In Vivo Tracking of Dendritic Cells in Patients With Multiple Myeloma

Abstract

Dendritic cell (DC) immunotherapy is being actively studied in multiple myeloma (MM). We aimed to use positron emission tomography or single positron emission tomography to determine the in vivo distribution of monocyte-derived nonmatured DC or matured DC (mDC) administered to patients with MM. Eligible patients had stable or slowly progressive MM and elevated serum MUC-1 or MUC-1 expression on marrow plasma cells. DCs were derived from granulocyte-macrophage colony-stimulating factor+ interleukin-13 stimulated autologous monocytes, pulsed with mannan-MUC1 fusion protein, and matured by FMKp and interferon-gamma. Before injection, DCs were labeled with either 18fluorine-fluorodeoxyglucose, 111indium-oxine or 64copper-pyruvaldehyde-bis-N-4-methylthiosemicarbazone. Labeled DCs were given either as a single intravenous dose or by concurrent subcutaneous (SC), intradermal (ID), and intranodal routes. 18Fluorine-fluorodeoxyglucose tracking was unsuccessful owing to high radiolabel efflux. 64Copper-pyruvaldehyde-bis-N-4-methylthiosemicarbazone-labeled mDC (n=2 patients) demonstrated tracking to regional nodes but quantitation was also limited owing to cellular efflux. 111Indium-oxine, however, gave reproducible tracking of both nmDc and mDC (n=6) to regional lymph node after either SC or ID administration, with mDC revealing superior migration to regional lymph node. SC and ID routes produced similar levels of DC migration.

Lymphoid tissue–specific homing of bone marrow–derived dendritic cells

“…23 Thus, we performed an exhaustive evaluation of lymph nodes and other tissues to which BM-DCs can migrate following intravenous or intraperitoneal administration, and attempted to characterize the mechanism(s) underlying the preferential homing to the PLNs. Our observations on the DC homing to large tissues (spleen, lungs, liver) after intravenous injection confirm previous studies done in mice [17][18][19][20][21]30 and humans 11,12,16,22 in vivo using scintigraphy, positron emission tomography, or magnetic resonance imaging, or in vitro using scintigraphy or bioluminescence. However, such imaging methods quickly reach their limit when it comes to detecting DCs in smaller tissues such as lymph nodes.…”

“…Imaging methods applied to mice and humans have consistently described homing of DCs to the spleen, lungs, and liver, all well-vascularized organs, after intravenous injection. 11,12,[16][17][18][19][20][21][22] Probably due to limited sensitivity, resolution, or time duration of the methods used, these in vivo imaging studies failed to demonstrate lymph node homing, unless ex vivo biodistribution was performed, but this has not been well characterized. 17,18 Prompted by our initial observation that bone marrow-derived DCs (BM-DCs), modified by lentivirus to express the Firefly luciferase (Luc) reporter gene and injected intravenously into nonobese diabetic (NOD) mice, home preferentially to the pancreatic lymph nodes (PLNs), 23 we set out to conduct a more detailed analysis of the biodistribution of BM-DCs from different Luctransgenic mice following intravenous and intraperitoneal injection.…”

“…These local routes of treatment have been extensively studied in DC homing studies. [11][12][13][14][15][16] Likewise, the biodistribution of DCs following systemic intravenous administration has received much attention, but remains poorly characterized in regard to the different lymph nodes to which DCs traffic. In addition, other routes such as intraperitoneal injection have been less well studied.…”

64 Cu antibody-targeting of the T-cell receptor and subsequent internalization enables in vivo tracking of lymphocytes by PET

“…One frequently used cell-labeling compound for PET is [ 64 Cu]Pyruvaldehyde bis(N 4 -methylthiosemicarbazone) ([ 64 Cu]PTSM), which has been applied to mouse lymphocytes, primate stem cells, and human dendritic cells (7)(8)(9). We recently established a [ 64 Cu]PTSMlabeling protocol that minimizes the harmful effects on T-cell functions (10).…”

18F-FDG Labeling of Mesenchymal Stem Cells and Multipotent Adult Progenitor Cells for PET Imaging: Effects on Ultrastructure and Differentiation Capacity

“…18 F-FDG has been used for the imaging of initial stem cell biodistribution after injection into subjects (20). 18 F-FDG has already been used to image different cell types, such as dendritic cells, bone marrow-derived cells, or hematopoietic stem cells, both in preclinical models and in humans (21)(22)(23). However, the effects of labeling stem cells with 18 F-FDG have not been extensively studied with respect to their function and viability.…”