Abstract
Vaccines against tumor associated antigens represent an appealing strategy for preventing tumor recurrence. A novel immunotherapy platform is represented by a dendritic cell vaccine that originates from a human myeloid leukemia cell line, DCOne, which endogenously expresses a range of leukemia associated antigens, including PRAME and WT-1, and can be differentiated into mature dendritic cells (DCs). Mature DC derived from DCOne are being developed to replace patient-derived DC vaccines. The first indication in which vaccination with mature DCs derived from DCOne has been tested clinically is Acute Myeloid Leukemia (AML) because of the high unmet medical need and substantial evidence that AML is a suitable target for immunotherapy. A Phase I/IIa study enrolled 12 AML patients (age range 58-71) who were either in CR1/CR2 (n=5) or had smoldering disease (n=7). Patients had received all available standard care, were at high risk of relapse and ineligible for all available post-remission therapies, including allogeneic stem cell transplantation. Patients were selected for the study because they had an estimated life expectancy of 3-6 months.
A standard 3+3 design was used, starting with 4 bi-weekly intradermal DCOne DC vaccinations of 10E6 (n=3), 25E6 (n=3) or 50E6 (n=6) cells. Patients were monitored for clinical and immunological responses for 126 days and surviving patients underwent long-term follow-up after study completion. Primary endpoints were safety and feasibility; secondary endpoints were clinical and immunological responses. Treatment was well tolerated in all patients, with related adverse events mainly limited to injection site reactions. During the 5 months duration of the study 3 patients died: 2 from infections and 1 from leukemia. Clear evidence for induction of multi-functional immune responses was obtained, including increased post vaccination delayed type hypersensitivity reactions, increases in CD4+ and CD8+ T cell proliferative responses and/or sero-conversion to DCOne DCs and/or AML blasts in 6 out of 9 patients. Three of 7 patients who were evaluable by IFNgELISpots showed vaccination-induced reactive T cell responses to WT-1 and/or PRAME, antigens which are present in DCOne. The patients who survived more than 6 months post-vaccination showed strongly prolonged survival. Four patients are still alive 28, 22, 12 and 10 months after study entry and 1 patient survived for 23 months. Patients in CR1 or CR2 at study entry were all in CR at the end of the study and these patients were more likely to exhibit prolonged survival. Patients not in CR at study entry, with one exception, all had persistence of disease at the end of the study and died due to disease progression.
Together, these results suggest that patients who have a capable immune system can induce a multi-functional and lasting immune response to the vaccine. As expected this most likely translates into long-term clinical benefit if patients are in CR at the time of vaccination. This is in keeping with the expected kinetics of cancer immunotherapy. We conclude that vaccination with DCOne derived DCs is safe and feasible in elderly AML patients, and generates both cellular and humoral immune responses. The hypothesis that DCOne-derived DCs induce immune responses against the patients’ leukemia cells, translating into clinical benefit in patients with a capable immune system who are in CR at the time of vaccination, will now be investigated in a multi-center randomized Phase II trial in AML patients in first remission.
Disclosures:
van Wetering: DCPrime: Employment. Kaur Singh:DCPrime: Employment. Hall:DCPrime: Consultancy. Kruisbeek:DCPrime: Employment.
m6A Regulator-Mediated Methylation Modification Patterns and Tumor Microenvironment Infiltration Characterization in Acute Myeloid Leukemia
