Chemokine gene modification of human dendritic cell-based tumor vaccines using a recombinant adenoviral vector.
Previous animal studies conducted in our laboratory have shown that tumor antigen-pulsed dendritic cells (TP-DC) can mediate antitumor effects in vivo. However, durable and complete regression of established tumors has been difficult to achieve through the administration of TP-DC alone. To better augment immune priming to tumors in vivo, we have hypothesized that it is necessary to achieve an increased number of host-derived, naïve T cells at the site of TP-DC vaccine injections. To accomplish this goal, we have embarked on a series of studies that utilize defined chemokines. One of these molecules, secondary lymphoid tissue chemokine (SLC), has been shown to be uniquely chemoattractant for naïve T cells and dendritic cells. We propose that gene modification of DC-based tumor vaccines to produce human SLC will enhance T-cell recruitment and immune priming to tumor-associated antigens, and thereby translate into improved antitumor vaccine efficacy in vivo. Utilizing an E1-, E3-deleted adenoviral vector containing the gene for human SLC, we have been able to transduce human DC to produce biologically active human SLC that chemoattracts human T cells in vitro. SLC production by transduced DC was markedly enhanced upon DC maturation. Additionally, these SLC-secreting DC were found to be viable to a large extent despite the cytopathic effect inherent in adenoviral gene transfer and, most importantly, functional as determined by their ability to prime autologous T cells to a known melanoma-associated antigen, MART-1. Based on these encouraging results, we plan to initiate Phase I clinical studies utilizing DC-SLC to treat patients with advanced solid tumors.
Terando
Alicia
A
Department of Surgery, University of Michigan Medical Center, Ann Arbor, Michigan 48109, USA.
Roessler
Blake
B
Mulé
James J
JJ
D000256:Adenoviridae / Q000235:genetics*; D015703:Antigens, CD / Q000378:metabolism; D019496:Cancer Vaccines / Q000235:genetics* / Q000494:pharmacology; D054421:Chemokine CCL21; D019742:Chemokines, CC / Q000235:genetics*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D003713:Dendritic Cells / Q000276:immunology*; D003911:Dextrans / Q000737:chemistry / Q000378:metabolism; D005434:Flow Cytometry; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D005822:Genetic Vectors / Q000235:genetics*; D049452:Green Fluorescent Proteins; D006801:Humans; D008164:Luminescent Proteins / Q000378:metabolism; D010587:Phagocytosis / Q000187:drug effects; D013601:T-Lymphocytes / Q000737:chemistry; D014161:Transduction, Genetic
D015703:Antigens, CD; C515478:CCL21 protein, human; D019496:Cancer Vaccines; D054421:Chemokine CCL21; D019742:Chemokines, CC; D003911:Dextrans; D008164:Luminescent Proteins; C015219:fluorescein isothiocyanate dextran; D049452:Green Fluorescent Proteins; D016650:Fluorescein-5-isothiocyanate