Dendritic cell vaccination in malignant pleural mesothelioma: A phase I/II study.
ABSTRACT
Background: The prognosis of malignant pleural mesothelioma (MPM) is dismal, with a median overall survival from diagnosis of 12 months. New therapeutic approaches are needed. We evaluated the feasibility, safety, immunogenicity and clinical efficacy of consolidative treatment with autologous dendritic cells (DC) electroporated with mRNA encoding the MPM-associated Wilms‘ tumor 1 (WT1) antigen.
Methods: Ten patients (median age 62 [range: 53-73]) with unresectable MPM and non-progressive disease after platinum/pemetrexed-based chemotherapy underwent leukapheresis. CD14+ monocytes were isolated, cultured into mature DC according to our clinical-grade protocol (Van Tendeloo et al. PNAS 2010) and electroporated with mRNA derived from a codon-optimized WT1 construct with a sig-LAMP sequence and a deletion of the nuclear localization signal. Biweekly intradermal vaccinations were administered for an intended period of 6 months, followed by monthly or bimonthly injections. Delayed type hypersensitivity (DTH) was tested, in order to assay in vivo T-cell responsiveness to the DC vaccine. Overall survival was measured from entry into trial.
Results: Leukapheresis was successful in all patients, with a mean number of 19.4 ± 6.9 DC vaccines produced (range: 7-29); 3 patients underwent an additional leukapheresis. A mean number of 18.4 ± 10.7 vaccines were administered (range: 5-44). DC vaccination was well-tolerated; no systemic toxicity was recorded; local reactions at the injections sites occurred in all patients, but were mild and self-limiting. At a median follow-up of 22.7 months, 6 patients are alive, 4 have died and median survival has not yet been reached. The 6-, 12- and 18-month survival rates were 100%, 90% and 75%, respectively. Significant DTH responses (i.e. ≥ 10 mm² induration [Disis et al. Clin Cancer Res 2000]) were elicited in all patients except UPN006, who had the lowest survival (7.3 months).
Conclusions: WT1-targeted DC vaccination is feasible and well-tolerated in MPM patients. In vivo evidence of vaccine-elicited immunity to the DC vaccine administered was obtained in 9/10 patients. Overall survival data suggest that adjuvant DC-based immunotherapy provides a clinical benefit for patients with MPM. Clinical trial information: NCT01291420.