Phase I/II clinical trial of a Wilms' tumor 1-targeted dendritic cell vaccination-based immunotherapy in patients with advanced cancer

Abstract

Dendritic cell (DC)-based immunotherapies have been created for a broad expanse of cancers, and DC vaccines prepared with Wilms' tumor protein 1 (WT1) peptides have shown great therapeutic efficacy in these diseases. In this paper, we report the results of a phase I/II study of a DC-based vaccination for advanced breast, ovarian, and gastric cancers, and we offer evidence that patients can be effectively vaccinated with autologous DCs pulsed with WT1 peptide. There were ten patients who took part in this clinical study; they were treated biweekly with a WT1 peptide-pulsed DC vaccination, with toxicity and clinical and immunological responses as the principal endpoints. All of the adverse events to DC vaccinations were tolerable under an adjuvant setting. The clinical response was stable disease in seven patients. Karnofsky Performance Scale scores were enhanced, and computed tomography scans revealed tumor shrinkage in three of seven patients. Human leukocyte antigen (HLA)/WT1-tetramer and cytoplasmic IFN-γ assays were used to examine the induction of a WT-1-specific immune response. The immunological responses to DC vaccination were significantly correlated with fewer myeloid-derived suppressor cells (P = 0.045) in the pretreated peripheral blood. These outcomes offered initial clinical evidence that the WT1 peptide-pulsed DC vaccination is a potential treatment for advanced cancer.

Keywords: Cytotoxic T lymphocytes; Dendritic cell; Immunotherapy; Tumor-associated antigens; WT1.

Fig. 1

Frequency of WT1-specific CTLs before and after DC vaccination in the tetramer assay. The black horizontal bar shows the median. Differences between values before and after WT1 vaccination were statistically significant (P < 0.05)

Fig. 2

WT1-specific CTLs induced by DC vaccination. a Upper panel, WT1-peptide/HLA-A*2402 tetramer assays. Percentages represent the frequency of tetramer⁺CD8⁺ T cells. Cases 1, 3, 7, and 8 show a significant increase in the frequency of tetramer⁺CD8⁺ T cells after DC vaccination compared to pre-therapy (*P < 0.05). b Lower panel, IFN-γ-producing clones in ELISPOT assays with WT1 peptide. Cases 1, 3, 7, and 8 show a significant increase in the response in the ELISPOT after DC vaccination compared to pre-therapy values (*P < 0.05)

Fig. 3

Tumor regression occurred in patient 3 a with metastatic breast cancer and in patient 7 b with ovarian cancer during the course of DC vaccination. (Left) Before and (right) after DC vaccination, respectively. Arrows indicate the presumed location of the tumor

Fig. 4

Pretreatment total lymphocyte numbers and the frequency of various circulating lymphocyte phenotypes in the peripheral blood of all patients. The immunological responses were significantly correlated with fewer myeloid-derived suppressor cells (MDSCs). MDSCs were identified as CD14⁻CD11b⁺CD33⁺. IR, immunological responses