Safety and Efficacy of Allogeneic Natural Killer Cells in Combination with Pembrolizumab in Patients with Chemotherapy-Refractory Biliary Tract Cancer: A Multicenter Open-Label Phase 1/2a Trial.

BACKGROUND AND AIM: This study investigated the administration of combination therapy, allogeneic natural killer (NK) cells and pembrolizumab in the treatment of advanced biliary tract cancer to determine the safety and tolerability (phase 1) and the efficacy and safety (phase 2a). METHODS: Forty patients (phase 1, n = 6; phase 2a, n = 34) were enrolled between December 2019 and June 2021. The patients received highly activated allogeneic NK cells ("SMT-NK") on weeks 1 and 2 and pembrolizumab on week 1. This 3-week schedule (one cycle) was repeated until confirmed disease progression, intolerable adverse events (AEs), patient withdrawal, or finishing the maximum treatment schedule. The tumor response was evaluated after every three cycles. RESULTS: In phase 1, four patients (66.7%) experienced seven AEs, but no severe AE was observed. In phase 2a, 126 AEs occurred in 29 patients (85.3%). Severe AEs (≥grade 3) were reported in 16 patients (47.1%). The overall response rate (ORR) was 17.4% in the full analysis set and 50.0% in the per-protocol set. CONCLUSIONS: SMT-NKs plus pembrolizumab resulted in no severe AEs directly related to the drug combination. The combination therapy also exerted antitumor activity with improved efficacy compared to the recent monotherapy with pembrolizumab in patients with advanced biliary tract cancer.

In Vivo Study of Natural Killer (NK) Cell Cytotoxicity Against Cholangiocarcinoma in a Nude Mouse Model.

BACKGROUND/AIM: Natural killer (NK) cells are one of the lymphocytes clinically used for various cancer types. Cytotoxicity of NK cells to cholangiocarcinoma (CC), however, has not yet been studied. Nor NK cell therapy against CC has been clinically applied. In this study, relevance of NK cell therapy for anti-tumor efficacy against CC was pre-clinically investigated. MATERIALS AND METHODS: Human HuCCT-1 cells, an intrahepatic CC cell line, were xenografted into nude mice. The HuCCT-1 tumor-bearing nude mice then received multiple infusions of ex vivo-expanded human NK cells (SMT01) and in vivo cytotoxic activity of the NK cells against the CC cells was evaluated. RESULTS: SMT01 infusion resulted in significant inhibition of the CC tumor growth. Body weight of the mice administrated with chemotherapy was found to be maintained at the lowest level among all treatment groups while all the SMT01 infusion groups well maintained their body weight. CONCLUSION: The present in vivo study demonstrates that NK cells contain cytolytic activity against cholangiocarcinoma and show beneficial effect of NK cell therapy in relevance to quality of life. Further investigation of the NK cell-based immunotherapy can be useful to determine cancer therapeutics for the specific tumor.

Effect of Lipopolysaccharide (LPS) Exposure on the Reproductive Organs of Immature Female Rats.

Lipopolysaccharide (LPS), an endotoxin, elicits strong immune responses in mammals. Several lines of evidence demonstrate that LPS challenge profoundly affects female reproductive function. For example, LPS exposure affects steroidogenesis and folliculogenesis, resulting in delayed puberty onset. The present study was conducted to clarify the mechanism underlying the adverse effect of LPS on the delayed puberty in female rats. LPS was daily injected for 5 days (50 µg/kg, PND 25-29) to treated animals and the date at VO was evaluated through daily visual examination. At PND 39, animals were sacrificed, and the tissues were immediately removed and weighed. Among the reproductive organs, the weights of the ovaries and oviduct from LPS-treated animals were significantly lower than those of control animals. There were no changes in the weights of uterus and vagina between the LPS-treated and their control animals. Immunological challenge by LPS delayed VO. Multiple corpora lutea were found in the control ovaries, indicating ovulations were occurred. However, none of corpus luteum was present in the LPS-treated ovary. The transcription level of steroidogenic acute regulatory protein (StAR), CYP11A1, CYP17A1 and CYP19 were significantly increased by LPS treatment. On the other hand, the levels of 3ß- HSD, 17ß-HSD and LH receptor were not changed by LPS challenge. In conclusion, the present study demonstrated that the repeated LPS exposure during the prepubertal period could induce multiple alterations in the steroidogenic machinery in ovary, and in turn, delayed puberty onset. The prepubertal LPS challenge model used in our study is useful to understand the reciprocal regulation of immune (stress) - reproductive function in early life.