Targeting of 111In-labeled dendritic cell human vaccines improved by reducing number of cells
Erik H J G Aarntzen, Mangala Srinivas, Fernando Bonetto, Luis J Cruz, Pauline Verdijk, Gerty Schreibelt, Mandy van de Rakt, W Joost Lesterhuis, Maichel van Riel, Cornelius J A Punt, Gosse J Adema, Arend Heerschap, Carl G Figdor, Wim J Oyen, I Jolanda M de Vries, Erik H J G Aarntzen, Mangala Srinivas, Fernando Bonetto, Luis J Cruz, Pauline Verdijk, Gerty Schreibelt, Mandy van de Rakt, W Joost Lesterhuis, Maichel van Riel, Cornelius J A Punt, Gosse J Adema, Arend Heerschap, Carl G Figdor, Wim J Oyen, I Jolanda M de Vries
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 (111)In-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 (19)F-labeled DCs over a period of up to 12 hours using (19)F 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 × 10(6) or less cells per injection improved migration. Furthermore, scintigraphy is insufficient to study migration of such small numbers of (111)In-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.
Source: PubMed