Journal Article

Tetanus toxoid and CCL3 improve dendritic cell vaccines in mice and glioblastoma patients

Huang, Min-Nung, Coan, April, Gunn, Michael D., Batich, Kristen A., Congdon, Kendra L., Vredenburgh, James J., Sampson, John H., Nair, Smita K., Sanchez-Perez, Luis, Bigner, Darell D., Friedman, Henry S., Reardon, David A., Herndon II, James E., Mitchell, Duane A., Friedman, Allan H., McLendon, Roger E., Archer, Gary E., Reap, Elizabeth A., Desjardins, Annick

2015

Overview

A clinical trial in patients with glioblastoma shows increased immune and anti-tumour responses to dendritic cell vaccination after pre-conditioning the site of vaccination with tetanus toxoid (Td); similar results are also seen in mice in part due to the actions of the chemokine CCL3, and the findings may represent new ways to improve the efficacy of anti-cancer vaccines. A novel anti-tumour immunotherapy strategy John Sampson and colleagues report on a small clinical trial in glioblastoma patients that shows that the immune and anti-tumour response to dendritic cell vaccination is increased by pre-conditioning the site of vaccination with tetanus/diptheria toxoid (Td). Experiments in mice showed similar effects and demonstrated that pre-conditioning with Td enhanced migration of dendritic cells to the tumours, at least in part due to the action of the cytokine CCL3. Although the clinical trial reported is small, these findings may pave the way for new ways of improving the efficacy of anti-cancer vaccines. After stimulation, dendritic cells (DCs) mature and migrate to draining lymph nodes to induce immune responses 1 . 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 2 , 3 , 4 including glioblastoma 5 , 6 , 7 , 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 8 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 9 , 10 , 11 , 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/250/251/1567 / 631/67/1922 / Animals / Antigens, Neoplasm - immunology / Cancer Vaccines - administration & dosage / Cancer Vaccines - immunology / Cancer Vaccines - therapeutic use / CD4-Positive T-Lymphocytes - drug effects / CD4-Positive T-Lymphocytes - immunology / Cell Movement - drug effects / Chemokine CCL3 - immunology / Chemokines / Clinical trials / Dendritic cells / Dendritic Cells - cytology / Dendritic Cells - drug effects / Dendritic Cells - immunology / Female / Glioblastoma - drug therapy / Glioblastoma - immunology / Glioblastoma - pathology / Glioblastoma - therapy / Glioblastoma multiforme / Humanities and Social Sciences / Humans / Immunization / Immunotherapy / Immunotherapy - methods / letter / Lymph nodes / Lymph Nodes - cytology / Lymph Nodes - drug effects / Lymph Nodes - immunology / Lymphocytes / Medical prognosis / Medical research / Medicine, Experimental / Mice / Mice, Inbred C57BL / multidisciplinary / Phosphoproteins - chemistry / Phosphoproteins - genetics / Phosphoproteins - immunology / Physiological aspects / Science / Substrate Specificity / Survival Rate / Tetanus / Tetanus Toxoid - administration & dosage / Tetanus Toxoid - pharmacology / Tetanus Toxoid - therapeutic use / Treatment Outcome / Tumors / Vaccines / Viral Matrix Proteins - chemistry / Viral Matrix Proteins - genetics / Viral Matrix Proteins - immunology