Effective Clinical Responses in Metastatic Melanoma Patients after Vaccination with Primary Myeloid Dendritic Cells

Abstract

Purpose: Thus far, dendritic cell (DC)-based immunotherapy of cancer was primarily based on in vitro-generated monocytederived DCs, which require extensive in vitro manipulation. Here, we report on a clinical study exploiting primary CD1c þ myeloid DCs, naturally circulating in the blood. Experimental Design: Fourteen stage IV melanoma patients, without previous systemic treatment for metastatic disease, received autologous CD1c þ myeloid DCs, activated by only brief (16 hours) ex vivo culture and loaded with tumor-associated antigens of tyrosinase and gp100. Results: Our results show that therapeutic vaccination against melanoma with small amounts (3-10 Â 10 6 ) of myeloid DCs is feasible and without substantial toxicity. Four of 14 patients showed long-term progression-free survival (12-35 months), which directly correlated with the development of multifunctional CD8þ T-cell responses in three of these patients. In particular, high CD107a expression, indicative for cytolytic activity, and IFNg as well as TNFa and CCL4 production was observed. Apparently, these T-cell responses are essential to induce tumor regression and promote long-term survival by stalling tumor growth. Conclusions:We show that vaccination of metastatic melanoma patients with primary myeloid DCs is feasible and safe and results in induction of effective antitumor immune responses that coincide with improved progression-free survival. Clin Cancer Res; 22(9); 2155-66. Ó2015 AACR.

Dendritic Cell–Based Immunotherapy: State of the Art and Beyond

“…Therefore, shorter culture protocols have been developed (11). Furthermore, natural DCs do not require extensive culture, and recently, it has been proven feasible to obtain more than 10 million pDCs and even higher numbers of BDCA-1 þ mDCs after a single leukapheresis despite their low frequency in blood (12)(13)(14). Even BDCA-3 þ mDCs, constituting approximately 0.05% of the PBMCs, can now be isolated from a leukapheresis, but this process has not been applied in clinical trials yet.…”

“…Even BDCA-3 þ mDCs, constituting approximately 0.05% of the PBMCs, can now be isolated from a leukapheresis, but this process has not been applied in clinical trials yet. Recently, the first clinical trials with pDCs and mDCs have proven the safety and feasibility of this mode of treatment (12)(13)(14). Although these phase I studies in melanoma patients were primarily aimed at determining potential toxicity, the clinical results were promising, with a relatively larger number of patients surviving more than 2 years after DC vaccination (12,14).…”

“…Recently, the first clinical trials with pDCs and mDCs have proven the safety and feasibility of this mode of treatment (12)(13)(14). Although these phase I studies in melanoma patients were primarily aimed at determining potential toxicity, the clinical results were promising, with a relatively larger number of patients surviving more than 2 years after DC vaccination (12,14). A major advantage of these natural DCs is their rapid isolation procedure with antibody-coated magnetic beads (CliniMACS Prodigy).…”

CMRF-56+blood dendritic cells loaded with mRNA induce effective antigen-specific cytotoxic T-lymphocyte responses

“…The density gradient separation methodology used in Sipuleucel-T 44-46 enriched for low-density cells, but only 18% of these were CD54 C HLA-DR C cells, 46 and of these, only a small proportion were BDC. Magnetic bead immune selection of individual populations of CD1c C mDC 19,20 or CD304 C pDC 22 is starting to be explored in clinical trials. The generic platform used in this study built on previous work with the original mouse IgG1 CMRF-56 mAb 47 by developing a clinically suitable hCMRF-56 mAb to enrich for a similar heterogeneous BDC population.…”

“…The major myeloid CD1c C DC have been isolated clinically using a two-step immune selection technology, but these isolations take a long time and the low yields limit the DC vaccination dose. 19,20 The minor CD141 C XCR1 C mDC subset generates excellent cytotoxic T lymphocyte (CTL) responses due to their strong capacity to cross present antigen 17,21 but their low frequency makes their purification unrealistic using current technologies. 2 Immune-selected pDC have also been explored in the context of vaccination, and have been shown to induce T-cell responses in patients with melanoma.…”