A New Peptide Vaccine Ocv-501, Phase 1 Study in Patients with Acute Myeloid Leukemia and In Vitro Pharmacology
Authors: Sakura Tohru , Kobayashi Yukio , Miyawaki Shuichi , Toga Kazuyuki , Sogo Shinji , Heike Yuji 
Published: October 2019

Abstract
Acute myeloid leukemia (AML) is the most common leukemia in older adults. Chemotherapy is the standard treatment, however, treatment efficacy and tolerability deteriorates with age, and patients are susceptible to relapse after complete remission (CR). Therefore, new therapeutic strategies for preventing relapse after consolidation therapy are urgently needed. Wilms' tumor 1 (WT1) is a promising target of new immunotherapies for acute myeloid leukemia (AML) as well as other cancers. OCV-501 is a helper peptide derived from the WT1 protein. Preclinical studies have shown that it induced OCV-501-specific Th1 responses dose-dependently and stimulated helper activity of the specific Th1 cells in peripheral blood mononuclear cells from healthy donors. OCV-501 also enhanced the increase in WT1-killer peptide-specific cytotoxic T lymphocytes (CTLs). The stimulated OCV-501-specific Th1 clones in an HLA class-II restricted manner formed a complex with HLA class-II protein and showed significant OCV-501-specific cytolytic activity against B-lymphoblastoid cell lines (B-LCL). These results suggested that OCV-501 activates both direct and indirect antitumor (anti-leukemic) cellular immunity, including specific cytotoxic Th1 cells and WT1-peptide-specific CTLs. Based on this, a phase 1 trial was carried out to assess the safety and tolerability as well as efficacy of OCV-501 in elderly AML patients in CR.
This was an open label, multi-center trial conducted in Japan. The study involved AML patients who have achieved their first CR with an induction regimen and completed standard consolidation therapy, and have been identified as WT1 mRNA positive, with one of the following HLA class II types: HLA-DRB1*01:01, *04:05, *15:01, *15:02, *08:03, or *09:01. The trial consisted of 3 cohorts at a dose of 0.3 mg in cohort 1, 1 mg in cohort 2, and 3 mg in cohort 3, whereby administration commenced with cohort 1 and progressed to subsequent cohorts, depending on the assessment for dose limiting toxicity (DLT) in the preceding cohort. OCV-501 was administered subcutaneously weekly for 4 weeks, followed by end of treatment and post-treatment examinations after 1 and 4 weeks from the last administration, respectively. Safety and tolerability which included any occurrence of treatment-emergent adverse events (TEAEs) and DLT were assessed, and the maximum tolerated dose (MTD) was determined. Efficacy was evaluated by relapse of AML, WT1 mRNA level and immune response to OCV-501 using delayed-type hypersensitivity (DTH) test.
Nine patients were enrolled and all completed the study. No DLT was observed in any of the 3 cohorts. Injection site reactions, including erythema, induration, mass, pain, and pruritus were observed in all patients. However, these drug-related TEAEs were Grade 1 or 2 in severity. There were neither deaths nor serious TEAEs during the treatment period and none of the patients discontinued OCV-501 administration due to TEAE. The result of this trial suggested that OCV-501 once a week for 4 weeks at doses of 0.3, 1, and 3 mg was safe and well-tolerated in AML patients in CR and the MTD was considered to be ≥ 3 mg. In the efficacy analysis, neither relapse nor blast cells were observed in any patients and a reduction in WT1 mRNA level was found in 5 patients. Immunological response was observed in all patients in the OCV-501-specific DTH test.
In conclusion, OCV-501, which was suggested to activate both direct and indirect anti-leukemic cellular immunity, showed a favorable safety and tolerability profile in elderly patients who have AML in CR, and the MTD was shown to be ≥ 3 mg. The results suggested the clinical beneficial of this vaccine and further clinical studies are highly warranted. This trial was registered at www.clinicaltrials.gov as NCT 01440920.

Disclosures
Sakura: Otsuka Pharmaceutical: Research Funding. Kobayashi:Celgene: Research Funding; Pfizer: Research Funding; Ohtsuka Pharmaceutical: Research Funding; Ariad: Research Funding; SymBio Pharmaceuticals: Research Funding. Toga:Otsuka Pharmaceutical: Employment. Sogo:Otsuka Pharmaceutical: Employment. Heike:Sumitomo Dainippon Pharma: Consultancy; Chugai Pharma: Consultancy; Otsuka Pharma: Consultancy.