes.

 Various clinical studies have been conducted to treat cancers using NK cells worldwide
 including Korea and therapeutic clinical results are shown for various cancers. The clinical
 application of NK cells is carried out by culturing and activating the NK cells isolated from
 blood of either patient (autologous) or blood donor (allogeneic). Recently, NK cell therapy
 for cholangiocarcinoma has been successfully done (NCT03358849) with allogeneic NK cell,
 showing safety and potential efficacy.

 Like T cells, a recent study with digestive cancer has shown that NK cells also express PD-1,
 especially with more number of PD-1 in cancer patients than in healthy individuals,
 suggesting that blocking PD-1 can be used as a potential strategy to increase the anticancer
 activity of NK cells. Therefore, combined therapy with the immune-check point such as
 pembrolizumab can be useful in elevating the anticancer activity of NK cells.
[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.

 1. 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.

 2. Be ≥19 years of age on day of signing informed consent.

 3. Histopathological or cytologic diagnosis of advanced adenocarcinoma of the biliary
 tract.

 4. Have a performance status of ≤2 on the ECOG Performance Scale.

 5. Patients who survival period is expected to be at least 3 months.

 6. 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

 7. Patients who agreed to the allogeneic natural killer cells therapy separated from the
 family of the patient or healthy donor's blood.

 8. 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.

 9. 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]

 1. 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).

 2. Diagnosis of immunodeficiency or is receiving systemic steroid therapy.

 3. Have with pneumonia, colitis, hepatitis, nephritis, endocrine disorders(for example:
 Pituitary gland, thyroid dysfunction, Type 1 diabetes, etc.) associated with
 immunodeficiency.

 4. Other malignant tumors within 5 years before the study enrollment.

 5. Previous history of anti-angiogenic agent treatment before the study enrollment.

 6. Received chemotherapy not less than 4 weeks old before the first administration of
 investigational products.

 7. Apparent myocardial infarction or uncontrolled arterial hypertension.

 8. Serious allergic history.

 9. Serious mental illness.

 10. Female who are pregnant, breastfeeding or intending to become pregnant during the
 study period.

 11. 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.).

 12. Previously administrated Pembrolizumab and other anti-PD-1/PD-L1 agent.

 13. Previously administrated natural killer cell.

 14. Patients who did not resolve the adverse event of the drug administered 4 weeks prior
 to enrollment.

 15. Previous history of active central nervous system (CNS) metastasis and/or
 carcinomatous meningitis.

 16. Previous history of non-infectious pneumonia.

 17. Previous history of Has an active infection requiring systemic therapy.

 18. Previous historyof Human Immunodeficiency Virus (HIV).

 19. Previous history of active Hepatitis B (e.g., HBsAg reactive), Hepatitis C, Active
 tuberculosis.

 20. Have received a live vaccine within 4 weeks before the first administration of
 investigational products.

 21. Hypersensitivity to Pembrolizumab additive.