Clinical grade OK432-activated dendritic cells: in vitro characterization and tracking during intralymphatic delivery.
Dendritic cells (DC) are under intense preclinical and early clinical evaluation for the immunotherapy of cancer. However, the optimal culture conditions and route of delivery for DC vaccination have not been established. Here we describe the first human application of DC matured with the bacterial agent OK432 (OK-DC), using a short-term serum-free culture protocol, which generates mature DC from CD14+ precursors after 5 days. These cells were prepared within the framework of a National Blood Service facility, demonstrating that DC represent a product which is potentially deliverable alongside current standardized cell therapies within the UK National Health Service. In vitro analysis confirmed that OK-DC were mature, secreted tumor necrosis factor-alpha, interleukin-6, and interleukin-12, and stimulated both T cell and natural killer cell function. To explore effective delivery of OK-DC to lymph nodes, we performed an initial clinical tracking study of radioactively labeled, unpulsed OK-DC after intralymphatic injection into the dorsum of the foot. We showed that injected DC rapidly localized to ipsilateral pelvic lymph nodes, but did not disseminate to more distant nodes over a 48-hour period. There was no significant toxicity associated with OK-DC delivery. These results show that OK-DC are suitable for clinical use, and that intralymphatic delivery is feasible for localizing cells to sites where optimal priming of innate and adaptive antitumor immunity is likely to occur.
West
Emma
E
Cancer Research UK Clinical Centre, Leeds Institute of Molecular Medicine, Leeds Teaching Hospitals NHS Trust, St James's University Hospital. Leeds, UK.
Morgan
Ruth
R
Scott
Karen
K
Merrick
Alison
A
Lubenko
Anatole
A
Pawson
David
D
Selby
Peter
P
Hatfield
Paul
P
Prestwich
Robin
R
Fraser
Sheila
S
Eves
David
D
Anthoney
Alan
A
Twelves
Chris
C
Beirne
Debbie
D
Patel
Poulam
P
O'Donnell
Dearbhaile
D
Watt
Suzanne
S
Waller
Michael
M
Dietz
Allan
A
Robinson
Philip
P
Melcher
Alan
A
D000970:Antineoplastic Agents / Q000494:pharmacology*; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology / Q000637:transplantation*; D005770:Gastrointestinal Neoplasms / Q000628:therapy*; D006801:Humans; D016219:Immunotherapy, Adoptive; D007272:Injections, Intralymphatic; D016753:Interleukin-10 / Q000276:immunology / Q000378:metabolism; D018664:Interleukin-12 / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D010844:Picibanil / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
D000970:Antineoplastic Agents; D019496:Cancer Vaccines; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D018664:Interleukin-12; D010844:Picibanil