Targeting of 111In-Labeled Dendritic Cell Human Vaccines Improved by Reducing Number of Cells

Abstract

Purpose: Anticancer dendritic cell (DC) vaccines require the DCs to relocate to lymph nodes (LN) to trigger immune responses. However, these migration rates are typically very poor. Improving the targeting of ex vivo generated DCs to LNs might increase vaccine efficacy and reduce costs. We investigated DC migration in vivo in humans under different conditions. Experimental Design: HLA-A*02:01 patients with melanoma were vaccinated with mature DCs loaded with tyrosinase and gp100 peptides together with keyhole limpet hemocyanin (NCT00243594). For this study, patients received an additional intradermal vaccination with 111In-labeled mature DCs. The injection site was pretreated with nonloaded, activated DCs, TNFα, or Imiquimod; granulocyte macrophage colony-stimulating factor was coinjected or smaller numbers of DCs were injected. Migration was measured by scintigraphy and compared with an intrapatient control vaccination. In an ex vivo tissue model, we measured CCL21-directed migration of 19F-labeled DCs over a period of up to 12 hours using 19F MRI to supplement our patient data. Results: Pretreatment of the injection site induced local inflammatory reactions but did not improve migration rates. Both in vitro and in vivo, reduction of cell numbers to 5 × 106 or less cells per injection improved migration. Furthermore, scintigraphy is insufficient to study migration of such small numbers of 111In-labeled DCs in vivo. Conclusion: Reduction of cell density, not pretreatment of the injection site, is crucial for improved migration of DCs to LNs in vivo. Clin Cancer Res; 19(6); 1525–33. ©2013 AACR.

Antitumor dendritic cell–based vaccines: lessons from 20 years of clinical trials and future perspectives

“…route was recently shown to improve their homing to the lymph nodes and, consequently, to potentially enhance vaccine efficacy. 126,127 The authors suggested that 1187 1188 1189 1190 1191 1192 1193 1194 1195 1196 1197 1198 1199 1200 1201 1202 1203 1204 1205 1206 1207 1208 1209 1210 1211 1212 1213 1214 1215 1216 1217 1218 1219 1220 1221 1222 1223 1224 1225 1226 1227 1228 1229 1230 1231 1232 1233 1234 1235 1236 1237 1238 1239 1240 multiple i.d. injections with small amounts of DCs would be a preferable strategy.…”

ERK1 as a Therapeutic Target for Dendritic Cell Vaccination against High-Grade Gliomas

“…Taking advantage of the full therapeutic potential of DC vaccines will require a better understanding of their role in eliminating tumor tissue. A major limiting factor in DC vaccinations is the small proportion of DCs (fewer than 5%) that reach draining lymph nodes (LN) following administration (6). This might hamper their therapeutic efficacy.…”

“…This might hamper their therapeutic efficacy. Noninvasive methods such as MRI are, therefore, necessary to study DC migration as measure of therapy outcome and might help identify strategies overcoming the poor DC migration observed in patients (6). ERK MAP kinases have been shown to control cell migration by regulating cytoskeletal and focal contact dynamics (7).…”

Ultrasound contrast agents: bubbles drops and particles

“…18.3b, and Supplementary videos). These injections mimic the clinical situation, where cells can be injected directly in the lymph nodes of patients in DC vaccination therapy 517 . Free nanoparticles (equivalent to 100,000 labeled DCs) were injected instead of cells as the total volume that can be injected in murine lymph nodes is too small for the injection of cells (< 10 µL).…”

“…Free nanoparticles (equivalent to 100,000 labeled DCs) were injected instead of cells as the total volume that can be injected in murine lymph nodes is too small for the injection of cells (< 10 µL). In comparison, 3-15 million cells are typically injected intranodally in human trials 517 . High frequency US imaging showed that the mean contrast of the node changed over 10-fold, from the presence of nanoparticles equivalent to 100,000 labeled cells.…”