A Phase 1/2 Study of WT1 Peptide Cancer Vaccine WT4869 in Patients with Myelodysplastic Syndromes (MDS)

Background: Based on its favorable effects on survival, azacitidine (AzaC) is now recognized as a first-line treatment option for higher-risk MDS. But the prognosis of patients who become resistant or intolerant to AzaC is still dismal (the median overall survival was 5.6 months, J Clin Onclol 2011;29:3322-7 Prebet T et. al.), and development of effective salvage therapies is eagerly awaited. A large number of tumor-associated antigens (TAAs) have been identified, and cancer vaccines utilizing their epitopes have shown some degree of clinical efficacies in various types of tumors. Wilms’ Tumor 1 (WT1) is one of such promising TAAs with broad expressions in various tumors including MDS. WT4869 is a synthetic peptide vaccine derived from WT1 protein, and the phase 1/2 clinical study of WT4869 was conducted to evaluate the safety and efficacy in HLA-A*24:02+ MDS patients, with some exploratory biomarker analyses.

Methods: The objectives of this study were to assess the tolerability of WT4869 treatment in MDS patients in phase 1 portion and evaluate the preliminary efficacy of WT4869 in higher-risk MDS patients in phase 2 portion. Higher-risk or transfusion-dependent lower-risk MDS patients including the AzaC-resistant population were enrolled in the study, and WT4869 at a dose of 5 to 1,200 µg/body was administered with intradermal injections every two weeks in dose-escalation cohorts according to the 3 + 3 design until discontinuation criteria were met. Clinical efficacy was evaluated according to the IWG response criteria 2006, and the time to acute myeloid leukemia and overall survival (OS) were also analyzed. We also evaluated immune responses including delayed type hypersensitivity and WT1-specific CTL induction. Expression of WT1 mRNA in peripheral blood and bone marrow cells were analyzed as surrogate markers for clinical efficacy.

Results: Twenty six patients including 17 higher- and 9 lower-risk patients were enrolled in the study, and safety profiles were evaluated. Although dose-limiting toxicities (DLTs), including pneumonitis, muscle hemorrhage, pyrexia, and  hypoalbuminemia, were observed in one patient at each dose of 50 and 400 µg/body, all of them were confirmed to be resolved or resolving, and no DLT was observed at other doses. As a result, WT4869 treatment was considered well-tolerated at the highest dose of 1,200 µg/body in MDS patients. Although there was no safety concern noted in phase 1 portion, further enrollment in phase 2 portion was not conducted to focus on the development with newly designed WT1 peptide vaccine. Twenty two out of 26 patients were analyzed for clinical efficacy. Decrease of bone marrow blasts was observed in one patient (marrow complete remission (mCR)), and 12 patients remained in stable disease (SD). Hematological improvement (HI) was observed in one mCR and three SD patients; two were in the erythroid lineages, one in the erythroid and neutrophil lineage and the other in the all three lineages. Very interestingly, two patients showed cytogenetic response, although hematopoietic improvement was not observed in these patients. In total, the overall response rate (mCR + any HI) was 18.2%, and the disease control rate (mCR + SD + any HI) was 59.1%. Though preliminary, prolongation of OS was observed in higher-risk patients and the median survival time in the AzaC-resistant higher-risk population was 13.0 months. CTL induction was observed in almost half of the treated population, and patients with any clinical response showed a trend of higher CTL induction.

Conclusions: In the phase 1/2 study, WT4869 was well-tolerated in MDS patients, and preliminary but promising efficacy was suggested. WT1 peptide vaccination is expected to be a new treatment option for AzaC-resistant MDS. Further evaluations of WT1 peptide vaccination are warranted.