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After stimulation, dendritic cells(DCs) mature and migrate to draining lymph nodes to induce immune responses1. As such, autologous DCs generated exvivohave been pulsed with tumour antigens and injected back into patients as immunotherapy. While DC vaccines have shown limited promise in the treatment of patients with advanced cancers2-4 including glioblastoma5-7, the factors dictating DC vaccine efficacy remain poorly understood. Here we show that pre-conditioning the vaccine site witha potent recallantigen such as tetanus/diphtheria (Td) toxoid can significantly improve the lymph node homing and efficacy of tumour-antigen-specific DCs. To assess the effect of vaccine site pre-conditioning in humans,we randomized patients with glioblastoma to pre-conditioning with either mature DCs8 or Td unilaterally before bilateral vaccination with DCs pulsed with Cytomegalovirus phosphoprotein 65 (pp65) RNA. We and other laboratories have shown that pp65 is expressed in more than 90% of glioblastoma specimens but not in surrounding normal brain9-12, providing an unparalleled opportunity to subvert this viral protein as a tumour-specific target. Patients given Td had enhanced DC migration bilaterally and significantly improved survival. In mice, Td pre-conditioning also enhanced bilateral DC migration and suppressed tumour growth in a manner dependent on the chemokine CCL3. Our clinical studies and corroborating investigations in mice suggest that pre-conditioning with a potent recall antigen may represent a viable strategy to improve anti-tumour immunotherapy.
To evaluate the influence of vaccine site pre-conditioning on DC migration clinically, we conducted a randomized and blinded clinical trial in newly diagnosed glioblastoma (GBM) (Extended Data Fig. 1). A total of 13 patients consented to this trial but only 12 were randomized as 1 progressedbeforerandomization(ExtendedDataTable1).Patientswere randomized to unilateral vaccine site pre-conditioning with unpulsed, autologous DCs8 or Td, on the basis of our hypothesis that it would induce inflammationatthe vaccinesite13. The accumulation of injected DCs in vaccine site-draining lymph nodes (VDLNs) was significantly greater in patients given Td (Fig. 1a). Moreover, Td-treated patients also showed a significant increase in both progression-free survival (Fig. 1b) andoverallsurvival (Fig.1c)comparedtoDC-treatedpatients.Fromthe time of diagnosis, patients in the DC cohort had median progressionfree and overall survivals of 10.8 and 18.5 months, respectively. Thus, the median progression-free and overall survivals for the DC cohort were consistent with patients treated with the standard of care14. Three censored patients from the Td cohort did not progress and...