Acute toxicities of intravenous, intraperitoneal, or intratumoral injection of natural killer cells in human pancreatic adenocarcinoma-bearing mice: Randomized study.

AIMS:To investigate the possible acute toxicities and pathological changes associated with intravenous, intraperitoneal, or intratumoral injection of natural killer (NK) cells in mice subcutaneously bearing human pancreatic adenocarcinoma (PaC). METHODS:100 NPG tumor-bearing mice (50/sex) were engrafted subcutaneously with human PaC BXPC-3 cells 9 days before administration. They were randomly divided into 10 groups with 5 males and 5 females in each group. Mice in Group 1 were given sodium chloride intravenously as vehicle control, and mice in Groups 2-4 human peripheral blood-derived NK cells intravenously at doses of 2 × 107, 1 × 108, and 5 × 108 cells/kg, respectively; mice in Groups 5-7 were injected with NK cells intraperitoneally at doses of 2 × 107, 1 × 108, and 5 × 108 cells/kg, respectively, and mice in Groups 8-10 with NK cells intratumorally at doses of 4 × 103, 2 × 104, and 1 × 105 cells/mm3, respectively. Each group was given a single dose; the mice were observed clinically, and body weight, food intake, blood biochemistry, and tumor volume were measured. On Day 15, the mice were euthanized for gross anatomy and histopathology. RESULTS:On planned euthanasia, in Groups 2-4 no gross or microscopic pathological changes related to cells injection were found; in Groups 5-7 mice of both sexes showed a decrease in extramedullary hematopoiesis of spleen, and at the dose of 5 × 108 cells/kg, mice of both sexes showed an increase in the composition of spleen white pulp cells. In Groups 8-10, mice of both sexes at doses of 4 × 103 and 1 × 105 cells/mm3 and female mice at the dose of 2 × 104 cells/mm3 showed a decrease in extramedullary hematopoiesis of spleen, and female mice at a dose of 4 × 103 cells/mm3 and mice of both sexes at doses of ≥ 2 × 104 cells/mm3 showed an increase in the composition of spleen white pulp cells; perivascular/peribronchiolar inflammatory cell infiltration in lung and bronchus was observed in mice of both sexes at doses of ≥ 2 × 104 cells/mm3, and inflammatory cell infiltration in liver was observed in mice of both sexes at a dose of 1 × 105 cells/mm3. No other abnormal changes with toxicological significance in clinical observation, body weight, food intake, or blood biochemistry were observed in each group. CONCLUSIONS:In our study intravenous injection appears the safest way to give NK cells to human PaC-bearing mice. Using intraperitoneal or intratumoral administration, spleen, liver, and lung were the most often affected organs, albeit with mostly mild pathological changes.