A Study of Combinations of D-CIK Immunotherapy And Anti-PD-1 In Refractory Solid Tumors

Overview

Background: Combinations of dendritic and cytokine-induced killer cell (D-CIK) based adoptive immunotherapy and anti-PD-1 antibody may enhance the immune response and stop cancer cells from growing. Objective: Phase II clinical trial to investigate the safety, clinical activity and toxicity of combinations of D-CIK and anti-PD-1 antibody in patients with treatment-refractory solid tumors. Methodology: Phase II clinical trial in patients with advanced metastatic hepatocellular carcinoma, renal cell carcinoma,bladder cancer,colorectal cancer,non-small-cell lung cancer,breast cancer and other solid cancers. The D-CIK was isolated from peripheral blood of participants,then activated,expanded and incubated with anti-PD-1 antibody before infusion. The enough number (1.0-1.5 \*10\^10 cells) of D-CIK were infused back into participants.

Heparinized peripheral blood was obtained from participants over a 2-week period. PBMCs were separated by Ficoll-Hypaque gradient centrifugation, suspended in X-VIVO 15 serum-free medium, and culture with 1000 U/ml rhIFN-γfor the first 24 h, followed by stimulation with 100 ng/ml OKT3 , 1000 U/ml rhIL-2 and 100 U/ml IL-1α to activate the CIK.Dendritic cells were incubated with CIK. Fresh medium containing 1000 U/ml rhIL-2 was added every 2 days and the cell density was maintained at 2×10\^6 cells/mL.D-CIK were harvested, washed, and resuspended after culture for 14 days. Before cell transfer,D-CIK were incubated with anti-PD-1 antibody,and a fraction of the D-CIK were collected to assess their number, phenotype, and viability of cells, and to test for possible contamination by bacteria, fungi, or endotoxins. Then, autologous D-CIK (1.0-1.5\*10\^10 cells) were transferred to patients via intravenous infusion. Generally, participants received at least 4 cycles of treatment at 2-week intervals or received doses until disease progression occurred. If the participants were disease-stable, additional cycles of maintenance treatment were eligible. Participants will be evaluated for the safety, clinical activity and toxicity. The primary end point was the objective response for each participant at the time of D-CIK and anti-PD-1 infusion as assessed by RECIST. Peripheral blood of patients were also assessed for related cytokine using ELISPOT assays. Additional,the investigators will evaluate tumor markers in participants with clinical response/non-response by immunohistochemical staining of tumor sections from previous diagnostic or therapeutic biopsy samples to determine the predictive biomarker that may be used in future studies.