A Phase I Clinical Trial of CD1c (BDCA-1)+ Dendritic Cells Pulsed With HLA-A*0201 Peptides for Immunotherapy of Metastatic Hormone Refractory Prostate Cancer

Abstract

Preclinical studies have suggested that purified populations of CD1c (BDCA-1) blood-derived dendritic cells (BDC) loaded with tumor-specific peptides may be a feasible option for prostate cancer immunotherapy. We performed an open-label dose-finding Phase I study to evaluate the safe use of CD1c BDC in patients with advanced metastatic hormone refractory prostate cancer. HLA-A*0201-positive patients with advanced metastatic prostate cancer were recruited and consented. The vaccine was manufactured by pulsing autologous CD1c BDC, prepared by magnetic bead immunoselection from apheresed peripheral blood mononuclear cells, with a cocktail of HLA-A*0201-restricted peptides (prostate-specific antigen, prostate acid phosphatase, prostate specific membrane antigen, and control influenza peptide) and keyhole limpet hemocyanin. The vaccine was administered intradermally or intravenously and peripheral blood was taken at predetermined intervals for clinical and immunologic monitoring. The vaccine was manufactured with a median purity of 82% CD1c BDC and administered successfully to 12 patients. Each patient received between 1 and 5 × 10 fresh CD1c BDC on day 0, followed by cryopreserved product in the same dose on days 28 and 56. The vaccine was well tolerated in all patients, with the most frequent adverse events being grade 1-2 fever, pain, or injection-site reactions. Vaccination with CD1c BDC is therefore feasible, safe, and well tolerated in patients with advanced-stage metastatic prostate cancer.

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

“…1 Initial clinical studies have shown that immune selected BDC preparations are safe and able to induce clinical responses in patients. 19,22 , 43 The readily obtained CMRF-56 C BDC preparation described here was enriched for all myeloid BDC subpopulations and these were shown to have the expected intrinsic migration capacity, without the need for modulatory compounds such as PGE 2 . Furthermore, we found that these BDC were also superior to Mo-DC with respect to their ability to process and present mRNA antigens for MHC presentation to T cells.…”

“…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.…”

“…Our experience using two-step isolation of CD1c DC from patient apheresis collections for our clinical trial made it clear that the processing time and the ultimate DC yield were practical issues. 19 Culturing PBMC without additional supplements in the apheresis bag for 12-16 h (done conveniently overnight) upregulated the CMRF-56 antigen sufficiently for hCMRF-56 mAb isolation. CD83, CD86 and CCR7 were induced and the use of GM-CSF as a stimulating agent supports their survival in vitro.…”

“…Expanded specific WT-1 126-134 ¡ T cells (Figs. 5 G-H) killed WT-1 126-134 , but not irrelevant KLK4 [11][12][13][14][15][16][17][18][19] peptide loaded T2 cells (Fig. 5I).…”

“…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.…”