Dendritic Cell-Based Adjuvant Vaccination Targeting Wilms’ Tumor 1 in Patients with Advanced Colorectal Cancer

Abstract

Despite significant recent advances in the development of immune checkpoint inhibitors, the treatment of advanced colorectal cancer involving metastasis to distant organs remains challenging. We conducted a phase I study to investigate the safety and immunogenicity of Wilms’ tumor (WT1) class I/II peptides-pulsed dendritic cell DC vaccination for patients with advanced colorectal cancer. Standard treatment comprising surgical resection and chemotherapy was followed by one course of seven biweekly administrations of 1–2 × 107 DCs with 1–2 KE of OK-432 (streptococcal preparation) in three patients. Clinical efficacy was confirmed based on WT1 expression using immunohistochemistry on paraffin-embedded tissues and immune monitoring using tetramer analysis and enzyme-linked immunosorbent spot (ELISPOT) assays. WT1 expression with human leukocyte antigen (HLA)-class I molecules was detected in surgical resected tissues. Adverse reactions to DC vaccinations were tolerable under an adjuvant setting. WT1-specific cytotoxic T cells were detected by both modified WT1-peptide/HLA-A*24:02 tetramer analysis and/or interferon-γ-producing cells through the use of ELISPOT assays after the first DC vaccination. Immunity acquired from DC vaccination persisted for two years with prolonged disease-free and overall survival. The present study indicated that DC vaccination targeting WT1 demonstrated the safety and immunogenicity as an adjuvant therapy in patients with resectable advanced colorectal cancer.

WT1-pulsed Dendritic Cell Vaccine Combined with Chemotherapy for Resected Pancreatic Cancer in a Phase I Study

“…Mature DCs were defined as CD11c + , CD14 -, HLA-DR + , HLA-ABC + , CD80 + , CD83 + , CD86 + , CD40 + , and CCR7 + cells. The following criteria were met for DC vaccine administration: purity (proportion of CD11c + , CD14 -, CD86 + , HLA-DR + ) >90%; >80% viability; mature DC phenotype; negative for bacterial and fungal infection after 14 days; endotoxin ≤0.05 EU/ml; and negative for mycoplasma (27).…”

“…We excluded patients who received chemotherapy before surgery. Other eligibility criteria have been previously described (27). The following competent standards were adhered to for DC therapy and eligibility: (I) Age, 20-70 years; (II) performance status, 0/1; (III) normal organ function and absence of infectious disease, blood abnormality, and bleeding tendency; (IV) no history of cardiovascular disease or respiratory disorders tolerable for blood apheresis; (V) toleratant to chemotherapy and radiotherapy as standard cancer treatments; and (VI) diagnosed less than 6 months prior, or with recurrence of cancer sensitive to chemotherapy.…”

“…The WT1-DC vaccine was prepared according to a previously reported method (27,28 (27). WT1-DCs were suspended in a total volume of 1 ml of OK-432, and 1-4×10 7 WT1-DCs were injected at each time according to the number of DCs in each case.…”

“…Safety evaluations were undertaken for the following: (I) allergic reactions post intradermal injection of DC vaccine (presence of reduced blood pressure, tachycardia, breathing difficulties, or rash); and (II) local reactions, fever, nausea, vomiting, diarrhea, appetite loss, mucosal ulcer, damage of the central nervous system, anemia, decreased white blood cell count, decreased platelet count, abnormal kidney function, or abnormal liver function during or after treatment completion (27). Adverse effects, including fever and skin reactions at the injection site, were monitored and graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events Version 4.0 (29).…”

“…Mature DCs were defined as CD11c + , CD14 -, HLA-DR + , HLA-ABC + , CD80 + , CD83 + , CD86 + , CD40 + , and CCR7 + cells. The following criteria were met for DC vaccine administration: purity (proportion of CD11c + , CD14 -, CD86 + , HLA-DR + ) >90%; >80% viability; mature DC phenotype; negative for bacterial and fungal infection after 14 days; endotoxin ≤0.05 EU/ml; and negative for mycoplasma (27).Evaluation of adverse events and clinical response. Safety evaluations were undertaken for the following: (I) allergic reactions post intradermal injection of DC vaccine (presence of reduced blood pressure, tachycardia, breathing difficulties, or rash); and (II) local reactions, fever, nausea, vomiting, diarrhea, appetite loss, mucosal ulcer, damage of the central nervous system, anemia, decreased white blood cell count, decreased platelet count, abnormal kidney function, or abnormal liver function during or after treatment completion (27).…”