- Clinical cancer trials that target WT1 (Wilms tumor protein)
- Differences between successful and unsuccessful cancer vaccines
- Mechansisms for memory T cell function following cancer vaccine administration
- Study of the immunocompetent cell network before and after vaccine administration
- Improvements in the clinical effectiveness of cancer vaccines
Cancer vaccines that target WT1
Cancer immunotherapy is now a standard treatment for cancer along with surgery, radiation therapy, and chemotherapy. To further cancer immunotherapy, we are developing peptide vaccines that target WT1 (Wilms tumor 1), a protein that is highly expressed in many types of human tumors (Figure 1). In 2001, we started translational research on WT1 peptide vaccine and have now administered it to more than 800 patients with leukemia or solid-tumor cancers. Excellent clinical results with no serious adverse effects have been shown in leukemia, pancreatic cancer, brain tumors and other cancers (Figure 1).
Clinical research 1. In 2010, we began a Phase I clinical trial using WT1 peptide vaccine therapy combined with temozolomide to treat brain cancers, finding an overall survival rate after 2 years of 100% and after 5 years of 57%. These numbers greatly surpass the survival rates of standard treatment, which are 25% and 10%, respectively, demonstrating that this combination therapy is a very promising new treatment (Figure 2).
2. A clinical trial of WT1 peptide cocktail vaccine therapy in which WT1 killer peptide and WT1 helper peptide were mixed to treat recurrent malignant glioma was performed. In the cocktail vaccine, a strong induction of WT1-specific CD4-positive T cells and WT1-specific CD8 positive T cells was observed, and the immune response persisted for more than one year. Long-term induction of the immune response is an important determinant of the effectiveness of vaccine therapy. This study provides new information on how to solve this problem. Basic research Elucidation of the immune response mechanism against WT1 peptide vaccine 1. T cell antigen receptor (TCR) was isolated from WT1-specific CD4 positive T cells and transfected into CD4 positive T cells. We found this transfection could suppress the proliferation of tumor cells expressing WT1 specifically. This finding showed that CD4 positive T cells can express direct antitumor activity along with helper action. Further, the finding supports the use of vaccines that incorporate helper peptides to induce tumor-specific CD4 + T cells. 2. Similarly, TCRs were isolated from WT1-specific CD8 positive T cells. The TCR-WT1/HLA avidity was found to reflect the differentiation patterns of memory T cells. This finding too provides new insights on the immune response by T cells to tumor cells and vaccine therapy. Overall, our laboratory utilizes basic and clinical research to advance tumor immunotherapy.