Results of a phase 1 study utilizing monocyte-derived dendritic cells pulsed with tumor RNA in children and young adults with brain cancer

Abstract

We conducted a phase 1 study of 9 pediatric patients with recurrent brain tumors using monocyte-derived dendritic cells pulsed with tumor RNA to produce antitumor vaccine (DCRNA) preparations. The objectives of this study included (1) establishing safety and feasibility and (2) measuring changes in general, antigen-specific, and tumor-specific immune responses after DCRNA. Dendritic cells were derived from freshly isolated monocytes after 7 days of culture with IL-4 and granulocyte-macrophage colony-stimulating factor, pulsed with autologous tumor RNA, and then cryopreserved. Patients received at least 3 vaccines, each consisting of an intravenous and an intradermal administration at biweekly intervals. The study showed that this method for producing and administering DCRNA from a single leukapheresis product was both feasible and safe in this pediatric brain tumor population. Immune function at the time of enrollment into the study was impaired in all patients tested. While humoral responses to recall antigens (diphtheria and tetanus) were intact in all patients, cellular responses to mitogen and recall antigens were below normal. Following DCRNA vaccine, 2 of 7 patients showed stable clinical disease and 1 of 7 showed a partial response. Two of 7 patients who were tested showed a tumor-specific immune response to DCRNA. This study showed that DCRNA vaccines are both safe and feasible in children with tumors of the central nervous system with a single leukapheresis.

Fig. 1

Magnetic resonance imaging of patient 8. Coronal (A and B) and transverse (C and D) T1-weighted scans were performed at 3 time points as shown, demonstrating a clear reduction in size and degree of enhancement of the tumor.

Fig. 2

Antitumor ELISA. Patient serum was diluted in blocking buffer and added to tumor lysate–coated wells and PBMC lysate–coated wells (control for nonspecific binding; data not shown). Panel A shows the results for patient 4, and Panel B shows the results for patient 7. Error bars represent standard deviations of the mean from triplicate samples.

Fig. 3

Lymphocyte proliferation, expressed as an average number of counts per minute (CPM [avg]), in response to stimulation with PHA. PBMCs from normal controls and from patients at baseline prior to DC_RNA vaccine were stimulated with PHA or not treated (NT). PHA-induced proliferative responses were significantly lower in patients as compared with controls (P = 0.0016).

Fig. 4

IL-10 levels pre- and post-DC_RNA vaccination. Patient serum samples were assayed for induction of IL-10 levels. No samples were above detectable levels post-DC_RNA vaccination. Error bars represent standard deviations of the mean from triplicate samples.