Tetanus toxoid and CCL3 improve dendritic cell vaccines in mice and glioblastoma patients
Duane A Mitchell, Kristen A Batich, Michael D Gunn, Min-Nung Huang, Luis Sanchez-Perez, Smita K Nair, Kendra L Congdon, Elizabeth A Reap, Gary E Archer, Annick Desjardins, Allan H Friedman, Henry S Friedman, James E Herndon 2nd, April Coan, Roger E McLendon, David A Reardon, James J Vredenburgh, Darell D Bigner, John H Sampson, Duane A Mitchell, Kristen A Batich, Michael D Gunn, Min-Nung Huang, Luis Sanchez-Perez, Smita K Nair, Kendra L Congdon, Elizabeth A Reap, Gary E Archer, Annick Desjardins, Allan H Friedman, Henry S Friedman, James E Herndon 2nd, April Coan, Roger E McLendon, David A Reardon, James J Vredenburgh, Darell D Bigner, John H Sampson
Abstract
After stimulation, dendritic cells (DCs) mature and migrate to draining lymph nodes to induce immune responses. As such, autologous DCs generated ex vivo have 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 cancers including glioblastoma, the factors dictating DC vaccine efficacy remain poorly understood. Here we show that pre-conditioning the vaccine site with a potent recall antigen 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 DCs 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 brain, 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.
Conflict of interest statement
The authors declare the following competing financial interests: D.A.M., K.A.B., and J.H.S. have filed provisional patents related to the use of Td pre-conditioning as a method to improve immunization efficacy. D.A.M. has served as a paid member of the Schering Plough North American Investigators Advisory Board. S.K.N. is a co-inventor on a patent that describes the use of DCs transfected with tumor antigen encoding RNA that has been licensed by Argos Therapeutics (Durham, NC) through Duke University. S.K.N. has no financial interests in Argos Therapeutics and is not compensated by Argos Therapeutics. D.A.R. has served as paid speaker for Schering/Merck and Genentech/Roche. The remaining authors declare no competing financial interests.
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