Abstract Date: 4/7/2014
John H. Sampson, MD, PhD
Elizabeth Reap, PhD
Luis Sanchez-Perez, PhD
Gary Archer, PhD
David Snyder, MS
Smita Nair, PhD
Michael Gunn, MD (Durham, NC)
Duane Mitchell, MD, PhD (Gainesville, FL)
Dendritic cell (DC) vaccine efficacy is limited by suboptimal migration to vaccine site-draining lymph nodes (VDLNs). We assessed the impact of DC migration on clinical outcomes by randomizing patients with newly-diagnosed glioblastoma (GBM) to one of two conditioning strategies, unpulsed DCs or tetanus-diphtheria (Td) toxoid prior to DC vaccination.
We compared effects of vaccine site conditioning on migration of 111Indium-labeled DCs using SPECT/CT imaging and evaluated clinical outcomes with progression-free and overall survival (OS). Transgenic mouse models were used to determine if increased DC migration induced greater antitumor responses.
Td-conditioned patients showed increased DC migration (p=0.04) and significantly improved OS (p=0.013). Td-conditioned mice demonstrated increased DC migration to VDLNs (p=0.0001) and suppressed tumor growth (p=0.0001). Adoptive transfer of Td-activated CD4+ T cells increased DC migration in naïve mice (p=0.01), and CD4+ depletion in Td-conditioned mice abrogated increased DC migration (p=0.005). Td administration induced a significant increase in serum CCL3 levels (p=0.028). In vitro, we observed increased chemotaxis of mature human and murine DCs towards serum from Td-conditioned hosts, which was abrogated with CCL3 blockade (p=0.02). In vivo, DCs migrated to VDLNs in a CCL3-dependent manner (p=0.003). Td-conditioned CCL3 knockout mice demonstrated accelerated growth comparable to that of controls, owing to the importance of this chemokine in driving the trafficking of DC vaccines to VDLNs (p=0.01).
Td administration increased DC migration and tumor responses in a preclinical model corroborating effects of Td conditioning on DC migration observed within our phase I/II clinical trial.
Article ID: AA-28762