Abstract
Background:
Wilms' tumor gene 1 (WT1), broadly expressed in hematological malignancies and solid tumors, is a promising candidate for development as a cancer vaccine. WT4869, one of our WT1 vaccine candidates demonstrated early signs of clinical activity in Azacitidine (AZA)-resistant higher-risk MDS patients with a median survival (OS) of 13.0 months in a phase 1/2 study (Suzuki T, Ueda Y, Ogura M, et al. A Phase 1/2 Study of WT1 Peptide Cancer Vaccine WT4869 in Patients with Myelodysplastic Syndromes (MDS). Blood. 2015;126:2868). In this study, we report the characterization of DSP-7888 and the potential synergic effect with anti-PD-1 antibody. DSP-7888, which is a novel cocktail peptide vaccine designed to induce cytotoxic T lymphocytes (CTLs) that recognize WT1 antigen in an HLA-A*02:01, HLA-A*02:06 or HLA-A*24:02 restricted manner, has entered early clinical trials in patients with MDS and pediatric brain cancer in Japan and solid tumors in the U.S.
Methods:
WT1-specific T cells were measured by WT1 tetramer staining following stimulation of human peripheral blood mononuclear cells (PBMCs) with DSP-7888. In vivo CTL inducing activity of DSP-7888 was evaluated by ELISPOT assay and 51Cr-release assay after immunization of HLA-A2.1/DR1 transgenic (Tg) mice or HLA-A24.2 Tg mice. The response of induced CTLs against the WT1 epitope was measured by IFN-ɣ ELISA assay following co-culture with irradiated cancer cells. The frequency of PD-1 positive CTLs in spleen and tumor was analyzed by flow cytometry. The anti-tumor effect of DSP-7888 with or without anti-PD-1 antibody was evaluated using HLA-A24.2 Tg mice bearing mouse EL4 cells expressing both HLA-A24.2 and WT1.
Results:
HLA-A*02:01- or HLA-A*24:02-restricted and WT1-specific CTLs were induced in HLA-A2.1/DR1 Tg mice, HLA-A24.2 Tg mice and human PBMCs. Two groups of DSP-7888-induced CTLs recognized WT1 in an HLA-A*02:01-restricted manner and one in an HLA-A*24:02-restricted manner. Compared to its component vaccine without helper peptide, DSP-7888 induced a large number of WT1-specific CTLs in HLA-A2.1/DR1 Tg mice. The activity of DSP-7888-induced CTLs was relatively maintained in the environment including cancer cells. In addition, it was further activated by treatment with anti-PD-1 antibody. On the other hand, the activity of the component vaccine-induced CTLs was very low even when treated with anti-PD-1 antibody. In DSP-7888-administered tumor-bearing mice, half of WT1-specific CTLs in spleen expressed PD-1; however, in tumor more than 90% of the CTLs expressed this protein. Combination therapy of DSP-7888 and anti-PD-1 antibody showed a higher anti-tumor effect than each monotherapy alone in this model.
Conclusions:
In this study, DSP-7888 induced CTLs that recognize multiple WT1 epitopes. The helper peptide included in DSP-7888 enhanced the response of the CTL induction, and contributed to the lasting cytotoxic activities even in the tumor immunosuppressive environment, suggesting potential of DSP-7888 as a cancer vaccine. In addition, the in vitro treatment with anti-PD-1 antibody furthermore enhanced the activity of DSP-7888-induced CTLs. The combination of DSP-7888 and anti-PD-1 antibody may induce multiple WT1 epitope-specific CTLs and maintain the intratumoral cytotoxic activity. Further evaluations of DSP-7888 are warranted.
Disclosures
Goto: Sumitomo Dainippon Pharma Co.,Ltd: Employment. Nakamura:Sumitomo Dainippon Pharma Co.,Ltd.: Employment. Suginobe:Sumitomo Dainippon Pharma Co.,Ltd.: Employment. Takasu:Sumitomo Dainippon Pharma Co.,Ltd.: Employment. Takanashi:Sumitomo Dainippon Pharma Co.,Ltd.: Employment. Ban:Sumitomo Dainippon Pharma Co.,Ltd.: Employment. Li:Sumitomo Dainippon Pharma Co.,Ltd.: Employment.
Immunologic hierarchy, class II MHC promiscuity, and epitope spreading of a melanoma helper peptide vaccine